Journal of Clinical Oncology (JCO) Podcast

In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on  "Pathologic Exploration of the Axillary Soft Tissue Microenvironment and Its Impact on Axillary Management and Breast Cancer Outcomes" by Naoum, et al and "Optimization of Breast Cancer Regional Nodal Management" by Braunstein et al published in the January 10, 2024 issue in Journal of Clinical Oncology. The original report discusses how the examination of axillary soft tissue beyond lymph nodes is often omitted and it predicts breast cancer outcomes and need for nodal radiation.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare. 

Giselle Carvalho: Welcome to the JCO Article Insights episode for the February issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host, one of the ASCO editorial fellows at JCO this year. Today, I'll be providing a summary of an article focused on “The Association of Axillary Soft Tissue Involvement on Outcomes for Breast Cancer Patients.” It was published in November 2023 and was partially presented at the 64th Annual ASCO in October 2022.

Although lymph node involvement in breast cancer patients is correlated with a worse prognosis, the impact of extracapsular involvement is still a matter of debate, and the implications of axillary soft tissue involvement are still not fully understood. There is some evidence indicating a decrease in disease-free survival for patients with less than four lymph nodes and with extracapsular extension, while other studies show that extracapsular involvement has no prognostic role in these patients and that the number of positive lymph nodes might matter more. Patients with node-positive disease may present with only lymph node involvement or lymph node involvement plus extracapsular extension and/or axillary soft tissue involvement. The axillary soft tissue involvement can result from either direct lymph node extension through the capsule or direct microscopic spread from the primary tumor. It is pathologically defined in this article as axillary lymphatic channel invasion, axillary soft tissue deposits, axillary blood vessel invasion, or any combination of these.

This was a retrospective study of patients with invasive breast cancer who received treatment at Massachusetts General Hospital in Boston, Massachusetts, from 2000 to 2020. Lymph nodes and surrounding adipose tissue were submitted in their entirety for histopathologic evaluation using hematoxylin and eosin stain, and immunohistochemical stains could be added at the pathologist's discretion. Eligibility criteria included primary breast cancer and positive lymph nodes without prior or contralateral breast cancer. 2,162 patients were included. They were divided into four groups according to their axillary pathology: the first group was composed of patients with positive lymph nodes with no additional axillary involvement; the second group of patients with positive lymph nodes and extracapsular involvement; the third group of patients with positive lymph nodes and axillary soft tissue involvement but with no extracapsular extension; and the fourth group of patients with positive lymph node and both extracapsular extension and axillary soft tissue involvement.

Primary endpoints were 10-year rates of local-regional failure, which was defined as recurrence in the breast or chest wall or ipsilateral axilla, axillary failure, and distant metastasis. Among 2,162 patients, 58% had lymph node involvement only, 25% had lymph nodes with extracapsular extension, 3.5% had lymph node involvement with axillary soft tissue involvement, and 14% had lymph node involvement with both extracapsular and axillary soft tissue involvement. 51% of cases of axillary soft tissue involvement were in the form of axillary lymphatic channel invasion. The median follow-up was 9.4 years, and 74% of the cohort had hormone receptor-positive breast cancer, 10% had triple-negative disease, and 16% had HER2-positive disease.

The groups with axillary soft tissue involvement, extracapsular extension, or both had more advanced tumor pathologic features when compared to the lymph node-only group, including a higher median size of breast tumors, a higher number of malignant lymph nodes, and an increased likelihood of breast lymphovascular invasion. Additionally, more patients in these three groups received mastectomy, axillary lymph node dissection, regional lymph node radiation, and systemic therapy.

The lymph node-only group had the lowest 10-year incidence of distant failure, 13%, while the group with extracapsular extension and the group with axillary soft tissue involvement both had a 23% rate of distant failure at 10 years. The risk of distant failure reached an impressively high rate of 42% for the group with both extracapsular extension and axillary soft tissue involvement.

Considering 10-year local-regional failure, the first group had a 6.2% rate, the second group a 5.7% rate, the third group a 10% rate, and the group with lymph node positivity with extracapsular extension and axillary soft tissue involvement had a 14% rate. The 10-year axillary failure rates were only 1.6% and 0.8% for the groups with no axillary soft tissue involvement but rose to 4.6% and 4.5% for the groups which did have axillary soft tissue involvement. In multivariable analysis, including tumor size, grade, number of positive nodes, and receptor status, axillary soft tissue involvement remained significantly associated with distant failure with a hazard ratio of 1.6, local-regional failure with a hazard ratio of 2.3, and axillary failure with a hazard ratio of 3.3. Of note, the number of axillary failures was overall low, only 4.6% in the group with both lymph node and axillary soft tissue involvement.

Delivery of regional lymph node irradiation, defined as treatment of axillary, supraclavicular, and internal mammary nodes, was associated with improved local-regional outcomes in patients with extracapsular extension or axillary soft tissue involvement with a hazard ratio of 0.5 and a p-value of 0.03 but was not associated with any improvement in distant failure.

The authors described the main limitations of this study as the retrospective nature and the absence of genomic marker results. In summary, although current guidelines do not emphasize axillary soft tissue examination, this study shows the importance of reporting axillary soft tissue involvement beyond the number of positive lymph nodes and the presence of extracapsular extension, as there is an increase in local-regional, and axillary failure rates for patients with axillary soft tissue involvement even without extracapsular extension. Therefore, both extracapsular extension and axillary soft tissue involvement should be consistently reported in large randomized trials as we continue to work to tailor local therapy to individual patient risk.

This is Giselle Carvalho. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin and her guest, Dr. Reshma Jagsi, discuss the paper "Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA" recently published in the JCO.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that were published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the JCO. It is my pleasure to speak with Dr. Reshma Jagsi. Hello, Dr. Jagsi.

Dr. Reshma Jagsi: Hello. Thanks for having me.

Shannon Westin: I am so excited that you're here. Dr. Jagsi is the Lawrence W. Davis Professor and Chair of the Department of Radiation Oncology at Emory University School of Medicine, Winship Cancer Institute. She is going to be talking about her incredible work, "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA," which was published in JCO in February 2024. 

All right, let's get right to it. First, I want to levelset. Can you run us through some brief facts and figures about breast cancer just to make sure that all the listeners are on the same page? 

Dr. Reshma Jagsi: Breast cancer is the most common cancer in the world. It’s 12.5% of all new annual cancer cases worldwide and is the most commonly diagnosed cancer among US women. About a third of all newly diagnosed cancers in women are breast cancer, and about 13% of US women develop invasive breast cancer over their lifetime. In 2023, there were nearly 300,000 new cases of invasive breast cancer. The median age of breast cancer diagnosis is 62, meaning an awful lot of people are getting diagnosed with breast cancer in the population that we specifically chose to study. 

Shannon Westin: Wow, you're really good at this. That's like the perfect transition to move to the next piece. So, first, I think I'd love to hear about the standard of care for the population that you were studying and how we got to this point. 

Dr. Reshma Jagsi: We offer women who are diagnosed with early-stage invasive breast cancer the option of breast conservation, and we encourage breast conservation because, of course, it is a better-tolerated surgery than mastectomy. Many women are eligible for breast-conserving therapy. And years ago, we as radiation oncologists encouraged our surgical colleagues to refer to breast-conserving therapy as lumpectomy plus radiation, just as one set. Because the studies that have been done in the 1970s and 1980s to establish that breast conversation was equally safe and effective in treating breast cancer relied on radiation therapy to minimize in-breast tumor recurrence rate, which one of those trials independently showed that there was no difference in survival. But the ones that compared lumpectomy surgery alone to lumpectomy followed by radiation therapy did show a pretty substantial improvement in local control with the addition of radiation treatment. And so radiation treatment became a part of a parcel of breast conservation in the early 1990s when consensus statements came out favoring breast conservation as a treatment approach. 

And so the net analysis has combined all of these studies together and showed that overall, without radiation treatment, a patient treatment with a lumpectomy had a 30% risk of in-breast tumor occurrence in those historical studies. And it was reduced by about two thirds to about 10% when that lumpectomy was followed by radiation in those historical randomized trials. But of course, we’ve made many advances in our understanding since that time, and so that’s what this study is seeking to build on.

Shannon Westin: It makes sense. We all know that radiotherapy can lead to other issues, acute and chronic morbidities, as well as cost and having to do the treatment itself. So we're all interested in de-escalation of therapy. Tell me, prior to your study, what data were out there potentially supporting the de-escalation and avoiding radiotherapy in that specific population?

Dr. Reshma Jagsi: In the ‘90s, after those landmark foundational historical trials have been completed, there was a lot of interest in seeing if we could identify a population of patients in whom the risk of local recurrence was sufficiently low that they might safely choose to omit radiation therapy. All of these randomized trials have shown very consistently that there is a relative risk reduction. Whatever your risk is without radiation, radiation reduces that risk. The overall disease recurrence risk is cut in half with the addition of radiation treatment. But, if I told you that your overall risk was 1%, and I could cut that in half with radiation, you might say, “I might be willing to tolerate the 1%.” At least some women might be willing to tolerate that. So can we find a population in whom the risk is low enough that at least some of those women say, "Look, I want to go without radiation." And of course, the balance of where that number should be changes as we get better and better at delivering radiation.

So you mentioned, radiation comes with toxicity, comes with burden and yet, there have been some tremendous advances, and particularly in recent years, to shorten the course of radiation. We have evidence that we can treat partial breast radiation safely in five treatment fractions. We have five-year data that we can treat the whole breast in five-treatment fraction. We certainly have long term evidence that we can the whole breast with 15 fractions from many patients diagnosed with breast cancer. So the burden has decreased. We’ve also found that with hypo fractionated shorter courses of radiation, the toxicities are much lower, patients tend to tolerate radiation treatment both in terms of acute side effects and long term side effects extremely well.  So that balance of what is low enough is changing with time. 

But the trials that were started in the 1990s included the CALGB 9343 trial, a landmark trial published in the New England Journal of Medicine, with its five-year results showing only a 4% risk of recurrence at five years in patients who were 70 or older with clinical stage one disease that was hormone receptor-positive if they received a lumpectomy and tamoxifen alone, not receiving radiation - that risk, if we added radiation in this randomized trial, was only 1%. So there was still a substantial relative risk reduction with radiation treatment. This was published in 2004 in the New England Journal of Medicine. 

At the same time, there was a Canadian trial that was published, and in that trial that included women who were 50 years of age and older, there were more concerning results with, even in a very favorable prespecified subgroup of patients who had node-negative breast cancer and T1 hormone receptor-positive tumors, the risk of ipsilateral breast tumor recurrence was 15% at eight years. So that started to feel excessive for women 50 and older. 

Meanwhile, we went on to get the update of the CALGB trial, and the 10 -year results showed that the risk was, in the women 70 and older, was only about 10% without radiation. It was 2% with radiation. So again, there was a benefit from radiation, and it's up to each individual woman to decide whether they'd prefer to proceed and minimize their risk, or would be willing to tolerate something like a 10% risk. More recently, just this past year in the New England Journal, the PRIME 2 study from the United Kingdom, looking at women 65 and older, again, early-stage node-negative hormone receptor-positive tumors, and very similar results - 10% versus 1% local control at 10 years.  

So you get an improvement with radiation. But there are some women who are 65 or 70 and older who say, I'm willing to tolerate the 10% risk. And so the question was, could we identify some patients who are younger than 65 to 70, but still postmenopausal, like in that Canadian trial, who might actually have similar outcomes - low risks at five and ten years - such that they might want to entertain the option of omitting radiation therapy, which right now is not standard or in any guidelines? So we have some promising information from some retrospective analysis of that Canadian trial that suggested that looking at biology might help. And in fact, the LUMINA trial, published just this year from Canada, did a prospective cohort study selecting patients based on immunohistochemistry, and suggested very low risks, five years in patients who were somewhat younger, although it ended up that the median age of the patients in that study was 67. So we still sort of had this question of what about the younger postmenopausal patients? And that's what took us to IDEA. 

Shannon Westin: And just for my education and for the education of the listeners, when you have an in-breast recurrence, how likely are you to be able to cure that? Is that tough to cure, or can you usually get control again?

Dr. Reshma Jagsi: It's an excellent question. And so often these recurrences are caught early and are still completely curable with additional intervention. Now, there can be an impact, of course. You can talk to any survivor about the devastating impact of being diagnosed with breast cancer recurrence, and no one wants to go through that. And so there are reasons that people will want to reduce that, and there are implications for breast conservation because it may be that the remaining breast tissue is insufficient to allow a second breast conserving surgical procedure. It may also be that when one experiences recurrence, one decides, "I'm done with this. I'm having a mastectomy at this point." So, in-breast recurrences are very meaningful to patients and something that we should not take lightly.

Shannon Westin: It seems, though, the majority of the studies that you were talking about, aside from the LUMINA study, were predominantly based on those clinical features like stage and things like that. So, can you talk a little bit about the role of molecular features, genomic testing, things like that, to select patients? 

Dr. Reshma Jagsi: Yeah. So, we have seen a tremendous change in the way we think about breast cancer in recent years, with a real focus on tumor biology, rather than classic clinical pathologic features alone to help us make decisions about systemic therapy. And so, there is a body of work that suggests that genomic assays, including the 21-gene recurrence score, that's commonly used for treatment decision making already ordered in many of these patients and available to us, that it may be useful in understanding patients' risk of local recurrence, both when they are treated with radiation and when they are treated without radiation. So, Terry Mamounas did some wonderful work looking at NSABP data where you know that the mastectomy patients at the time of the studies that were included were not receiving radiation treatment. And it did appear that the 21-gene recurrence score was helping to discriminate for local regional recurrence risk, suggesting it might be useful to use that to select patients who might be at lower risk.  

Shannon Westin: All right, perfect. So, that leads us to your study. So, let's talk a little bit about the design and the population and kind of how you put it together. 

Dr. Reshma Jagsi: This was really a true collaboration, a partnership across multiple 13 collaborating sites, where my colleagues, the lead investigators at each site, were extremely committed to this question. And we sought to do a preliminary cohort trial, really involving 200 patients. And over the course of three years, we enrolled those 200 patients who were aged 50 to 69 years old and had unicentric invasive breast cancer and lumpectomy surgery that led to negative margins of 2 mm or greater. And their disease needed to be PR positive, HER2 negative, it needed to be node negative, pathologically node negative, and the Oncotype DX 21-gene recurrence score needed to be less than or equal to 18. And then these patients were offered the opportunity to consent and register on a trial to receive five years of endocrine therapy as standard of care alone, and 10 years of surveillance on study, or to proceed with the standard of care treatment off trial, which would have been a recommendation to receive radiation treatment. And so, we ended up with patients with a mean age of 62 years, which, as I said, that's really more mapping the overall population of patients in the country. And we were able to report our results at the San Antonio Breast Cancer Symposium and with simultaneous publication in JCO, with a median follow up of 5.2 years.

Shannon Westin: Okay, and let's talk about a little bit about your major findings. Tell us what your good work demonstrated.

Dr. Reshma Jagsi: So, the overall and breast cancer-specific survival rates at five years were both 100%, and the five-year freedom from any recurrence was 99%, with a 95% confidence interval that went from 96% to 100%. But I want to emphasize that these are five-year data in a younger postmenopausal population, where five-year data are not typically sufficient to guide decision making. So, I really want to emphasize that these are very early results. But really, what happened here was we only had a couple of patients who had recurrences before five years, two patients, and that was one isolated ipsilateral axillary recurrence, and one ipsilateral breast event. But we also did see six additional patients who recurred later than five years after breast conserving surgery. And because we don't have much long-term follow-up, it makes it incredibly important for us to continue to follow this cohort over time before people make any Monday morning practice implications of offering this cohort of patients, or patients like this cohort of patients, omission off trial. 

The good news is that there are ongoing trials that are building on this work, including NRG-BR007, the DEBRA ,that includes a population of patients really similar to those enrolled on IDEA and randomizes them to radiation or no radiation, which is actually incredibly important. Because what we want to understand is also the quality of life effects of omitting radiation therapy because what we don't want is to inadvertently cause an increase in worry about recurrence. Or, you could imagine that patients who omit radiation treatment then feel really stuck with their endocrine therapy. Now, endocrine therapy is the standard of care, but if they're experiencing terrible endocrine therapy side effects and they didn't get radiation treatment, are they more likely to persist with that endocrine therapy and to be miserable because they omitted a treatment that, as I mentioned earlier, can be administered now in five days or less? 

And one of the questions that keeps coming up from older patients that I treat, where we already offer the option of omitting radiation, those CALGB and PRIME II patients, those patients will often say to me, "I’ve got to say, Doc, that whole experience of radiation that you described for five days, and the toxicity, and that doesn't sound so bad to me. What sounds bad to me is multiple years of endocrine therapy." And so, there are also ongoing trials in Europe, and I hope one day in the United States, also looking at older women and offering them a de-escalation of a different sort. Now that we have made so many advances in radiation treatment, maybe the optimal monotherapy for an older adult is actually, for many patients, given their values and preferences, going to involve omission of endocrine therapy. And we need to find out if that's safe. And again, Europa in Europe is investigating that question, and I hope that the American cooperative groups take up something similar.

Shannon Westin: That’s awesome! And what else is going on in this space? Any other trials? That was like, such a great review of ongoing trials, and I'm sure our listeners would love to have your expertise. Anything else that you're looking forward to that might impact the treatment landscape here?

Dr. Reshma Jagsi: Absolutely, and if there are listeners in other parts of the world, there are trials going on also looking at this. There is PRIMETIME, which is a cohort study designed, but with a much larger cohort that's going on in the United Kingdom. There's the EXPERT trial that is randomizing patients to radiation treatment or not in Australia and New Zealand. So, there are many trials that are ongoing, again, looking at de-escalation of radiation therapy. And I want us all, regardless of our specialty, to think about ways that we can de-escalate and optimize the options that are offered to our patients. And I think there's a tendency for patients to be very scared of radiation, sometimes, for our colleagues to be very scared of radiation. I mean, we are the only specialty that has a special “danger radiation sign” that comes to mind when you hear the word radiation therapy. So, it can be this very frightening thing that we often leap to efforts to avoid. 

And what I don't want to be the conclusion of this is, “Isn't it great? Radiation oncologists themselves recognize that radiation is terrible and that you should avoid it.” That's not the case. What I hope people will say is, “Isn't it great that radiation therapists are trying to offer as many options to patients as possible?” Because it means a lot to a patient who's had the sense of power and control and autonomy ripped away from them by a breast cancer diagnosis, to be given many options to articulate their values and their preferences and to decide what treatment makes most sense for them. I think, for a lot of patients, that involves radiation treatment. And I think what we need to do as physicians is think about what other things are our patients really concerned about.  

Our medical oncology colleagues have done tremendous work to de-escalate systemic therapy in the form of chemotherapy. Our colleagues in surgery have, again, de-escalated mastectomies, axillary dissection. So, there are these ongoing efforts, and I do honestly believe that the next frontier is endocrine therapy and optimization of endocrine therapy. It is so powerful. It is why we have such wonderful outcomes. We know that we should have a healthy respect for ER-positive cancer, which can recur in the long term. We don't want to throw out the baby with the bathwater, but baby steps towards understanding what happens if we peel back our treatments is our obligation. 

Shannon Westin: I think this is a perfect place to end/ I agree - less is more is really becoming a resonant statement across all of our different subtypes. We're certainly seeing it in GYN oncology, and just like you said, systemically or even surgically. So I agree. I think we have a call to action to really assess what we've always done and make sure that we're not over-treating patients for whom it's inappropriate. 

So I think this is great. And I just want to commend you again on your work. These types of multicenter trials are really hard to do, and getting it done in such a short period of time and really getting the data out to patients is so important. And I appreciate what you're saying about needing more follow-up, but it is certainly very reassuring and very in line with what we've seen. So congratulations on your work.

Dr. Reshma Jagsi: Thank you. And I just again want to thank all the patients who enrolled, the Coleman Foundation for their support, the University of Michigan for doing the multi-site coordination and the biostatistic support, and all of the collaborating investigators. I mean, this was a labor of love for everyone involved.

Shannon Westin: Yeah, these types of trials definitely take a village. Well, great work. Thank you for taking the time. I know how busy you are. So again, we are so honored and so excited to talk about "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA,” just published in print, February 2024 in the JCO. Definitely check it out. And please check out our other episodes of JCO After Hours. We'd love to have your feedback. Take care.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

Dr. Jagsi:

Stock and Other Ownership Interests
Company name: Equity Quotient

Research Funding
Company name: Genentech"

Dr. Shannon Westin and her guests, Dr. Jeremy Davis and patient advocate Kathryn Carr, discuss the paper "Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy" recently published and printed in the JCO.

TRANSCRIPT

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, a professor of GYN Oncology at MD Anderson, and the JCO social media editor. I am so thrilled to have wonderful authors here today who do not have any conflicts of interest. We are going to be discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” This was published in the Journal of Clinical Oncology online on October 30, 2023, and in print on February 1st, 2024. 

And I am excited. I am accompanied by the lead author, Dr. Jeremy Davis, who is an Associate Professor and Surgical Oncologist at the NIH, National Cancer Institute Intramural Research Program. Welcome, Dr. Davis. 

Dr. Jeremy Davis: Thank you.

Shannon Westin: If it is okay with you, I'll call you Jeremy.

Dr. Jeremy Davis: Yes, please. 

Shannon Westin: Fabulous. We also have patient advocate Kathryn Carr, who is a board member for No Stomach for Cancer. Welcome, Kathryn.

Kathryn Carr: Thank you so much. 

Shannon Westin: So let's get right into it. I think this is really thought-provoking work. First, I'd love to level set. So this was work around hereditary diffuse gastric cancer syndrome. Can we get a little bit of information about what causes this and how common it is?

Dr. Jeremy Davis: So, hereditary diffuse gastric cancer syndrome, also referred to as the diffuse gastric cancer and lobular breast cancer syndrome, is basically early-onset diffuse gastric cancer and in women, lobular type breast cancer attributed to germline mutations in the CDH1 gene. If we look at all cases of gastric cancer in the United States, only about 1-3% may be considered hereditary in nature. But when we do study hereditary causes of cancer, it is by far the most common one that we are aware of.

Shannon Westin: What is the likelihood that someone who is a carrier of a germline CDH1 variant will develop gastric cancer?

Dr. Jeremy Davis: That's a good question. Early on, when the syndrome was first described, the estimates of cancer risk were quite high, probably upwards of 70-80%. The good news is that more current estimates published in the last few years suggest that that risk in a lifetime is probably in the 25-40% range. It’s interesting, we do have our own data that are under review right now, where in some families where there’s no history of stomach cancer, that risk of stomach cancer in a lifetime getting a CDH1 mutation might be as low as 10%. So I think the takeaway is that there’s clearly a spectrum and that spectrum of risk is probably based on factors that we don’t quite yet understand.

Shannon Westin: What are the options for management of this hereditary syndrome, really focusing on the gastric cancer syndrome portion today? How good does it do to reduce the risk?

Dr. Jeremy Davis: The options are really two. One is probably the prevailing recommendation that most people would be aware of, is to prophylactically remove the stomach, and we choose to use the term most often ‘risk-reducing gastrectomy’, but to remove the entire stomach and really eliminate the risk of cancer from ever developing. The other option is enhanced surveillance, and people might think of this as akin to other high risk cancer syndromes. But for this we would do yearly or annual endoscopic surveillance. Many people think that that may not be the best option, but it is certainly an option. We discussed some of that in the paper about what are the risks and benefits of gastrectomy, and then what may be the benefit of enhanced surveillance for some people.

Shannon Westin: Well, I would love to hear Kathryn. I think this is a perfect opportunity to hear a little bit about your journey with carrying this variant, as much as you are willing to share with our listeners.

Kathryn Carr: Yeah, absolutely. So I found out that I have this spicy little gene back in 2019. My whole family got tested so the gene comes down from my paternal great grandmother. There are five of us who actually all had our stomachs removed by Dr. Davis. Within a year, he had five Carr stomachs. For me when I found out, I was extremely overwhelmed. I mean, “You want to take my stomach out? Like, what do you mean?” But after talking to Dr. Davis and his entire care team, I knew for me, having the total gastrectomy was the only option simply because I know my personality type enough that I was not going to be able to move forward with life unless I got rid of this overwhelming worry.

Shannon Westin: Yeah, I think that makes sense. I'm a GYN oncologist by trade, so I often reference all things surgery around that. We have the same thing when we talk about risk-reducing surgeries for endometrial and ovarian cancers. This seems more like what we do in Lynch syndrome, where patients are at risk for endometrial cancer. Removal of the uterus is almost definitive in its ability to reduce that risk, but it's obviously a very large surgery. Jeremy, can you review the gastrectomy in general? What are the most common short-term and long-term adverse events? What did you have to discuss with Kathryn and her five family members around what they could expect from this surgery?

Dr. Jeremy Davis: Yeah, I think this is a great question because it's the thing at the top of most patients' minds. When I sit down to talk to somebody about gastrectomy, usually a lot of the conversation initially centers around ‘how long does the operation take, how long am I at the hospital, and what are the most likely risks of the operation?’ The good news is that as operations go, it can be done in two to three hours, and most people are in the hospital for maybe five to seven days. The risks of this operation, however, at least during the operation or immediately afterward have to do with how we have to reconnect everything and reconnecting the intestine to the esophagus so that people can continue to eat. Because I think a lot of people wonder, "Well, how am I going to eat?” The stomach's gone, but we recreate intestinal continuity. We put things back together in a way that people can eat and absorb their food. 

But that connection we make between the esophagus and intestine is almost like the Achilles heel of this operation. It's the one thing that keeps surgeons up at night, and it's probably the one thing that causes the most trouble in terms of immediate risks, like leaking. If that connection leaks, it can lead to infection. There are other aspects of the operation that relate to any kind of intestinal surgery, such as leakage, blockage, or narrowing or something like that. So these are the things you need to worry about in the short term. But you mentioned the long-term consequences, and that was really one of the reasons why we wrote the paper. If you look in the literature, the focus is on the acute problems, things that happen within 30, 60, or 90 days of the operation. Which, yes, those are very, very important. But since we're talking about an operation that's supposed to prevent cancer and therefore allow the patient to live a long and happy life, I think it's important for us to think about what happens well beyond the time that the patient essentially heals from the operation. 

Shannon Westin: It's so critical. And I think before we go into the work that you did and what you all found, Kathryn, I would love to get your perspective. Having gone through the procedure, what was your experience? Give us as little or as much detail as you want, whatever you're comfortable with. But also, what did you wish you had known? What surprises kind of came up during the course? 

Kathryn Carr: I'm going to quote Rachel, who works with Dr. Davis at the NIH. She's the clinical dietitian. And my question to her was, "Seeing all the patients you've seen and knowing all that you know, what would be the advice that you would give me?" She told me to have the patience to get through the first year. I think that really set my expectation of, "Okay, this is not just a surgery where in a week or two weeks I’m going to be up skipping along." It is a marathon. I really worked hard with Dr. Davis in the hospital. I'm allergic to everything. I was convinced that my spleen was erupting. I think I scared many fellows, and they were like, "That's actually not where your spleen is. It's fine. You're okay. Stop getting on WebMD." But once I got home, those first eight weeks, they’re hard. There were several moments where I would just sit and stare off into space and think, "Oh my gosh, what have I done?" But for me when Dr. Davis called to tell me the pathology report and that they did find some signet cells, I was 100% sure that I made the right decision. I would have been worried every second of every day that my body was going to turn on me. So once I kind of had that relief, it was like, "Okay, my body can do this. We're built to do hard things." Then it was just getting through the first six months, learning what I could eat, what I couldn't eat, working with Rachel on different strategies of, “Okay, I’m going to maximize my protein in the morning and then maybe get a little more adventurous as the day goes on.”

But what I wish I had known before surgery, because I'm a planner, I want everything scheduled and figured out. I was in the hospital, I had a different outfit for every day, and I just wanted it to go perfectly. I think taking away the expectations of what your journey is going to look like would be the best advice I could go back and give myself. Because I am very competitive, and my dad and I were separated by seven months of this surgery. He can do things that I still can't do, and that's okay. Everyone's healing journey is going to look very different because everybody is going to respond incredibly different. It's like the body is doing roll call and the stomach is nowhere to be found, and everybody is going to respond totally differently to that.

Shannon Westin: That's so insightful. I really appreciate that. 

I guess now it's a good time to turn to the work that you did, Jeremy, and you kind of already hinted at what your objectives were, but can you maybe walk through your primary objectives in the way you designed the study.

Dr. Jeremy Davis: You know, I think as somebody who trained to take care of people with cancer and do big operations to cure people, this was a little bit of a different experience in the beginning for me. Because here I was taking ostensibly normal people - Kathryn may argue with that statement - but normal people, and I was going to take them to the operating room and do something to them to prevent a problem. And this is not a minor thing, it's a big deal. What I learned pretty quickly was how much I was disrupting people's lives. And what I mean by that is that a patient comes to clinic three or six months after surgery. We all document the typical things. They are healing well, they are recovering as expected, their incisions are healed and all this stuff. But it was the stuff that didn't always go down in the medical record. The comments that the patients made to my team, the nurses, the dietitian, about how their lives were being disrupted. And this started to change my viewpoint on, “Oh my goodness, we're paying attention to important things, but we're really not paying attention to what's happening.” So, the idea behind the study was really to explore those consequences that don't get talked about a lot. That was the nature of the idea behind the study. It was easy enough for us to conduct the study because my research at the NIH is about gastric cancer, but more specifically, this hereditary form of gastric cancer. We have a natural history study that allows us to follow people for a long time, not just within three or six months of surgery, and then we're done. So that longitudinal aspect of the study is really what allowed us to accomplish that.

Shannon Westin: What I thought was really interesting here is how many different types of questionnaires you were able to utilize to really assess beyond kind of the straightforward quality of life Yes/No. Can you speak a little bit about some of the questionnaires you chose and why? 

Dr. Jeremy Davis: My concern going into this was that I had read a lot of the literature related to quality of life after gastrectomy for gastric cancer. There are certainly these validated questionnaires out there. And my sense was, having read those questions and papers, that those validated typical questionnaires- I'm referring to the FACT-G or the FACT-Ga might not capture the things that we wanted to capture. So, I spoke to our palliative care service here at the NIH clinical center, which is the hospital here on campus in Bethesda. They had developed a questionnaire many years ago that they called the NIH HEALS or Healing Experience of All Life Stressors. They designed that to identify stress causing changes associated with chronic illness. You might argue that having a germline mutation that puts you at risk for cancer is kind of a chronic condition. So, we thought we would use that. 

And then the last part was we just sat around the table and we thought, “Well, jeez, what are all these things that people are telling us that would never be captured in almost any questionnaire?” And that's when we designed a series of questions that we thought were relevant to our patient population because we wanted to capture all the things that people had told us. Those were things like, “I had to change my job because I couldn't do the same work anymore, right?” Or, “My partner, our relationship changed substantially, and we grew apart, and we ultimately got divorced.” How do you capture that? So that's how we designed it. We basically looked at all the patients that we had done the prophylactic gastrectomy on and applied all of those validated and unvalidated questionnaires.

Shannon Westin: That's so great. And I bet, Kathryn, you participated quite a bit in that, in addition to other people in the study.

Kathryn Carr: I did, and I'm so grateful that Dr. Davis is doing this study because it is so important to look at what life is like without a stomach. You have this immediate thought of, “Okay, I just want to save my life. I want to make my life longer. But how is it going to change my life? How is it going to alter my day-to-day?” Because even Dr. Davis has said it would be weird if it didn't change your life. I mean, you're taking away a very important piece of the puzzle. So, I think this study is going to help people make more accurate decisions. I don't doubt my decision to have my gastrectomy at all, but this is beautiful information just so that you can be more well-prepared to walk into the surgery of, “Okay, now I have a very clear understanding of what my life could look like.”

I've been very fortunate that I have not had a lot of the physical problems. I don't deal with a lot of bile reflux. My weight has stabilized, so I am very blessed in that way. But emotionally, this has been a really tough surgery. You start to feel misunderstood, like you have to walk into every day being very prepared of, “Okay, every two hours I have to eat something or else I get real hangry, not just a little hungry, real hangry. Also, my body will start to shake.” That's how I get my hunger signal. My whole body will start shaking, which is very scary. It's very unpleasant. I'm almost four years post-op, and so I lean into my schedule and routine. 

One piece of advice for anyone walking into this surgery is to make sure you're anchored in something. For me, my faith anchors me, but if you're not anchored in something that is secure and true, like, you are going to float away, because this is a storm. 

Shannon Westin: Jeremy, do you want to just pass on a few of the key findings? I encourage everyone to read the paper. There are so many different things that were explored and identified as part of this study. It's amazing with the number of patients that were involved, what the depth of the findings was. But perhaps you can kind of hit some of the major high points.

Dr. Jeremy Davis: Yeah, I think the key takeaways for me, and obviously I'm still learning from all of this, is that I think we talk a lot about the surgery, in this case especially, but we don't talk enough about what life is like afterwards. I've started to talk to people about how much you think your stomach plays a role in your life, and you think about how much of our life centers around eating and drinking and holidays and family gatherings. And you have to imagine that means those activities are potentially disrupted. So for me, the key takeaways from this are, number one, we have to be aware. We have to be aware that risk reducing surgery of almost any kind has consequences. Yes, we want it to have a positive impact on the patient, but we have got to be aware of the negative impact. This is like systemic chemotherapy. It can do a lot of good, but toxicities are real. In terms of the specific findings from this study, listen, 94% of people in the study, 126 of people, 94% had some long term consequence. And it wasn't just like some long term, “Oh, I don't like my scar.” No, it was 94% of people had a long term problem, such as “I have daily bile reflux that interferes with my activities of daily living.” Something like that.  

And I think the range of consequences is really important, too. And so, again, they range from things like GI symptoms, which you would imagine would be quite typical for a gastrectomy, but mental health, right? People talking about worsening symptoms of anxiety or depression, some substance abuse. Whether it was alcohol or otherwise, disruptions in relationships, I mentioned earlier, and even occupation change. I can't physically do the job that I used to do. So I think as clinicians, as surgeons that walk into this, yes, we need to focus on the surgery and the immediate consequences, but we also need to think, “How am I going to change this person's life? Not just for the better, but how might I really impair their life in the long term?”

Kathryn Carr: Well, in one, just very simple example. So like going out to eat with people. There's a natural cadence of conversation. I take a bite, you talk and vice versa. But when you're chewing your food to the nth degree it interrupts that natural cadence. I avoid dinner dates because then I have to talk about my stomach on a first date or going out to dinner with friends. It's nice if there's a group of us because then other people can carry the cadence but then you kind of feel left out of the conversation because you're like, “Oh, well. I’ve got to eat, otherwise I'm going to pass out.” So that's just like a very simple, you wouldn't think of, “Okay, I'm going to dinner at 7:30 so I should probably eat a snack before I go because I might not get my food until 8:00 or 8:30.” So it's just like you're constantly thinking about, “Okay, I've got to make sure that I have food in my body. 

Shannon Westin: It’s so critical. 

Well, this has been an awesome discussion and I'm sad that it's coming to a close. I guess just final thoughts around what's next in this space. Like what are you working on now, Jeremy?

Dr. Jeremy Davis: I'm a cancer surgeon and a cancer researcher so my goal is to find a way for us to prevent stomach cancer that doesn't require me having to take out somebody's stomach. So in the laboratory that's what we're doing, right? We're working on finding a way to prevent stomach cancer so that I don't have to do this operation anymore. But on the clinical side of things, the next thing that we're exploring is how do patients think about, talk about, or express concerns to their physicians about reproduction - reproduction in the setting of a cancer predisposition syndrome. And I think that's going to be really important work. 

Shannon Westin: That's great. Kathryn, any thoughts?

Kathryn Carr: I know that being four years out, I'm not like an old timer, but I do just want to help anyone who's at the beginning stages of this journey and just making other patients feel less alone. I told Dr. Davis I just entered the world of TikTok to talk about gastrectomy and just opening up a conversation of what does life without a stomach look like? And just making people feel less alone and more understood throughout this process.

Shannon Westin: Thank you both for the work you're doing, and thank you to all of our listeners for tuning in to JCO After Hours. Again, we were discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” Please do not be a stranger to our podcast. Check out our other offerings and reach out to us on X and Instagram if you have other topics you want us to cover. Have an awesome day.

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

In this JCO Article Insights episode, Subodh Selukar summarized findings from the original article published in the January 2024 JCO issue: “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” and accompanying editorial “Patient Experience, Adverse Event Reporting, and Clinical Trial Design”. The summary provides information regarding low and moderate grade adverse events and the patient experience in clinical trials.

TRANSCRIPT

Welcome to the JCO Article Insights episode for the January 2024 issue of Journal of Clinical Oncology. This is Subodh Selukar, your host, and today I will be providing a summary on 2 articles focused on low and moderate grade adverse events. The first article, titled “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues, investigated low and moderate grade adverse events and the patient experience in clinical trials. Their article is accompanied by an editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman. 

In clinical trials, a standardized system for reporting adverse events is the Common Terminology Criteria for Adverse Events (or “CTCAE”) established by the NCI, the United States National Cancer Institute. The CTCAE categorizes adverse events at 5 severity grades across 26 system organ classes. However, some clinical trials may only report adverse events at grade 3 or higher, with one possible rationale being that low and moderate grades are unlikely to affect patient safety or key trial endpoints.

In Dr. O’Connell’s article, the team investigated how the numbers of grade 1 and 2 adverse events related to patient self-reported side-effect burden and treatment discontinuation. To do this, they analyzed data from the Phase 3 trial E1912 conducted by ECOG-ACRIN comparing two treatments for chronic lymphocytic leukemia. They chose this trial as an example because the study data included all adverse event grades throughout the duration of treatment for each patient.

The authors studied side-effect burden based on GP5, which is the fifth item in the FACT-G subscale in the Functional Assessment of Cancer Therapy. GP5 rates the patient’s agreement with the statement “I am bothered by side effects of treatment” in the past 7 days, and it has previously been connected with adverse event grade and treatment discontinuation.

For treatment discontinuation, the authors focused on those discontinuations that were recorded as being due to “adverse events, side effects or complications.” They found that, for each adverse event grade, there were, on average, more adverse events in cycles that ended with a patient discontinuing treatment compared to other cycles.

Next, they used Bayesian models to assess how the numbers of grade 1 and grade 2 adverse events in a treatment cycle were associated with the odds of higher side-effect bother and odds of treatment discontinuation, after adjusting for cycle number, treatment and occurrence of grade 3 or higher adverse events within the cycle. Baseline GP5 was also included in the models, and these models also accounted for the inclusion of multiple cycles for each patient.

When adjusting for baseline GP5, treatment, cycle and presence of grade 3 or 4 adverse events, both the number of grade 1 and the number of grade 2 adverse events were each strongly associated with increasing side-effect bother. The adjusted odds of treatment discontinuation were also higher with more grade 2 adverse events. However, with the same adjustment variables, the odds of treatment discontinuation were actually lower with larger numbers of grade 1 adverse events.

In their primary analysis, they focused on adverse events that were attributed to treatment, so they excluded non-treatment-related adverse events from the counts. Sensitivity analyses including these adverse events have similar conclusions but with a weaker magnitude of effect. They attributed this to issues like existing adverse events not causing new bother.

Next, the authors analyzed whether symptomatic versus asymptomatic adverse events affected these results by re-fitting the models and separating the predictors into numbers of asymptomatic and symptomatic grade 1 or 2 adverse events.

In these results, they found no evidence for associations between numbers of asymptomatic adverse events at any grade and side-effect bother. On the other hand, they found strong evidence for associations with symptomatic adverse events of grade 2 and 3 or higher both for side-effect bother as an outcome and with treatment discontinuation. Asymptomatic grade 2 adverse events were associated with treatment discontinuation but not side-effect bother, and symptomatic grade 1 adverse events were associated with side-effect bother but not treatment discontinuation. 

·       The authors conclude that adverse events of all grades, especially symptomatic adverse events, should be recorded regularly in cancer clinical trials. Formal patient reported outcomes are not typically collected as frequently as adverse events are recorded, so identifying patients with a high number of lower grade adverse events could be used to facilitate early supportive care to improve patient quality of life and reduce the likelihood for treatment discontinuation.

·       They also highlight their result identifying lower odds of treatment discontinuation with larger numbers of grade 1 adverse events. They provide one explanation that patients may perceive grade 1 adverse events being associated with treatment efficacy, but this perception changes with higher grades.  In their call to collect more lower grade adverse events, the authors acknowledge that recording more adverse events may be time-consuming and burdensome for sites and recommend cost-benefit analyses to develop future guidelines.

·       This balance between the benefits and costs of increased adverse event data collection is the focus of Dr. Neuman’s editorial. Dr. Neuman acknowledges that Dr. O’Connell’s article provides a convincing argument for how low grade adverse event information is valuable, but notes the clinical trial context that current efforts at the NCI are to more efficiently conduct cancer research, which could be supported by streamlining data collection.

·       Requiring the collection of low grade adverse events could have important impacts to trial logistics. Due to the high volume of low grade adverse events, reporting all low grade events could delay reporting higher grade and more serious adverse events; and it would require an increase in the effort of clinical trial research staff, which would be difficult if not accompanied by an increase in reimbursement to sites.

·       Dr. Neuman suggests 3 approaches to balance the costs and benefits of collecting low and moderate grade adverse events. First, investigators could consider limiting low-grade adverse event reporting to the experimental arm. The standard of care regimens may not always have low-grade adverse event data available, but this may still be justified when there is extensive clinical experience with the standard of care. However, this approach is only practical when the experimental arm is not blinded.

·       A second approach for moderating the effort in collecting low-grade adverse events is to limit collection to symptomatic adverse events, connecting with Dr. O’Connell’s example E1912 dataset. This approach could be addressed by prespecifying types of symptomatic adverse events that would be most impactful during the trial design phase.

·       Dr. Neuman’s third suggestion is to plan for a follow-up study after the phase 3 trial to collect low-grade adverse event data and their impact on patients’ experiences and treatment discontinuation. This would be beneficial by only requiring low-grade adverse events in an experimental regimen that has successfully passed phase 3. However, a new study would require funding and site enthusiasm, which could prove challenging.

·       Overall, Dr. Neuman emphasizes that investigators should develop trial-specific considerations and engage with the relevant stakeholders during study design. Because of the complexity of adverse events in these patient populations, the best uses of grade 1-2 adverse events will likely continue to develop in the future. In their article, Dr. O’Connell’s team studied grade 1 and 2 adverse events as separate predictors, but I would be curious to know how the accumulation and trajectory of these adverse events affect the patient experience. For example, even if the severity does not rise to grade 3, an increasing trend in a patient’s adverse event severities could signal the treating physician to modify study dose or to discontinue the treatment. I’m not sure if that type of information was available in their trial E1912, but perhaps that could be a factor to consider for the future. And, of course, it will be important to assess how these grade 1-2 adverse events relate to the patient experience in different studies, especially across different cancer patient populations, acknowledging that this is inherently challenging to study because the data to inform this research is not universally available. As Dr. Neuman indicates, trial-specific goals and expertise will remain critical when considering the data collection for a given trial. 

That concludes this episode of JCO Article Insights regarding a summary of the article “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues and the editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman. This is Subodh Selukar. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.

Dr. Shannon Westin and her guest, Dr. Ash Alpert and Spencer Adams, discuss the paper "Debunking Sex and Disentangling Gender From Oncology" recently published in the JCO.

TRANSCRIPT

The guests on this podcast episode have no disclosures to declare.

Shannon Westin: Hello and welcome to JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor and GYN oncologist by trade. I'm so excited to be discussing a very important manuscript. This is "Debunking Sex and Disentangling Gender from Oncology," which was published in the JCO Online on May 26, 2023. So I'm joined by two of the authors here today on the podcast. First is Dr. Ash Alpert. They are an instructor of medicine and hematology at Yale Cancer Center. Welcome.

Dr. Ash Alpert: Thank you.

Shannon Westin: And we also have Spencer Adams. They have a bachelor's in public health, are a certified health education specialist, and are currently pursuing a master's in public health at Western Michigan University. Welcome, Spencer.

Spencer Adams: Thank you for having me.

Shannon Westin: So let's get into it. I'm so excited. First off, I just want to say thank you because I learned a ton from this paper, and I'm hoping to be able to implement some of these changes that we're going to discuss over the next few minutes at my own institution. So I wanted to just make sure we kind of level set and everyone's on the same page. So let's start off by discussing ontological oppression. Can you explain to the listeners what this means and how it relates to sex and gender and oncology?

Dr. Ash Alpert: Sure. So, ontological oppression is actually a concept from one of my colleagues at Yale, Robin Demroff, who's a philosopher. Ontology is a way of thinking about what exists and how we categorize what exists. And so ontological oppression is discrimination or stigma that happens because of the ways people imagine us fitting or not fitting into social categories. For example, if we think that people are women or men based on their sex assigned at birth, then it makes sense that we would think of transgender people and nonbinary people as abnormal, weird, or pathologic. In oncology, if we think of ovarian cancer as something that happens to women and a man with ovarian cancer comes into our clinic, we may be confused or uncomfortable. We may respond to those feelings by denying his identity, for example, thinking he's actually a woman or using the wrong pronouns or name for him or even potentially denying him care. And we have some data to suggest that clinicians respond to lack of knowledge about transgender people by treating them as abnormal, weird, or bad in some way. 

Spencer Adams: Yeah. And to add to that, when we consider how we classify people, first, there's a problem within that. There's an ethical problem within that, but it's an idea or a construct that society has created and wants people to fit into these nice little boxes just because it's easier to digest, or you make the person more palatable if they're able to do these things. And life is not like that. We have differences, and we have things that make people fit outside the box. And I believe that when we keep reminding people that a box exists or a social construct exists, you're stifling who they are, their personality, their guiding light. You're stifling a lot of things about that person and ignoring something that's incredibly important to them.

Shannon Westin: I think that along those lines, kind of taking that to the next step, it would be really helpful to discuss a little bit more around this interaction between sex assigned at birth and gender and what assumptions are made. And I think you kind of started along this, like, how that impacts oncology care. But in your paper, you did, I think, a really great job of really laying out a lot of the problems that happen in this space, and I'd love to explore that more right now.

Dr. Ash Alpert: So sex is a designation made when a baby is born by somebody viewing that baby's external genitalia. And so I think we all, as doctors, know that that designation doesn't necessarily tell us what that person's karyotype is, what their later hormonal milieu will be, what their internal anatomy is, and it certainly can't tell us anything about their gender, which is how someone sees themselves as a man, woman, nonbinary, or something else, and usually develops around the age of four. And even though I think that we all know that, we're so used to sex and gender being used interchangeably, not just in the ways that we talk to each other, but in everything about the way that we do our work. And so it becomes very difficult to disentangle these concepts for ourselves. 

And we have used sex in particular as a proxy for so many other factors where it doesn't necessarily function. And parts of medicine are based on that. So it's very hard to start to unpack and disentangle those things. For example, the ways that we talk about certain types of cancer can be linked with gender, like we were talking about earlier, women with ovarian cancer, men with prostate cancer. And that's the way that we talk to each other. But it's also in our clinical trial eligibility criteria, sometimes, it's in our patient facing materials, it's in the ways that we name our clinics, the ways that we talk about our work. So then even just sometimes occupying space to get oncology care can be a form of being misgendered. 

Spencer Adams: Yeah, I think it's dangerous to conflate the two, sex and gender. As Ash was saying, that one is a visual inspection, the other is who the person is. And if we claim to be an institution that does patient-centered care, how can we be patient-centered if we are not properly respecting the patient? And to do that, you have to respect their gender as well. I see also one of the things that I want to add to the list is clothing that the patient is offered, especially going to a "women's clinic." We can change that to "reproductive health clinic," but usually the clothing is pink and that may be dysphoria-causing for some of our transgender and gender nonconforming friends. So it truly is in everything that is client facing, that is how the structural building is made. It truly is not just how we talk to each other, but how society runs. 

Shannon Westin: Yeah, let's talk a little bit more about training because I think that will be pretty important as we try to change these things. So the way we're trained in medicine and oncology, regarding sex, regarding gender, how does this negatively impact the health? We've talked a lot about the mental health, definitely impacts, but also, I think, overall physical health.

Dr. Ash Alpert: Well, I think something that we started to talk about, but didn't talk about in detail is not just the conflation of sex and gender, but the ways that this concept of sex is used as a proxy for a number of other factors, including anatomy, hormonal milieu, karyotype, and body size. One of the ways that this becomes problematic is in our laboratory values for example. Laboratory values are developed, as far as I understand it, based on looking at large studies of people that are categorized as women or men and looking at averages. So, averages are helpful, but they can't necessarily tell us about disease or no disease. So, for example, if a large number of cisgender women have iron deficiency that is undiagnosed, and we use their averages, then we're going to continue to underdiagnose iron deficiency anemia going forward. 

So, the ways that we've tried to use sex as a proxy for a number of things doesn't just hurt trans people, but potentially leads to very imprecise data in general. Specifically for trans people, we know that many trans people have negative experiences with care, that this leads to people avoiding care and likely leads to decreased screening for cancer and delayed cancer diagnoses. So we don't have a lot of data about this, but we do have some data to suggest that transgender people may present later with later stage cancers, be less likely to be treated, and have poorer outcomes than cisgender people.

Spencer Adams: And I think it's important to add that there are physicians who will - we call it like, “the trans illness" - but they will blame everything that you're experiencing on the fact that you're transgender or the fact that you're on hormones or the fact that you had the surgery, and say that you need a specialist. So you can't just go to your primary care physician anymore for the flu because they'll just blame it on your medical transition. When we take that into consideration, I think there's a whole host of physical ailments that come from just being denied care. I don't know if that is from the physician's own personal stigma around trans people or just them not being trained in trans healthcare to where they feel confident in going into that room. So it's a twofold attack. First, we need to make doctors who are competent in trans healthcare, and then second, we need to have more inviting spaces for trans and gender nonconforming people.

Shannon Westin: I think the next step is really better understanding this idea around degendering care, specifically in oncology, but I could really talk about medical care as a whole, but let's focus on what you all brought forward in the paper. I would love to hear how we think this idea of degendering care will promote better healthcare. And then, I think, some practical actions. What can we do on a day-to-day basis? And you've already started peppering this through this discussion but I’d love to like bullet point it out for the listener. 

Dr. Ash Alpert: Yeah. So the way we described it on our paper was: “disentangling oncology is a conscious and explicit disentanglement of gender, anatomy, hormonal milieu, karyotype, and other biological factors. In oncology, diagnoses, epidemiology, and knowledge production. As well as,” - and I think this is an important part and that's maybe the harder part of the paper - “eliminating sex from our conceptual framework of bodies and disease”. So, in other words, we're really trying to say that not only do we need to disentangle gender and sex, but we need to debunk the idea that sex is an immutable fact of the body that says something important about a person and their biology. Instead of thinking about sex as this immutable fact of the body, can we really break down and think about what exactly are we measuring? Is it anatomy, hormones, karyotype, size, or stigma? 

In terms of practical actions, some of the things we had in our paper include that oftentimes, the words "woman" or "man" can be replaced with the word "people." So like a very easy change. And actually, ASCO and the NCCN, both in the last few years, have worked to degender their guidelines by doing just this simple change. Then we also need to do this on our websites, in our patient education materials, and in our clinical trial eligibility criteria. Because if you have a trial for prostate cancer that says that one of the inclusion criteria is being male, then whether or not you actually mean that as an inclusion criteria, a transgender woman or her physician may see that as a barrier to enrollment.  

Ensuring that, as Spencer was saying, that gowns, binders, and wigs are available that are gender-neutral are available for all genders. Ensuring that people have access to bathrooms, so making sure gender-neutral bathrooms are available. And often, this is as simple as taking a one-style bathroom and putting a sign on it that says "gender-neutral." Ensuring the names of clinics, mammography suites, and titles do not contain gender. Ensure that intake forms don’t conflate gender with biological factors. For example, in a clinic I used to work in, one of the questions on the intake form was, "If you are a woman, when was your last menstrual period?" Which if I’m a man and I have a period, it might be hard to figure out how to answer that question.  

Spencer Adams: One of the biggest barriers for trans and gender nonconforming people is that intake form. It is the first person that you meet or see when you go to any healthcare establishment because that sets the tone for whether or not this establishment is trans-friendly. If you have, as Ash said, a "for women only" box or descriptor on your intake form, that is a sign that maybe they're not as trans-friendly as they could be. Or if you see "women's clinic" instead of "reproductive health clinic" or whatever, that could be a sign that they may not be as gender-friendly as they could be. These little changes actually make such a big impact on the trans community, and it's something that I believe would be very much appreciated and would close the gap between trans and gender nonconforming people and the medical community.

Dr. Ash Alpert: I know that for me, going to a doctor's office, these small moments, although they may seem small to other people, really add up in terms of stress. People talk about microaggressions, and I think that's really a good way of conceptualizing what it's like to have these little irritations or hits that happen over and over again throughout a clinical encounter. And I think in particular, for folks who are dealing with a cancer diagnosis and treatment, which can be experienced as a traumatic event, having these recurrent denials of identity on top of that can lead to additive trauma in a way that can be very distressing and have negative sequelae for patients.

Shannon Westin: Yeah, we're trying to look around this idea of allostatic load and how we can actually measure this because I think when we talk to policymakers about this, around not just the trans community, but also around underrepresented minorities, and the stresses that impact their risks of cancer, and how it's not just their race or ethnicity that's driving it, it's all of these microaggressions and everything. We get a lot of like, "Really? That's not science." So, I definitely think doing a better job around being able to objectively measure these other things and move forward in a very objective direction is going to help. Because if one of those things we know it's there, but for people who aren’t as ready to believe or understand that, it helps to have and embed that objective data. So that gets into the epidemiologic potential and cancer prevention.

Dr. Ash Alpert: Yeah. In some ways, we can't do much about the data that have been collected in the past, but we can start to think about them more critically and describe what we think is really going on in what we were calling sex or gender categories. But going forward, we can really think about collecting data on our clinical trials and in our large population-based surveys that actually speak to biological factors. So, if what we're concerned about is whether or not someone has ovaries, we can ask for an anatomy inventory. And when we're interested in hormonal milieu, we can check hormone levels. When we want to know about chromosomes, we can check a karyotype. And if what we're interested in is stigma, then we can ask about stigma, or we can ask about things that we think may cause someone to infer stigma. Once we have data that’s much more nuanced and granular, we’ll be able to better extrapolate it to all people in a much more rigorous and precise way, including trans people.

Spencer Adams: When it comes to cancer treatment and diagnosis within the trans community, it's such a unique thing because we have to consider also the social determinants of health. And this built environment that we've created, such as a hospital or cancer wing, or whatever you want to call it is directly impactful. As you were saying before, this microaggressions that add on and on to our trans friends. So, I think that when we look at the data and we look at stigma, we also have to look at where people are– We have to meet people where they are. It's going to be very difficult to bridge the gap between the medical community and the trans community when it comes to stigma. But if we have competent doctors trained in trans care and not always pushing off for a specialist, then I think we'll get better data. 

One thing that happens to trans people is doctors feel as if they cannot diagnose because being trans is seen as a disorder that they see as out of their wheelhouse. First, they classify it as a disorder, and secondly, they think it's outside of their wheelhouse. So they would refer to an endocrinologist or someone else to provide the care that the person is seeking. We call it the "trans disease" or the "trans injury,” because if I come in with a broken leg and the first thing you say to me is to go to an endocrinologist because we don't understand how hormones work, that's not care, and that's not patient-centered care. And that's what we're all moving towards, I believe. All hospitals are moving towards this patient-centered care. And to do that, to be patient-centered, you have to understand the person as a whole, and you have to be able to treat the whole person and then make a treatment plan that is specialized and custom to that person. This may involve different routes people take in order to feel comfortable or achieve what outcome that they wish to achieve. But it's really a patient-centered approach that we have to drive home in order to make some change. 

Shannon Westin: My last question is, what's next, and how do we get this information out? How do we actually enact? I mean, obviously this podcast reaches a lot of listeners, but beyond that, how can we educate people so that we can make these changes? This is something that hits close to home for me. I recently took over the gynecologic cancer center, which is where we house all below the belt malignancies. But there's work in progress, and we're discussing an overarching center to cover breast and gynecologic malignancies. And there's a discussion around how to title that. One of the suggestions was that it should be a "women's center," or something like that and that is not in line with what we've just been speaking about. So I think, certainly, that kind of individualized, like boots on the ground, people that are willing to speak up and say things and try to change these types of things, and I fully intend to do that - fingers crossed that it won't be me just waving my tiny fists in the air.  

But more broadly, I’d love to see more education at ASCO, large oncology symposia and conferences. It needs to go to the people who are not aware. It can't just be an echo chamber of people who have already been talking about this and are already knee-deep. It needs to reach the broader oncology community so that people realize that this is an issue that involves all of us and that we all need to be addressing. And like you said, even simple things around replacing language and saying people and making sure that the trial eligibility are broad, those simple things that individuals can do can. But I also think like NCCN and ASCO, we have to do something around the organizational levels to really make an impact. 

Dr. Ash Alpert: Yeah. And I think that the things that we talked about the we can do as individual clinicians, there’s the things that large institutions like NCCN and ASCO can do to sort of send out the inclusive messaging that is needed. And I think in the middle, we can create teams that are institutions of folks who we can be in allyship with to think about what are the most urgent changes that need to happen and the most feasible changes and start with those and then just keep going. Some of the changes that we make now will help us in the years to come, so I think being focused on the now and the future at the same time is helpful. 

Spencer Adams: I think that the teams within our individual institutions is really a great approach to this. When it comes to figuring out the next steps to be more gender-inclusive, I really think that institutions should get data from their community. They should understand the makeup of their community and see if that is something that aligns with the makeup of their hospital. Because we can go and talk about doctors getting training in trans care or more doctors of color being in your hospital to make the BIPOC community feel more accepting. But if we don't have teams whether it’s diversity, equity, and inclusion teams, or whatever you want to call it, that are willing to push to make policy change within the hospital, then there will be no movement. So, we really need to get people within their hospitals to give them the power to really push what has been taught for so long and really challenge the status quo and allow us to move forward with gender equity.

Shannon Westin: Well, I think that is the perfect mic drop moment, and I just want to thank both of my guests. Spencer, this was awesome and I always take copious notes when I talk with you all because I learn so much. It inspires me to try to do what I can at my institution and within the field of gynecologic oncology to make things better. So I hope that others who are listening are just as inspired as I am.

And to our listeners, thanks again for tuning into another episode of JCO After Hours. Please check out our other podcast offerings wherever you get your podcasts. Have a wonderful day.

The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and should not be used for the diagnosis or treatment of individual conditions.   

Guests on this podcast express their own opinions, experiences, and conclusions. These opinions do not necessarily reflect those of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.

Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO.

TRANCRIPT

The guest on this podcast episode has no disclosures to declare.  

Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, “Germline EGFR Mutations and Familial Lung Cancer.” It was published in the JCO on August 14, 2023. 

The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center. 

Welcome, Geoff.

Dr. Geoffrey Oxnard: Hi, Shannon. Thanks.

Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy.

Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff. 

Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time?

Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk.

Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me?

Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example.

Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk.

Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that’s pretty unclear? 

Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in. 

Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, “Well, I don't understand. Why is this sitting there?” And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics. 

Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”

Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.

Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.  

It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration. 

But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study.

Dr. Judy Garber: We were lucky that things were happening. The things you don’t expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?” 

I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff’s question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they’re around the country and that turned out to be true.

Shannon Westin: It's so fascinating, and I love how you kind of almost crowdsourced getting these patients to you because I was mystified because it's such a rare aberration and you had so many patients. Let's talk a little bit maybe about your patient population and who volunteered, and is it reflective of kind of you do think, the general population?

Dr. Geoffrey Oxnard: I want to give a shout out to the GO2 Lung Cancer Foundation. That really was a lot of the ‘rah rah’, getting people to know about this, having some word of mouth and spreading the word. And so certainly there are physicians around the country that have been like found patients that I've got to know because they sent us patients to study over the years. We ended up getting germline testing on 141 individuals who presented eligible for testing because of either a relative or a mutation that was suspicious for inherited. Most of those were enrolled remotely, in the end, as you might expect. We found what you might expect, that this was Mendelian in its inheritance, that if you had a first degree relatives, they had 50% chance of having this. And so we sort of slowly built these pedigrees of individuals who once they were positive, would refer in their relatives and say, “Please go get testing. Let's describe our family and help understand our risk.”  

It ended up boiling down to six individuals with a germline EGFR mutation from 39 different families. I remember one family where two different cousins presented separately to the program, not knowing each other was participating. And so, of course, there's not that many of these families around the United states, but we're really very lucky to have touched so many different individuals. What did we find? That if you had a germline EGFR mutation, your tumor almost always had an EGFR mutation. That really is the dominant biology of lung cancer that presents in these affected individuals, that it presents young, that the likelihood of developing lung cancer is around 55% by age 40 to 50. So it really is– I'm trying to make sure I'm quoting that right, actually, Shannon, I'm looking at the numbers here, but it was a really broad range of diagnosis. 

We had a 28-year-old who was affected and an 83-year-old who was affected. I saw a family where the grandson had lung cancer, but his father and grandfather who had germline EGFR mutations, did not. So variable penetrance. Judy, of course, told me, “Geoff, this is the way families present. Come on, Geoff.” But other families, incredible penetrance– not everyone having lung cancer, many of them smoking, some of them not smoking. But for these families, what a sense of empowerment to say, “Oh, this helps explain what's going on in our family, why this is happening at a younger age.” And helps explain the therapies that we had some concern about giving these potent EGFR inhibitors originally, understanding every cell in their body has this EGFR mutation. Are we going to somehow cause toxicity? No. These potent therapies can be effective, can be tolerated, and can work for many years. So we really feel hopeful that we've described a syndrome that's out there that people see and that has a distinct presentation, a distinct treatment pattern, and a clear association with lung cancer risk.

Dr. Judy Garber: And I think that now the opportunity is to say, can you find these people before they get their lung cancers? Some of them have abnormalities on scans. Think of it's like the APC, the polyposis coli of lung cancer. You can see these adenomas forming, but we can't really predict exactly who's going to develop tumor when. And that, I think, is a challenge that families have to help us with because we need to continue to identify some of these people who have not had cancer. They have children. They want to know what to tell them besides not smoking adamantly and maybe with some hopes that we're going to do some screening. 

I am afraid there probably is not good data that EGFR inhibitors could be used for prevention, but it's tempting to think that way. So there's plenty of work to do still to sort out the questions. This is the nature of genetics. We often find inherited susceptibility and people want to know, “Well, why would I want to know? What am I going to do about it?” And here I would say, “We're going to figure out what's your risk more specifically, and how can we help reduce that risk, in addition to telling you not to smoke.”

Dr. Geoffrey Oxnard: I do want to allude to Judy's comment about founder effect. I didn't tell you exactly about the presentation, but these families, first off, we only found germline EGFR mutations in Caucasian individuals and in black individuals, and it was mostly in the United States and in fact, enriched in the southeast United States. And don't get me wrong, we had enthusiastic participation from Vanderbilt. But still it seemed like there was more southeast United States prevalence. And even families I met in the Boston area would say, ‘Oh yeah, I have relatives going back to Arkansas.”  

And so we ended up with a bit of a suspicion for this geographic enrichment, studying the genomes of these affected individuals, and in fact did find a very large region of chromosome 7 that was shared in more than 90% of the folks we tested, suggesting a founder effect in the southeast United States, probably white and black. And that goes back hundreds of years, maybe 200, 300, 400 years, as far as we can estimate, making me think that this is a fairly unique syndrome that we're seeing in North America, but actually may not be prevalent in other parts of the globe. Though we did identify a single individual in Australia, it might be a unique phenomenon in North America.

Dr. Judy Garber: At least more common. But these days, people travel, so hard to know.

Shannon Westin: I don't know if you've gotten a chance to do this - any other cancer type seeming to be associated with this mutation?

Dr. Judy Garber: No, fortunately not.

Shannon Westin: Okay, very interesting. And what about outcome? What was the association, or was there any association of these mutations with cancer related outcomes?

Dr. Geoffrey Oxnard: I would say the survival of these cancers isn't that different than EGFR mutant lung cancers. If they get to effective therapy, they can live for years on therapy. If they don't, they can do quite poorly. One interesting finding is that they can present in a multinodular fashion that might be multiple primaries. And so you can kind of use an approach of eliminating individual clones. Sometimes it's been described these different tumors have different mutations, and so you might treat them like a stage IV lung cancer, but actually they lived for a long time because actually they had multiple stage I lung cancers, so it can present a little bit differently. And then we tried to collect CT scans on affected carriers who did not yet have lung cancer to see if they might develop lung cancer. It was not required on study, and it's sort of an area of future investigation. But as you can imagine, lots of lung nodules and certainly anecdotes of individuals where we found early precancers through the screening effort, motivating the investigation that Judy was alluding to.

Dr. Judy Garber: I think this is what you expect in inherited predisposition that you have an earlier chance. So some of them are younger, not the 84-year-old, but that they could be younger, that they could have multifocal disease, that their biology could be different, but could be the same, maybe accelerated, maybe not. Some of these are slower. And I think that's why we're excited to be able to continue this work with the group at Dana-Farber. 

Now, Jaclyn LoPiccolo is going to lead the INHERIT study, but much of the team is the same. And now the focus will be even more on trying to really quantify the risk and help think about prevention strategies and screening for these patients. It's a little tricky to want to do too much chest CT screening. On the other hand, there are lower dose CTs now, and we hope the guidelines will clarify the role of inherited risk. At ASCO this year there were a lot of talks about inherited lung cancer risk, but nothing is quite as well characterized as, I think, the T790M population.

Shannon Westin: Well, thank you all so much. This was fascinating. I learned a ton and I know our listeners did as well. And thank you to our listeners. This was “Germline EGFR Mutations and Familial Lung Cancer.” Again, published in the JCO August 14, 2023. So go check it out and check out our other podcasts on the website or wherever you get your podcasts. Have an awesome day. 

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this episode of JCO Article Insights, host Dr. Soldato discussed with Dr. Knikman and Dr. Cats the findings of a study that assesses the influence of fluoropyrimidine dosing based on DYPD genotype on both progression-free and overall survival. The article, featured in the December edition of JCO, presents groundbreaking and reassuring data. Furthermore, it highlights emerging research challenges aimed at refining the prescription practices of one of the most widely utilized chemotherapy agents, striking a delicate balance between safety and efficacy.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Davide Soldato: Welcome to this JCO Article Insights episode for the December issues of the Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Knikman and Dr. Cats, respectively first and corresponding authors of the manuscript titled "Survival of Patients with Cancer with the DPYD Variant Alleles and Dose Individualized Fluoropyrimidine Therapy: A Matched-Pair Analysis." 

Dr. Knikman is a clinical pharmacologist and assistant professor at the UMC Utrecht, while Dr. Cats is a gastroenterologist specializing in gastrointestinal oncology at the NKI in the Netherlands. 

Welcome, Dr. Knikman and Dr. Cats, and thank you for accepting our invitation today. 

Dr. Annemieke Cats: Thank you so much for the invitation.

Davide Soldato: So I just wanted to start by discussing the manuscript that you published. But before delving into the results of the manuscript that was published in the JCO, I just wanted to ask if you could give a brief overview of the DPD polymorphism and explain a little its relevance in the clinical practice. 

Dr. Annemieke Cats: The DPD polymorphism is very important in the metabolism of fluoropyrimidines. Fluoropyrimidines have been in practice for over seven decades now in the world and more than 2 million people received fluoropyrimidines in the beginning of this millennium. The indications for fluoropyrimidines have only been extended since then, so a lot of people are receiving this fluoropyrimidines. But with the good side of that there’s also another side and that is that there are a lot of side effects encountered by this chemotherapeutic drug. In the 1990s, it became clear that DPD was a key enzyme in the metabolism of fluoropyrimidines.

Dr. Jonathan Knikman: To better understand the toxicity associated which fluoropyrimidines are accompanied by, we have to take a closer look at the metabolism of fluoropyrimidines, and more specifically at the key metabolic enzyme which is dehydropyrimidin dehydrogenase, DPD in short. This enzyme breaks down the main active metabolite into inactive metabolites because 5-fluorouracil is the main active metabolite which is metabolized into inactive metabolites. However, if this enzyme does not function properly, this could lead to higher exposures of the active metabolites and subsequently more toxicity. This can be caused by mutations in the gene encoding for the DPD enzyme, which is the DPYD gene, and single nucleotide polymorphisms, so mutations in this gene can lead to less functional DPYD enzymes, subsequently can lead to more toxicity. 

Davide Soldato: So basically, patients that are harboring these SNPs in the gene encoding for the enzyme have a higher risk of toxicities. I think what is really important about the manuscript you published is that, apart from looking at the toxicities, side effects and pseudo profile among these patients who harbor these SNPs you also wanted to check whether this was associated with some reduction or at least with inferior clinical outcomes. The endpoints you selected were progression-free survival and overall survival. But I was really interested, and I think our readers and listeners would be interested in understanding a little bit the methods of the study. What was the cohort of patients that was selected? Was this a cohort composed only of patients with gastrointestinal malignancy or also different types of malignancies? And in this second case, if you included the patients with different types of malignancies, did you have any methods to be sure that there was not any differences among these patients at the very beginning? So basically, how you handled all the confounding factors that could potentially impact the analysis of clinical outcomes.

Dr. Annemieke Cats: To start your question, we have to go back to a previous study we performed, which was a prospective, multicenter study we performed in the Netherlands in 17 centers in which 1100 patients that had an indication for fluoropyrimidine therapy were included. In these 1100 patients, there were about 85 patients that were heterozygous carriers of a DPYD variant. What we did, we compared these two groups with each other, but before the DPYD carriers started, they had a reduced dose. The *2A variant carriers and the *13 carriers, they received a 50% dose, and the 1236 and 2846 they received a 75% dose. Those patients, a large amount of them consisted of patient with colorectal cancer, about 60%. And also breast cancer patients consist for a large amount of this group, it was about 20%. And then the rest were esophageal and gastric cancer mostly, and there was a group consisting of rare tumors as well like anal cancer. 

The comparisons showed that toxicity in the variant carriers was higher in the wild-type patients that received 100% dose. So despite those reductions, toxicity was higher in the carriers. But when we compared the variant carriers with historical controls, we saw that, especially for *2A, there was a large reduction of toxicity to a lesser amount. This was also the case for the 2846 variant carrier. But to a much lesser extent, there was a reduction in the 1236 carriers which worried us and this was the basis for a Clinical Pharmacogenetics Implementation Consortium (CPIC) to give a recommendation for starting for all these variant carriers with a 50% dose when treatment with fluoropyrimidine was indicated.

Davide Soldato: Thank you very much for the clarification. So basically, you started from one previous prospective study that was composed of a mix of different cancer types. And then in the study that you now published in the Journal of Clinical Oncology, you also added an additional part of patients who were carriers of this variants. I imagine that there was some variability between patients who were carrying the variants and those were not carrying a variant. So I wanted to understand a little bit, did you perform a matched analysis or did you try to be sure that there was not any confounding factors that could impact the results?

Dr. Jonathan Knikman: Yes, we performed an exploratory retrospective matched-pair analysis and we used a matched-pair analysis to select patients which are comparable between the DPYD variant carriers and the DPYD wild-type patients to ensure that on the most important factors, they were comparable and outcome was also comparable. In this matched-pair analysis, we compared progression-free survival and overall survival between DPYD variant carriers treated with the reduced dose and DPYD wild-type patients treated with the full dose. We matched these patients on five matching variables which were primary tumor type, stage of cancer, age within a range of plus or minus 10 years, sex, and treatment regimen to ensure the these patients as comparable as possible.  

Davide Soldato: And so now, moving on a little bit to the results, what were the results in brief regarding progression-free survival and overall survival for patients who were harboring a variant in the DPYD gene and those who were wild-type for this gene?

Dr. Annemieke Cats:The results of our study showed that there was no significant difference in progression-free survival and overall survival between the DPYD variant carriers pooled as one group, treated with the reduced dose, compared to wild-type patients treated with the full dose. This suggests that DPYD-guided dosing can be performed safely without compromising treatment effectiveness. However, when we take a closer look at the individual variants, our study showed that progression-free survival and overall survival were not negatively impacted by DPYD-guided dosing in the 2846 and the DPYD *2A variant groups. However, in the group of 1236 variant carriers, we did find a significant difference in progression-free survival with a hazard ratio of 1.43, indicating that progression-free survival  was shorter compared to the matched wild-type patients treated with the full dose. However, no difference was found in overall survival.  

So based on results on this study, we can conclude that DPYD-guided dosing can be used while treating patients with fluoropyrimidines without compromising effectiveness and improving safety. However, when patients do not experience toxicity or experience minimal toxicity, it is important to escalate the dose guided by toxicity to ensure maximum exposure to the treatment. 

Davide Soldato: Thank you very much. That was a very comprehensive overview of the results. I was really wondering regarding the variants in the 1236. So the one that you said was associated with a shorter progression-free survival. At the very beginning, Dr. Cats very well explained that in the first prospective trial that was done, among these patients, toxicity was still higher or they experienced more severe toxicities, even with a 25% dose reduction compared to what was planned. So I was wondering if you could speculate a little bit. Do you think that this reduction in the progression-free survival might potentially be associated with these higher rates of severe adverse events, and that maybe this has created a little bit of a gap in the adherence to chemotherapy?

Dr. Annemieke Cats: We looked into the mean dose that the 1236 variant carriers received, and this was about 75% of the dosage. So the dosage was what the protocol prescribed for the study. And also the number of cycles did not differ from the wild-type patients. So, I think the patients did not stop earlier with their treatment than was intended to. What we did see however is that in the whole group, only 10% of the variant carriers had some kind of dose modification, which could be both an increase of the dose or a reduction of the dose. So, there were only a few patients where the dose was modified. We know that the 1236 variant carriers are a very heterogeneous group. DPD enzyme activity also shows a wide range, ranging from normal to very low dose even we described a patient with a homozygous 1236 mutation. And we would expect that there would be no DPD enzyme activity, but there was still some activity in this patient. 

Davide Soldato: That's a very good insight on this particular topic. So, just related to the conversation that we were just having, do you think that in general, for all DPD variants, and in particular, as we discussed, for the 1236, do you think that genotyping is sufficient for now to understand which is the right dose for these patients, to balance toxicities and to obtain the best clinical outcomes? Or do you think that we need more sophisticated or more integrated types of monitoring? Should we, for example, in the 1236, look more carefully at pharmacokinetics and so understand if these patients can receive higher doses because maybe, as you were saying, the activity of the enzyme is really higher than what we are expecting based on the genotype? Do you envision something like this happening in the future, or do you consider it as a potential line of research on this topic? 

Dr. Jonathan Knikman: It's a very interesting question, and it's something we've thought about a lot. At the moment, I think genotyping is the way to go and is the most robust and most validated method currently available with fluoropyrimidines. And I think it's a bit of both. Currently, as mentioned, I would recommend DPYD genotyping, and also in the 1236 variant carriers, as we have seen in previous studies, that toxicity is still increased even while administering 75% dose instead of a full dose. So we see that there's still more toxicity. However, our study also shows that progression-free survival is shorter compared to wild-type patients. So, it's quite a complex situation as we still have more toxicity, but the progression-free survival is also shorter, and that's where we would advise the dose escalation part. So, I think it's a combination of genotyping and escalating the dose when possible, if there is no toxicity or limited toxicity, to ensure maximum exposure and to minimize the effect on progression-free survival while still trying to reduce toxicity.

Dr. Annemieke Cats: This is a very important question because we do not completely understand why toxicity is higher in the 1236 with a 25% dose reduction that may compromise progression-free survival. So we have to look in closer detail, and currently we are looking in closer detail to what do we have for a pharmacokinetic analysis, that you mentioned. What about DPD activity, enzyme activity? Can you titrate on that? And I think for now, it still stands that we should start with a 50% dose, but with the possible effectiveness of the dose in mind, you should go with an early titration, and I would say something about 25%. Although having said that, I have no data to underline this. And if you have the possibility to go for DPD enzyme activity in addition to genotyping, that would also help you to titrate doses on that. And that's where we stand now. But we need to know why these 1236 variant carriers have such a large range in activity and toxicity.

Davide Soldato: I also think, and I can ask you if you agree with me, that this analysis is really very important because I think it's one of the first reports regarding the analysis, specifically of progression-free survival and overall survival based on variants of DPD. But at the same time, I think that we also have to underline for our listeners that this was still a retrospective and exploratory analysis. So it's true that you observed this association with shorter progression-free survival. But still, I think that we will need also more core studies to validate these findings and to be really sure and also to perform additional analysis as to what the mechanism is as you were saying. I don't know if you agree on this limitation of the study, despite its importance in regarding clinical outcomes.

Dr. Annemieke Cats: We certainly agree with you that we have to keep in mind that it is an exploratory, retrospective analysis. Having said that, a randomized controlled trial certainly has some difficulties in it as well. Nowadays, it is not feasible to give patients with a DPYD variant a full dose. In 2018, there was a lawsuit in Oregon, and now recently in Ontario, Canada. There's also a lot of rumor in the news because of patients getting a full dose while having a DPYD variant. So the lethality of the toxicity in some variant carriers makes it not ethical to perform a randomized controlled trial. So we have to look for different designs that reflect real-world data and learn more about the genotype and also in different ethnicities. It is also very important because what we have studied considers the white population mostly and that's also a direction that future research should go to. 

Davide Soldato: Thank you very much. That was very insightful, especially the last part regarding ethnicity and the possibility that also these variants might be different according to that. 

So I think that the main message that we should pass is that when prescribing fluoropyrimidines, genotyping of DPD is fundamental because toxicities among patients harboring these variants can be severe and can also be lethal. You performed this retrospective exploratory analysis that provided us with overall reassuring data. There is still more research to be done, especially for the 1236 variant. So I think that that probably is our bottom line and main message for our listeners. 

And I just had one final question because in the manuscript that you published, you had localized, locally advanced, and also metastatic cancer that were all grouped together. Do you think that an additional line of research would be to specifically look at how these impactful outcomes only in the locally advanced and localized cancer compared, for example, with the metastatic?

Dr. Annemieke Cats: You raised a very good point because there is a lot of variety within this study, and now you're mentioning locally advanced, local, or metastatic cancer. It's also within the cancer types. We studied different cancer types as well to reach a large amount of patients. It would be good to have a more homogeneous population that you can derive your conclusions from. So, I think that would certainly help us in the future, and we should look into whether we could do this together because before we had such a large population, we would need several countries to work together. 

Davide Soldato: Yeah, you're totally right. Thank you very much for underlining that last point. 

Thank you very much, Dr. Knikman and Dr. Cats, for being here with us today and for explaining to us and our listeners the results of your research. That concludes this episode of JCO Article Insights. We discussed the manuscript titled "Survival of Patients with Cancer with DPD Variant Alleles and Dose of Individualized Fluoropyrimidine Therapy: A Matched Pair Analysis." This is Davide Soldato, your host. Thank you for your attention, and stay tuned for the next episode. 

The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin and her guest, Dr. Michael Anne Kyle and Dr. Nancy L. Keating, discuss the paper "Prior Authorization and Association With Delayed or Discontinued Prescription Fills" recently published in the JCO.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare. 

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that goes in depth on articles and manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. And as always, I'm so excited that you've joined us, and none of the authors have any conflict of interest today. We are going to be discussing a very exciting piece of work, “Prior Authorization and Association with Delayed or Discontinued Prescription Fills,” recently published in the Journal of Clinical Oncology. And I'm thrilled to be joined by the two authors of this important work. The first is Michael Anne Kyle. She's a PhD research fellow in the Department of Healthcare Policy at Harvard Medical School. 

Welcome, Michael Anne. 

Dr. Michael Anne Kyle: Hi. Thanks for having me.

Shannon Westin: We're so excited. And the second is Dr. Nancy Keating. She's Professor of Healthcare Policy at Harvard Medical School and Professor of Medicine at Brigham and Women's Hospital in Boston.  

Welcome.

Dr. Nancy Keating: Thank you. It's great to be here. 

Shannon Westin: So, we'll get right to it. First, I always like to level set because we have such an interesting and diverse audience. Can one of you describe the process and goals of prior authorization? What does this mean for our groups that maybe haven't experienced this? Lucky them. 

Dr. Michael Anne Kyle: Prior authorization is- the process can take many forms. Basically, what we're describing is before you can be prescribed a treatment, in this case, we're looking at medications, you have to submit a request to the payer, to the insurance company, asking for approval to receive that treatment, or in this case, that drug. The doctor's office does have to do a ton of work, but very often, the patient also receives a lot of the communication. So, there's a lot of work for everybody in prior auth often. And the uses of it- in principle, the purpose of prior authorization is to confirm that the reason this medication or this treatment is being prescribed is because the patient meets the criteria for need. So that can mean, you want to confirm that you have the right tumor markers for the drug that's being prescribed. You want to confirm that you are aligned with guidelines. And then I think the thing that's often on many people's minds is that in the US, we don't have a lot of controls on drug pricing, but drug prices are very high. And so, I think we often think about prior auth as being a mechanism to try and contain costs. 

Shannon Westin: And this isn't new, right? So, this is a process that's been going on for a while. I'd love to hear you speak a little bit about, maybe, some of the changes, like how have the requirements for prior authorization been changing over time, especially for patients with cancer?

Dr. Michael Anne Kyle: That's a great question. And that was the first step we took in this work because we've heard from oncologists, from patients, from researchers, that prior auth has been increasing. And we did find, looking at Medicare data, that that is true, that the use of prior authorizations for oral oncology drugs, so that will be Part D outpatient drugs you get at the pharmacy, has been rising over the past decade. And I think what's really interesting to point out here is we found the use of prior authorization increasing both for branded drugs and for generic drugs, and for specialty drugs, which are high cost, as well as non-specialty drugs, which are typically lower cost. So, across the board, prior auth is increasing. And why is this happening really is the million-dollar question. Some of it is surely like we have accelerated approvals happening predominantly in oncology. So, you could imagine that you do need to verify some evidence of these newer treatments, but some of it is a little bit harder to interpret. And that was one of the things in our paper that we were very interested in because we also see a lot of prior auth on drugs that have a very well-established record of efficacy. And we know our first-line therapies often now include some generics, and yet we still see that they have prior auth. And the reason for that is less clear.

Shannon Westin: Yeah. Just as a gynecologic oncologist, coming from this standpoint of PARP inhibitors, which have long been established as a standard of care and for years now have been a frontline treatment, we're getting so much pushback around that, and it's a huge issue because that impact of delays and things, and I know that's your work. So, I think that's one of the reasons I was very enthusiastic about this because I think it has such broad-based impact across all of our patient populations.  

So, I think that kind of definitely transitions into this. What are the potential negative impacts in this process of patients? And I would say not only patients with cancer, but what do we know also in patients with other disease types that are facing this prior authorization issue as well?

Dr. Michael Anne Kyle: What we were curious about is there's a sense that prior auth is increasing, the trends show it's increasing. And we were wondering, does that matter for patient care? And we could think about the benefits of prior authorization being like double-checking that you're getting the right treatment. But the negatives are that you can be delayed in getting treatment, and that can either be because you're going through the initial process or there can be some error or denial or dispute in a prior auth process that delays your access. And the clinical implications of that would vary by drug, how that would affect your treatment. In this case, in this paper, we're talking about drugs, but for any treatment, the implications would depend on what the treatment is and what the patient's condition is. But I really want to draw attention to this other piece, which is that it's stressful not to have your cancer medicine. And so even if you ultimately end up getting it, the time that you're on the phone trying to figure it out is time taking you away from other things. It's stressful. And very often, patients with cancer are taking multiple drugs and have complex health issues. So, they may be dealing with this for multiple parts of their care. And that can add up.

Shannon Westin: Perfect. Thank you. So, I guess next is to talk about how you address this. Let's talk a little bit about the overall objectives of the study that you just published and maybe briefly kind of go through the design for our listeners.

Dr. Michael Anne Kyle: What we were interested in doing, like I said, was trying to figure out what happens with prior authorization at the point of care. And our study looks at 11 oral anticancer drugs in Medicare Part D. And the reason for that is because data available to look at prior auth is fairly limited. And Medicare Part D for the outpatient formularies does have indicators for whether a drug has a prior auth. So, we were able to use that. The next piece is we're not inside the office understanding why these treatment decisions were made. So, what we decided to do was say, “Okay, let's look at patients who've been consistently taking this drug.” And we said, “Okay, let's say you've had to have at least three fills in the past four months.” And we sort of take that as an indicator that you're able to access this drug and it seems to be working for you. And then what we do is we look at who are patients in plans, same drug, same plan, where the plan introduced a new prior auth on this drug they're taking, as compared with patients in plans who did not have a change in their prior auth policy. And we said, “Okay, there's this new prior authorization introduced, does that affect whether you get that next fill or how long it takes to get it?”

Dr. Nancy Keating: I want to emphasize Michael Anne's point about these are patients who are already successfully filling and regularly taking their drugs. And unfortunately, due to data limitations and the inability to see prescriptions that aren't filled, we would love to look at the same question with people that are starting on a new drug but weren't able to do so but would imagine that you might even see bigger impacts in those patients. We both recognize from a health policy standpoint that there could be benefits of prior authorization policies. But it's also very unlikely to think that for a patient that's regularly filling an anticancer drug over a long period of time, that there's a reason that that patient should not be on that drug. And so, this is an area where we think that there may be really limited benefits of prior authorization, but potential harms. 

Shannon Westin: Yeah, it makes sense. And of course, it would be. There's always the ideal way to set research up, and then a practical way. So, I was struck by what you chose. I thought it was really very practical and rational and made a lot of sense. And certainly, there are inferences that we can make based on what you found. So, let's talk about that. Let's talk about your primary findings. What did you see as the impact of a new prior authorization policy on patient care?

Dr. Michael Anne Kyle: We found that for the patients who had a new prior auth policy introduced in their plan, compared to patients who didn't have a prior auth change, their odds of discontinuation within the next 120 days increased by about 7.1 times higher odds of discontinuation. And then for delays, we found that people were delayed an average of 9.7 days from when we last saw that they were expected to run out of their drugs based on their last fill, we said, “Okay, what's the last day we expect you to have meds on hand, and then when do we actually see you fill again if we see you fill? And the average delay there was 9.7, about 10 days. And that's a fairly conservative estimate that we decided to make. And I'm sure you and Dr. Nancy Keating can elaborate on how that's not just passive time. There's a lot of people scrambling around, probably in that interval, trying to close the gap.

Shannon Westin: I mean, you said it, like, 10 days. It's a huge time. And it's not just time sitting there twiddling your thumbs. They're probably stressing, anxious. They might be having side effects related to stopping their medication. They might be taking other medications and reduce the efficacy of the combination. I mean, there's so many implications here of the impact.

Dr. Nancy Keating: They're also calling the office, trying to get through to the office. Then the doctors are calling, trying to get through. People are like, what's going on here? Why isn't this medicine there? And so, there's a lot of individual patient and clinician effort that's happening at this time as well.

Shannon Westin: And I think, of course, you were limited by the databases that you were using and what you're able to access, but I think it really does make me wonder, what's the impact on cancer related outcomes. We know about delays in certain therapies and things and how that can negatively impact survival and response and all of those types of things. And I wish we did have access to that kind of data because obviously the time and the things that you've been able to demonstrate are important, but the more objective data we can get around patient outcomes, I think will help us impact the actual policies that are being implemented here. 

Dr. Nancy Keating: Right. And just to underscore too, Michael Anne highlighted the delays, but also there was a substantial increase in discontinuation within 120 days. So, there are some people that seem to not be able to get the med, maybe found another way to get it, or maybe were able to get samples from a drug company that we couldn't observe, but that's also concerning that there might be some people who fell through the cracks.

Shannon Westin: A very good point. I think that it's hard to know, but the potential there of losing the drug that's actually working for you is really distressing for providers and patients both.

One other thing I noticed that was interesting. Can you speak a little bit about some of the other factors that were associated with these findings with the treatment delays and what other things may be impacting these outcomes?

Dr. Michael Anne Kyle: We looked at some patient characteristics and insurance characteristics that may be associated with delays. And I just have to note here that our sample is fairly small because prior authorization is so prevalent. There aren't a lot of switchers. So, this sort of limited the amount of depth we could go into. But here's what we can tell you, which is that people who are under 65, so in Medicare that will typically be people who have eligibility through disability, were filling about a day later than that 9.7 average people, female sex also filling 0.7 days, nearly a full day later. Similarly, and this is compared to males and then compared to white, non-Hispanic patients, patients who are black and patients who are Hispanic Latino are filling about 0.6, 0.7 days later, which is, of course, quite concerning, given our desire to have a more equitable health care system. And then finally, we linked our data to census data. And for patients living in a residential zip code with higher rates of poverty, we found that for each 10-percentage point increase in proportion of residents in that zip below the federal poverty level, the delay was about 2.5 days. So, what you can sort of take from that is the risk factors in particular are in Medicare being younger, which I would say is having a disability, female sex, non-white, and people living in high poverty zip codes. And given what we know about racial segregation, I think the odds are likely that the patients themselves would potentially also be low income.

Shannon Westin: That's what's so important about this work, is it raises an awareness of, really, who's being impacted by this. Because I just want to draw back to kind of what you said at the beginning, that this is meant to do cost containment. It's meant to help the healthcare system. But what we're seeing in practice is it may be helping in some specific areas, but it's certainly creating quite a detriment. So perhaps there are other mechanisms that we could be exploring from a policy standpoint to try to work on cost containment, but not put the burden on the patients or on the people that are giving this health care. So, I think that's why I was so struck by this work. 

I guess the next question is, what are your next steps for the research, and how can we use these data to help the patients?  

Dr. Michael Anne Kyle: What a great question. I'll start, and then I'll let Nancy give her thoughts too. We're lucky that prior authorization is a very active policy area right now, both at the state and federal level. There's a great deal of interest in sort of certainly improving a lot of the information systems. Perhaps we can move away from the fax machine finally in 2023. I think there's a lot of policy relevant action happening around trying to make prior authorizations electronic, and you can automate them and make a lot of this move faster. There are also larger questions about what is the right price for a drug and how do we distribute it to people that I think are a lot more fundamental than any one study, but I think this is just another way. When we think about financial toxicity, there's just many challenges that come back to some way to this root cause of care is very expensive, and this is, I think, prior auth is one of the side effects of that. 

And so, hopefully, to help patients, we can get this data in the hands of policymakers who are trying to bring us to a more modern prior auth system. And hopefully also to payers, I would be very excited to see a little bit more examination of, like when is prior auth appropriate versus when is it not. I think there are cases where prior authorization is very appropriate, and we shouldn't take it away. But one of the drugs in our study is generic imatinib, and perhaps that is a lower value prior auth. And so, I'd be very interested in seeing payers think more strategically about when is prior appropriate, both to improve access and improve equity, and then also to improve the provider burnout and the poor docs who are really struggling under the weight of this.

Dr. Nancy Keating: Yeah, I couldn't agree more with everything that Michael Anne said, but really, we'll underscore that last point. The prior auth policy seems like it's this very broad policy and the way that it's implemented, it's sort of like, let's just hit everything and not take a nuanced, thoughtful approach. But just like Michael Anne said, generic imatinib, really? And then back to this point of patients that are doing well on a drug, people are not going to be taking anti-cancer therapies if they don't need to. And so there just doesn't seem to be any reason to implement a prior authorization policy on a drug that is being well tolerated. And so really, I think there could be a lot more thought and nuance put into applying these policies within health plans.

Shannon Westin: Yeah, I think that's a perfect way to end this. I would just add, I think this is beyond anticancer therapy for our patients with cancer. I mean, we're seeing it now with supportive care medications. And to your point, I mean, generic antiemetics, and you're like, come on, this is ridiculous. So, I think that this type of work is- the best type of work always spurs more questions and gets us fired up about what to do next. So, I just want to again commend you on all of this important work, and we need to add more data here so that policy will change.

And so, thank you both for your hard work in this area and for taking the time to educate our listeners. I'm sure we're going to hear a lot of intriguing questions for you about this work, and hopefully that'll move our policy forward.  

And thank you, listeners, for checking in again with JCO After Hours. Again, we were discussing prior authorization in association with delayed or discontinued prescription fills. I'm so grateful to Dr. Kyle and Dr. Keating for joining me today, and I hope you all will listen to our other podcast offerings wherever you get your podcasts. Have an awesome day. 

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and it is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO.

TRANSCRIPT 

The guest on this podcast episode has no disclosures to declare.

Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade.

And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023.

And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome.

Nanda Horeweg: Thank you. Happy to be here.

Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well.

Carien Creutzberg: Thank you.

Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer?

Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years.

Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%.

Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population?

Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy.

And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival.

Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2.

And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years.

Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of.

So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer.

Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups.

And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis.

Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis.

And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups.

And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal.

Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group.

Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone.

So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place.

So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies.

Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point.

Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2.

So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control.

And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile.

And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients.

Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study?

Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality.

In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases.

So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response.

So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed.

And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2.

Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers?

Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something.

And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials.

So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment.

Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all.

This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different.

So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer.

And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant.

So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT.

Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most.

So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding.

So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients?

Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe.

And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe.

So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on.

Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial.

Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients.

So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this.

Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming.

So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, like in the UK and the Netherlands, it's being reimbursed by healthcare insurances, and also, in many tertiary care centers in other countries, they're already systematically performing this test.

But of course, there will always be places where this is not feasible. And luckily, there are also cheaper alternatives coming up and are already available at the moment. So, one of them is, for example, standard sequencing, which is not so expensive, but a bit labor intensive.

Some colleagues we work with from India have implemented that in their clinical practice and are perfectly able to molecularly classify the endometrial cancers in daily practice.

Another alternative is a test that we've developed in Leiden that's called the QPOLE test, which is based on qPCR, so that's a technology which we use for our COVID test around the world, so that can be done almost anywhere. And with that, you have a very high accuracy to detect unknown pathogenic variants.

And this is also published in JCO Global Oncology, and can be implemented in any center after a local validation step. And even like more companies nowadays are realizing that this is important. So, I think commercial tests are already becoming available and very more on the market soon. So, I am really hoping that it'll be more available to endometrial cancer patients.

Carien Creutzberg: And they'll offer them at a very low cost and also a rapid turnaround because NGS can take like 10 days. But realizing on a more national level, if you have found one patient with a POLE mutation, the omission of cycles of chemotherapy with all of the patient care around in the hospital is worth much more than just a few POLE tests.

So, we have to look at this and that's I think why our healthcare reimbursement came through that if you look at a population level, it is cheaper, and we'll do an extensive cost analysis in PORTEC-4 just to show this.

Shannon Westin: That is such a good point. I love that and all of the downstream issues that happen potentially with radiotherapy or with chemotherapy, that's really brilliant. And I'm going to take that back, I love these podcasts. I always learn stuff that I immediately start to use.

So, I guess then the last question is, what's next for this particular research and how might we validate what you found?

Nanda Horeweg: Yes. Well, as mentioned earlier, for POLE, we have already put the next step in place. So, PORTEC-4a has completed accrual almost two years ago, and we're very much looking forward to do the final analysis within one to one and a half years.

So, that will be one of the important next step. And of course, the POLE-BLUE trial is open at the moment, and within a couple of years, we also hope to learn more about this group. So, that's very exciting.

Then for the mismatch repair deficient group, while we did not find any particular sensitivity for radiotherapy, and I also don't think that we will conduct another large randomized radiotherapy trial in this group — I think the results that we've observed in the metastasized setting, were really impressive results with immunotherapy are the way forward for this molecular class.

And I think the next thing we should do now is prove whether this works or not in the adjuvant setting. And if that's starting with the high-risk patients, which is something we are currently doing in the MMRd-GREEN trial, which is ongoing in the Netherlands, and soon, will open internationally. And from there on, we can work forward if we see that also in this setting the immunotherapy works well.

Shannon Westin: And I think GY020 also — NCI trial is also looking at the addition of immunotherapy to radiotherapy in that irony at risk.

Carien Creutzberg: Absolutely.

Nanda Horeweg: Yeah. And the KEYNOTE-B21 as well — oh, well, already complete accrue.

Shannon Westin: The B21, yeah. So, I think those are good. Yeah, that's a really good point for that MMRd group that the immunotherapy really is the way to go, and then more work to be done with the no specific molecular profile.

Nanda Horeweg: The NSMP, I think like for the early-stage group, it's quite clear that vaginal brachytherapy is a therapy of choice. But you can of course, try to identify those at such a low risk that you could deescalate treatment. And that's of course what's being done in the Taper trial and also in part, investigated in the PORTEC-4a trial.

Carien Creutzberg: And those with higher risk NSMP that we are revisiting hormonal treatments because 90% are estrogen receptor positive, and they have a clearly better prognosis than those with estrogen receptor negative tumors.

So, those with estrogen receptor positive tumors can in RAINBO-ORANGE, which will be run led by the UK group, see if we can improve quality of life with less intensive adjuvant treatment. And then you came to the p53 group, that's a good one to stop with.

Nanda Horeweg: Yeah, we have very good indications that radiotherapy and chemotherapy is working well for this group. And this is also in line with the guidelines that have been issued in the last few years by many societies. So, I don't think we should change this base of the treatment consisting of radiotherapy and chemotherapy.

But since the prognosis is still rather poor, we need to add systemic agents to reduce the risk of metastasis. And preferably, this should be like well-designed based on a proper biological underpinning, plus something that's not too toxic since we're combining the three therapies together.

So, this is what we try to do in the RAINBO-RED trial where we will investigate the addition of a PARP inhibitor to chemoradiation in the p53 group.

Shannon Westin: Oh, I love that. That's been my whole career, is adding PARP inhibitors wherever I can.

Carien Creutzberg): We might also want to mention the HER2 inhibitors, which are also in about 20% of the p53 group has HER2 overexpression. And there is a trial being set up in NCI with trastuzumab and pertuzumab.

Shannon Westin: My only concern with that one is I think that the antibody drug conjugates are so much more powerful, the TDX data that we just saw from DESTINY is so impressive. And so, I do wonder, like if we need to move on from kind of some of the older HER2, and get with the program and use some of these more powerful drugs.

But with that, I just want to thank Dr. Creutzberg and Horeweg. This was such a great discussion, and obviously, near and dear to my heart talking about endometrial cancer, but I hope our audience enjoyed as well.

Just as a reminder, this was a discussion on molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early stage endometroid endometrial cancer, published in the JCO on 9.20.23.

I am your host, Shannon Westin, and I hope you'll check out more JCO After Hours wherever you get your podcasts. Have an awesome day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions.

Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects.

In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization.

The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions.

The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration.

So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation.

The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively.

Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants.

Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting.

Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser.

Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death.

The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively.

Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer.

While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis.

All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors.

The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study.

In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial.

Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone.

More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe.

In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression.

No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients.

Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia.

For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity.

Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group.

Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events.

So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment discontinuation. These findings are in line with previous data obtaining the metastatic setting with other CDK4/6 inhibitors, and support the existence of a different pharmacodynamic profile influenced by BMI that translates in a more favorable toxicity profile.

At present, differences in BMI do not seem to affect palbociclib efficacy, but further analysis with additional follow-up time and events, as well as by type of endocrine therapy administered are planned in the PALLAS study. That concludes this episode of JCO Article Insights.

In these episodes, we summarized findings from two studies, the first titled, Pan-Cancer Analysis of Postdiagnosis, Exercise and Mortality by Lavery and colleagues. This trial shows that higher level of exercise are associated with lower risk of all-cause cancer specific and other cause mortality, although with some differences according to cancer site.

The second article titled Impact of BMI in Patients with Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial by Dr. Pfeiler and colleagues observed a significant different side effect profile for palbociclib according to BMI, but no differences in efficacy.

This is Davide Soldato, thank you for your attention and stay tuned for the next episode of JCO Article Insights. 

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions.Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we’re discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work. 

Welcome, Dr. Schapira. 

Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you.

Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who’s going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he’s the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez. 

Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work. 

Dr. Shannon Westin: Thank you. And congratulations to you. 

Dr. Schapira, thank you for being here and please do take it away.

Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first.

Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it’s been that way for many, many years.

Dr. Lidia Schapira: And how effective is the regimen?

Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes. 

Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities? 

Dr. Ramez Eskander: What we’re seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that’s really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we’ve really gone away from that, and now we understand that we’re seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it’s created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that’s important as we look to identify treatments strategies that are both effective and tolerable.

Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that’s changed the thinking and the design of the studies?

Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it’s important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that’s even evolved; some people term it TP53 wild type. That’s a bit of even a heterogeneous cohort amongst itself. So we’re going to take these subsets, independent of POLE and an MSI-high, and we’re going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it’s really revolutionized how we think about these patients, how we think about the disease, and how we design trials.   

Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we’re really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we’re going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we’re still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it’s going to be borne out as other clinical trials report.

Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E.

Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance. 

But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control.

Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort. 

Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust.

Dr. Lidia Schapira: So tell us the results.

Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling.

Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results? 

Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the  AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly.

Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found?

Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.  

The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space.

Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us. 

The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question.

Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez.

Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation.

Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important.

Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities.

Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps?

Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients.

Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs?

Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it. 

And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data.

Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you.

Dr. Ramez Eskander: Thank you.

Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here. 

And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, Davide Soldato interviews Dr. Jacob Sands, medical oncologist at Dana Farber Cancer Institute (Boston, MA) and Assistant Professor at Harvard Medical School, on their paper “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01”. The interview offers a deep dive into the safety and efficacy data of this novel drug and puts these data in the context of the current treatment landscape of NSCLC and of the revolution that ADC are bringing into the oncology world.

TRANSCRIPT

Davide Soldato: Welcome to this JCO Article Insights episode for the October issue of Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Jacob Sands, co-author of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.” Dr. Sands is a Medical Oncologist working at Dana-Farber Cancer Institute in Boston and Assistant Professor at Harvard Medical School. His main field of research and clinical interests revolve around improving screening and diagnosis of lung cancer and also on developing novel therapeutic agents for this disease. 

So, welcome Dr. Sans, and thank you very much for accepting our invitation today. 

Dr. Jacob Sands: Happy to join. Thanks for having me.

Davide Soldato: I just wanted to start with a very general question because I think that we are going to discuss a very important study and the manuscript that you co-authored is going to look at the safety and the efficacy of this novel ADC datopotamab-deruxtecan that is targeting TROP2. But I just wanted to have a little bit of context before starting to discuss the safety and efficacy data. So the population that was included in the study included more or less 60% of patients that received three or more lines of therapy and also 20% of patients who received five or more lines of therapy. So I think that this is a very particular population, especially considering that we are speaking about non-small cell lung cancer. And so I wanted to get from you like a general context, like what are the therapeutic options for these patients normally in clinical practice and what do we expect in terms of outcomes and in terms of toxicity?

Dr. Jacob Sands: Yeah, so as you point out, this is a highly pretreated population in general, which is to say that they've really gotten the most effective lines of treatment up to this point. Now, we certainly do see some efficacy from some of the later lines of therapies in some patients, but inherently there is a decreasing response rate and decreasing durability of these responses as patients get further along in their treatment courses as far as lines of therapy. So it's generally considered to be a challenging clinical scenario, which is part of what makes the data that we're going to discuss, I think, so meaningful. 

Davide Soldato: Yeah, I think that especially if we look at the population that was included first, I think that the very particular thing is that included both oncogene-addicted and non-oncogenic addicted patients, and also the great majority of these patients received the most effective treatments that are available because they all received more or less immunotherapy and platinum-based chemotherapy, if I'm not mistaken.

Dr. Jacob Sands: That's right. And that's an important distinction that you're drawing in the patients with oncogenic drivers and, of course, there's plenty of data with this compound with Dato-DXD in that population as well. But broadly speaking, in the non-oncogenic actionable alterations where they've gotten chemo-immunotherapy, those really are the most meaningful. Of course, docetaxel has been a long-standing second line that I'd say there is less and less enthusiasm about that as a line of treatment as we've seen some of these other more novel therapies that have just a better toxicity profile in particular, but also some with really durability that we don't quite see with docetaxel as well. And so once you're getting past that, you're really now reaching a bit deeper to then have something that is well tolerated and has efficacy. That's a setting where we really need it even more. 

Davide Soldato: So, going back to the results of the study, as we kind of pointed out, this was a very standard classic with a Bayesian design, phase I dose escalation and dose expansion study of this novel ADC datopotamab-deruxtecan. So I just wanted to go over with you and to provide our listeners a little bit with some data regarding the doses that were explored and then what were the doses that were selected for the expansion. And also to discuss a little bit the safety data. We were discussing the tradeoff between risk and benefit, especially in patients that are very pretreated, searching for these kind of sweet spots between the toxicity and the efficacy. So I just wanted to put in context a little bit the data that you reported in the manuscript.

Dr. Jacob Sands: Yeah, that's right. So, like phase I’s go, we started with a low dose at 0.27 milligrams per kilogram, and dose escalations occurred up to 10 milligrams per kilogram. The 10 milligram per kilogram dose did have toxicities that really made it not considered to be tolerable, and that mostly being mucositis and skin. And so it was then back down to 8 milligrams per kilogram. And then there was a dose expansion at 4, 6, and 8 milligrams per kilogram. The 4 and 6 milligram per kilogram doses had 50 patients enrolled within those cohorts and 80 patients within the 8 milligram per kilogram cohort to then get much more data, of course, for efficacy and tolerability within those levels. Ultimately, each of them really demonstrated some efficacy as well as general tolerability. The 6 milligram per kilogram dose was really the one selected overall for further testing and future trials based upon the data out of this one that we're going to discuss further.

Davide Soldato: What were the main side effects that you observed in the trial? And particularly, do you think that there is some kind of special toxicity that should be looked at when using this novel type of ADC?

Dr. Jacob Sands: Certainly there are some novel toxicities to really pay attention to. And maybe I'll just point out before diving into the toxicities, that this is in many ways chemotherapy. The antibody drug conjugates, as listeners probably know, are an antibody that has a linker bound to chemotherapy, what's called the payload. And in this case, it's a topoisomerase I inhibitor with the antibody, the TROP2. So the cells on the surface, when there's TROP2 expression, the drug binds to that, gets pulled into the cell and releases that chemotherapy intracellular, but it is still chemotherapy. And so some of the toxicities are things that we commonly see with chemotherapy drugs. Although, broadly speaking, I would say we're able to deliver higher doses of that chemo to the cells in this kind of targeted dosing of chemotherapy to give the chemo intracellular.  

Now, that being said, some of the toxicities that we see from this drug in particular that are a bit different is the stomatitis, mucositis. That is something that has occurred. Now, I've found that if it's really severe, then with a dose reduction that has really substantially improved any toxicities with future dosing. And at a 6 milligram per kilogram dose, a dose reduction to 4 milligram per kilogram is still within a dose range where we saw plenty of efficacy within the trial that we're discussing. That being said, if one can help patients tolerate it better, if it's more mild symptoms, if it's not severe, then that's better in maintaining that dose. And interesting things like ice chips at the time of infusion, so cold within the mouth, kind of like the cold caps to try to reduce alopecia at the time of infusion of the chemo may help some steroid rinses also can be helpful. But really these are things to help prevent stomatitis from being severe. It's harder when that occurs, then the treatment for improving it is a bit different.  

We do know, though, that that does improve with time. So even when it was severe with that infusion, it does improve as patients get further out from those doses. Of course, another one is dry eyes or irritation within the eyes. And if that is severe, then or even mild actually, I'd say when there's any known toxicity like this is to involve ophthalmology. Now, within this trial, ophthalmology was involved and patients had to get a baseline eye exam and they would get checked at different time points throughout the course of the trial. And so they were being monitored. I did not have anyone who needed to stop the drug because of this. The patient I had with the longest standing response to therapy did have some dry eye. It was not bothering him so much. And he had this real aversion to using eyedrops. It was very hard for him to make himself use these. But when I told him, “Look, if this gets worse, you might have to come off the trial, that it might not be our decision just by the way the trial describes it, if this gets worse.” And so for him, the fear of having to come off the drug was really the thing that helped him to then start using his eyedrops, which really helped to control that a bit more. And so that is something to monitor for. 

But the biggest thing really is interstitial lung disease. This is something that is a complex topic, I think because it's something that we need to be very aware of and monitor for. At the same time, a diagnosis of interstitial lung disease can be challenging. There really were not cases where we had pathologic confirmation of this diagnosis. These are clinical diagnoses in the cases on this. Now there was an adjudication committee that would review all of the data and come to a determination of whether this looked like drug related ILD or not. But for clinicians, when you see a patient whose scan shows some inflammatory markings or inflammatory appearing markings on a scan, we see that all the time with other drugs too. And so determining what is potentially incidental versus drug related, I think in most cases on a trial when we're unsure, we lean toward drug related. And in some cases there are reported out severe cases of drug related ILD. 

I think the really difficult thing that I'd want people to take away from all of this, though, the bottom line is, yes, we need to be very aware of the potential for drug related ILD while at the same time, we need to not reflex, just call things drug related ILD and really make sure that we're doing a workup when feasible rather than just that bottom line conclusion. We see it at a rate related to the drug, and I do think it's real. But we also need to, when treating individuals, try to identify any other potential etiology. I did have one patient that really looked absolutely classic for this diffuse drug related ILD that ended up ultimately really being what looked more like tumor progression in just a radiographic pattern that looked more like an inflammatory process than it did the way we would typically see cancer progression. And so this has really, for me, I think, highlighted this as a topic where I'm diving a bit more into that description. 

Davide Soldato: And I also think that in the population of lung cancer patients, as you were saying, this is even more complicated because frequently these are patients who had a history of smoking, who can have concomitant infections where progression is easier in the lung. If I think, for example, other ADC that have already been tested, for example, in breast cancer, it might be far easier to detect and to adjudicate an ILD to the drug that we are using compared to what could be, for example, for lung cancer patients. 

So if I understood correctly, the toxicity that in your opinion as a clinician, they are more complicated to treat, let's say on a more daily basis, are more stomatitis and inflammation, but maybe the one that you experience as potentially more severe are always related to lung toxicity. 

Dr. Jacob Sands: Well, I think the scary thing about the ILD is that we have higher grades of ILD, and this is a toxicity that then can become life threatening. When we see a grade I or a grade II ILD reported in numbers, where we see, okay, this looks like it's really happening, and then see some really higher grade toxicities, I think the concern amongst clinicians then is if they're seeing lower grade, which of those can potentially progress to those higher grade, which then becomes life threatening toxicities. Whereas dry eyes certainly can become a nuisance, we didn't see any blindness or something like this, and the stomatitis resolves as you hold the drug, and in some cases, really before the next cycle even comes, it's just more a matter of controlling the discomfort, which can be severe. I'm not minimizing that. I think that's why ILD stands out so much, is that that becomes a potentially life threatening thing. 

And to your point exactly, these patients with a smoking history on other drugs, we see these inflammatory findings. Now, in some cases, we know it can be from the drug. In other cases, we see it and know that it's essentially incidental. And I'll say to patients, “Hey, we see this. It's something we'll monitor on future scans, and these can wax and wane.” When you have a patient on a drug with a high attention towards something like ILD, there can be- what I'm cautioning against is a reflex attribution to that drug. In all cases. I'd urge clinicians to individually assess each of these patients to get a sense of whether they think that that's going on for that person, knowing that it's often not possible to say with 100% certainty in any of these cases. But we often see waxing and waning inflammatory findings. And in many of these patients with heavier smoking histories, in particular, there can be waxing and waning respiratory symptoms. So the question is, are there instances where there is what really is an incidental inflammatory findings and incidental respiratory waxing and waning that then suddenly we call a grade II? 

At the same time on the other part of that, if there is something that seems like it really may be drug related ILD, is doing that work up and really evaluating and diagnosing that before it progresses to a point that really there are severe symptoms. And it's kind of trying to do both of those things on the opposite ends of the spectrum that I'm speaking toward at the same time.

Davide Soldato: Just on a personal note, do you think that, as we continue the development of these drugs that are associated potentially with lung toxicity, do you think that we also need to pay attention to the drugs that were immediately previously received by the patients? What I mean is, do you have the feeling that the previous treatment could potentially impact on the risk of developing this type of toxicity in the lung?

Dr. Jacob Sands: I don't know that we yet have data to draw any real conclusions around that. But you raise an important question within this, and what potential toxicities could be related to prior treatments or synergy across those. Of course, we see inflammatory findings within the lungs and pneumonitis with prior immune-related therapies, and that it would be a good prompt to the question you're asking. And that in particular, we also see this in some of the targeted treatments, although not nearly to the same percentages. I don't know that we can draw conclusions from this. I would speculate that the mechanisms of action of each of these drugs are so different that I would not hypothesize real synergy in those toxicities. But it is certainly something to be aware of and an important question that you're raising.

Davide Soldato: I think that, apart from the safety data that I think we dissected, the other end of the spectrum would be finding a drug that this very pre-treated population could still give us some efficacy data. So you already mentioned that, in the dose expansion cohorts, so 4, 6, and 8 milligrams, we had more or less signals of activity and of efficacy of these novel drugs. So the therapeutic options, as you were mentioning, are potentially docetaxel or other types of mono chemotherapy. But we know that the objective response rate is not that high, and that progression-free survival is not that long with these types of drugs. And potentially the safety profile could also be complicated in patients that are also pre-treated. So I just wanted to discuss a little bit the efficacy data and to see if there is really promise in this type of delivery of chemotherapy as you were saying with the ADC.

Dr. Jacob Sands: We saw response rates of about 25% across all three of those cohorts. The manuscript outlines the 4, 6, and 8 milligram cohorts within a chart showing the efficacy outcomes. And really it's around 25% across the three of those, which in this patient population, as we've discussed, heavily pre-treated, to have a response rate of 25% is really quite promising that there really is a substantial treatment effect. On top of that, we also see a duration of response of really around 10 months. So, in the patients that are having a response, there really is some durability. Now, it's tragic that 10 months is considered durable within this population and it really highlights the ongoing need for further drug development because I don't think anyone would say that 10 months is enough, we need dramatically better. But within the context of what we currently have, a 10-month duration of response is really quite meaningful and a response rate of 25%. 

Now, it also describes a disease control rate. And I always have to put a little asterisk to this. I think we see this increasingly - the disease control rate being reported - and it always looks quite a bit better than the response rate. And that's essentially incorporating stable disease. And although I would never claim that everybody with stable disease is truly benefiting from a drug, across all of the studies where this is reported out, there is a spider plot which really highlights a number of patients that are not considered responders, but with responses, a handful of them beyond six months of disease control, even though they're not considered responders, and one of them beyond a year with still ongoing disease control. So, even within that stable disease group, I'd say there are some who are really clinically benefiting from the drug, which is to say that really, even beyond the 25% response rate, we are seeing some others that are truly benefiting from this. 

Davide Soldato: Yes, and I also think that for these patients, especially when they can develop very rapidly symptoms that can potentially also impact quality of life, having a drug that achieves this level of stability - with maybe no deterioration in clinical symptoms - I think that it's still probably a very meaningful objective to obtain for this type of population. Of course, I think that with future studies we will also have probably health-related quality of life data that will tell us more about the impact of this type of drug in this setting. But I still think that this could be potentially a relevant endpoint, even if we don't achieve what we officially consider as a response as per resistor criteria. 

So I think that we have talked a little bit about the efficacy data. So, we are kind of entering a novel area where more and more ADCs are being tested, are being included in clinical practice. For example, if I think about breast cancer, we already have two that are approved that can be used, the same in bladder cancer. So, as you participated in this phase one trial, I just wanted to have your opinion: if you think that, in the future, we are going to evolve completely towards this type of delivery of chemotherapy, using what we call now "smart drugs" in terms of delivery of these cytotoxic agents.

Dr. Jacob Sands: It'll be interesting to see. We certainly will see other generations of ADCs. I mean, I think we're really just at the beginning with this technology. We certainly have now a very solid foundation to build upon, where we have effective targets and effective payloads. We've highlighted some of the toxicities we're seeing from that. Also, I'd highlight within this drug with TROP2, the amount of expression has not seemed to really be a driver in this. And some of that may be the bystander effect, which I'd call a real benefit of the drug, where the payload as a drug goes through apoptosis and lysis, that payload that releases then into the surrounding- toward the surrounding cells is membrane permeable and crosses into other cells, leading to potentially more efficacy. That technology in itself, I'd say, is something that we may see incorporated further into next generations of ADCs. Whether there can be improvements in preventing toxic drug in other sites like the stomatitis, for example, with newer generations that evolve from this, we'll see. 

I don't know that I would anticipate all chemotherapy ultimately going through ADC technology, but I certainly believe that this is the beginning of what I would call a whole new class. But would future cytotoxic treatment happen more so through ADC than just broad circulating payloads? If we can call it that. And I certainly think we'll see a lot more development like that. But you know, we may see other ways of developing the cytotoxic drugs in other forms of delivery as well. It'll be exciting to see as we go forward.

Davide Soldato: I also think that one of the major challenges that we probably will have to deal with, in probably not so long, is also the sequencing of these types of agents. We are starting to have, as I was saying, accumulating data regarding the efficacy of these drugs. And some of them share either the same payload or they target the same antigen on the cell. And so, do you think that we will need as a new line of research to really go into the field of cross resistance when we are using and trying to sequence these types of novel agents? 

Dr. Jacob Sands: We're seeing that across various tumor types. I mean, to stick with lung in particular and small cell lung cancer, we've seen DLL 3 really be a demonstrated target for small cell lung cancer. And now we have a handful of drugs being developed that target DLL 3. How would we potentially utilize those drugs? In what orders and which ones over others is going to be an area for discussion, much like the area you're raising here, where we see TROP2 directed treatments. And so which one would you choose? On top of the fact that there are other targets, in this case, we're talking about TROP2, but of course, there's HER3 that we've seen, and especially when we're talking about an EGFR population, EGFR mutation population, we've seen good efficacy with this TROP2 antibody drug conjugate, as well as the HER3. And so how would we order those? And they both are using the same payload.

If we're talking about both of the deruxtecan compounds, this is going to take some sorting out. I think with time, it'll be tough. I don't know if we'll end up seeing head to head studies in this or if this is going to end up being shaped more by expert committees and their descriptions. But I imagine we'll see some heterogeneity in the treatment pathways at different centers just based upon preferences and familiarity with these different drugs. Of course, assuming that they all end up ultimately being approved and then that efficacy and tolerability that we're seeing continues to pan out in future trials.

Davide Soldato: So we were mentioning before that there is a very big line of development for this novel ADC. And I think that there are also some trials that are exploring the role of data DXD so the datopotamab-deruxtecan in lines where patients have received less therapy or in combination with other agents. So I wanted to ask you if you could give us some insights regarding the ongoing trials, if you know about them. And also what do you think could be the area of a met need where this drug could potentially give the most effect?

Dr. Jacob Sands: It'll be interesting to see. In the first line setting we have TROPION-Lung07 and TROPION-Lung08. These are studies with PDL-1 expression of less than 50% or greater than or equal to 50%, the greater than equal to 50% being plus pembrolizumab versus pembrolizumab alone. The less than 50% essentially being an incorporation with or instead of chemotherapy along with the platinum-based therapy plus pembro. And so that one is a more complicated three-arm study. Now, essentially what this is looking at is incorporating this antibody drug conjugate in place of chemotherapy for potential tolerability when given concurrently with the platinum and pembro. Whether or not we'll see some synergy with the chemo and the pembro, I guess I would hypothesize that we would likely see at least similar to when giving the chemotherapy, or at least that's the hypothesis driving the trial design.  

If anything, whether we note improved tolerability relative to those getting, I'd say the carboplatin component, because certainly within non-squamous, non-small cell, pemetrexed is generally very well tolerated. And so that's a bit tougher to beat out from a toxicity standpoint. The trials are really designed based upon the efficacy that we've seen from this trial you're pointing out. I think by the time that this podcast is heard, we'll have the data from TROPION-Lung01 that'll be reported out as well in the second line setting versus docetaxel as that data is near release. These are areas for ongoing attention, certainly.

Davide Soldato: Thank you, Dr. Sands, for being with us today. This concludes our episode of JCO Article Insights. We discussed with Dr. Sands the results of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.” 

This is Davide Soldato. Thank you for your attention and stay tuned for the next episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin, Dr. Stephanie Wheeler, and Dr. Caitlin Biddell discuss the paper "Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer," a simultaneous publication, podcast, and presentation at the ASCO Quality Care Symposium.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor of the JCO and GYN Oncologist. And I am so excited that today we have a simultaneous publication in JCO and presentation at the 2023 ASCO Quality Care Symposium here on 10/28/2023. And this is going to be the manuscript “Economic Evaluation of a Nonmedical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer.” Very exciting work. And I'm thrilled to tell you I have two of the authors here with me today. First is Dr. Caitlin Biddell. She's a Health Services Researcher at Mathematica Policy Research. 

Welcome, Caitlin. 

Dr. Caitlin Biddell: Thank you. Happy to be here.

Dr. Shannon Westin: And we also have Dr. Stephanie Wheeler. She is the Michael S. O'Malley Distinguished Professor in the Department of Health Policy and Management at the University of North Carolina, Chapel Hill, as well as being the Associate Director of Community Outreach and Engagement at UNC Lineberger Comprehensive Cancer Center. 

Welcome.

Dr. Stephanie Wheeler: Thank you. Happy to be here as well.

Dr. Shannon Westin: Please note that our authors and participants have no conflicts of interest. 

Let's get started. So first I would love to level set. Can you speak a little bit about what financial toxicity is and how common it is among patients with cancer? 

Dr. Stephanie Wheeler: Sure, Shannon. I'm happy to take that one. This is Stephanie. So we know that financial hardship is often reported by patients and survivors who've experienced cancer. And as many as 50% of people with cancer have trouble with financial toxicity. There has been prior work that has conceptualized financial toxicity in three domains. So there's the material hardship, kind of the out-of-pocket material costs associated with cancer, which include both medical and nonmedical expenses. There is the stress and the psychosocial effects of that material hardship. And then there's coping behaviors that patients and their caregivers may employ to help deal with the high cost of cancer care. And as we've seen, cancer care increases in cost over time, and these expenditures really have very burdensome effects on patients and their families. We've been interested in looking at ways that we can try to mitigate that harm and really thinking about interventions in addition to the health policy changes that are needed to really ensure that this doesn't become a barrier to patients seeking and receiving the best quality care that they can.

Dr. Shannon Westin: I think that kind of leads pretty nicely into my next question, which is really: How does this toxicity potentially impact equitable cancer care delivery? 

Dr. Stephanie Wheeler: Yeah, I'm happy to talk about that a little bit as well. So we know from prior research, including some of our own, that patients of color, those from rural areas, and those who are uninsured or underinsured face the largest financial burdens associated with their cancer care. So to the extent that those financial hardships influence people's ability to seek and continue with and complete their cancer care that's been recommended, this actually is directly in the pathway and a mechanism through which patients are not able to get recommended treatment and therefore can contribute to differences in cancer outcomes. So there's direct health impacts in terms of their ability to receive and respond to cancer treatment.  

In addition to that, we know that this financial hardship contributes to household-level harms both economic and psychosocial in nature. And in some other work, this financial hardship has translated to worse quality of life, worse economic outcomes, things like being able to stay employed and seeking changes in employment or remaining within a particular position because you don't want to lose your insurance—this is referred to as “job lock”—or can also contribute to higher mortality. So there's been some really important work showing that financial toxicity is directly linked with cancer mortality. 

And so, as we think about ways that we need to address this, it's really key to ensuring cancer health equity that we are thoughtful about multiple solutions implemented at multiple levels that can deal with not only the contributors to high cancer costs but that can also start to affect both the nonmedical and the medical components of this cost burden. And by nonmedical, I mean things like the cost associated with transportation and seeking care, accommodations for people who need to receive radiation therapy multiple days in a row at a different healthcare facility than where they live, childcare costs. These things really start to add up in addition to the medical costs associated with cancer treatment.

Dr. Shannon Westin: I really was intrigued by the intervention here that you all are studying around this Cancer Patient Assistance Fund. Can you tell me a little bit more about exactly what that was or is?

Dr. Caitlin Biddell: Yeah, absolutely. So this is a program at the North Carolina Basnight Cancer Hospital, located within the Lineberger Comprehensive Cancer Center, and it started back in 2013, actually, and has really grown in size. But the main goal of this program is to ensure that patients do not face the nonmedical financial barriers to care that Dr. Wheeler was just talking about. So thinking about giving patients gas cards so that they are able to drive to and from treatment. Lineberger has a catchment area of the entire state, so many people are coming a long distance to come for cancer treatment. They also provide things like lodging and accommodations, as Stephanie mentioned, and then even paying patients’ utility bills, things to keep them housed with electricity, the lights on, while they're undergoing cancer treatment. So just last year, in 2022, they distributed almost $350,000 to over 700 patients, and most of this is funded by philanthropic grants to ensure that patients can access the care they need. And it is a program that's really targeted to patients with low incomes. So they target patients with household incomes less than 250% of the federal poverty level.

Dr. Shannon Westin: And how does a patient get connected to the fund? How do they find it and get hooked up? 

Dr. Caitlin Biddell: Yeah, there's a couple different ways. So one path is through the outpatient social work team. So they often perform distress screening for new cancer patients. So they use the Distress Thermometer, which was developed by the National Comprehensive Cancer Network. And it measures a variety of different factors that may be contributing to distress, but that does include financial stress, job stress, and the expense of daily living stress. And so, when a patient scores a certain amount on that thermometer, a social worker will meet with them for a full assessment. And then part of the referral pathway from that assessment includes the Cancer Patient Assistance Fund. Patients who are in inpatient will often be screened with the Social Determinants of Health Module, which is housed in the electronic health record. And so that can also generate referrals for assistance. And then beyond the kind of standard pathways, there's also many other ways that a patient may express concerns to a nurse, a care coordinator, an oncologist, and then that provider can reach out directly to the Cancer Patient Assistance Fund.

Dr. Shannon Westin: Your objective was to basically try to formally assess the impact of this fund on missed radiation or chemotherapy appointments. And so what was kind of your rationale for choosing this endpoint? And kind of take us through the design.

Dr. Caitlin Biddell: Yeah, absolutely. So the idea for this study actually came about from the program coordinator of the Cancer Patient Assistance Fund several years back. We were just having a conversation about the program. I was commenting how important I thought it was, how interesting it was. And she was saying, “You know, I know anecdotally that this program makes a difference, but we've never really known how to quantify that.” And that's becoming increasingly important as they apply for philanthropic grants and really need to show that their program is having an impact. So that's what originally started our plan for evaluating the program. 

And then, in thinking about endpoints, of course we imagined this program could have an impact on a range of different endpoints. So missed appointments is quite practicable. We also imagine it could influence patient health-related quality of life, patient symptoms associated with their cancer treatment, even potentially other long-term outcomes like mortality. But for the purposes of this evaluation, we needed to identify an endpoint that we believed could be measured, the association could be measured, in the data we had. And so we had electronic health record data. Missed appointments is something that is routinely captured in the electronic health record data because it's an endpoint that matters financially to health systems. So they are regularly tracking missed or no-show appointments. And it's also an outcome that matters financially to the health system, so they want to reduce this. 

So we thought if we measure the impact of this program on missed appointments, there's potentially an opportunity to kind of align financial incentives so that if we show that the program has an impact on missed appointments, then that could be something that could get decision makers at the health system level to say, well, that's also an endpoint that we want to reduce, and so let's think about ways that we can align resources to reduce missed appointments through potentially the Cancer Patient Assistance Fund and other mechanisms.

Dr. Shannon Westin: It's interesting because it definitely caught my eye because we give radiation, obviously, for gynecologic malignancies, and there's some pretty decent data that longer treatment duration for radiation has worse outcomes, with the implication that patients have missed appointments and so then, to finish their work, it takes longer, or to finish their treatment plan, it takes longer. So I definitely would be really intrigued to see the cancer-related outcomes. But I completely agree, like something practical, straightforward, and something easily obtained was the right way to start. I was just curious. So that's really interesting. So why don't you just walk us through the design of how you laid this out?

Dr. Caitlin Biddell: Yeah, absolutely. So we conducted a retrospective evaluation between 2015 and 2019, and we chose that time point to end before the COVID-19 pandemic since we know that had many impacts on missed appointments. And we compared the proportion of missed appointments in the six months following treatment initiation between patients who were receiving Cancer Patient Assistance Fund assistance and then propensity-weighted comparators. And this is really just a method to make the pool of potential comparison patients look as similar to those receiving Cancer Patient Assistance Fund assistance as possible so that we can really tease apart that direct effect of the Cancer Patient Assistance Fund and separate it out from other characteristics that may be influencing missed appointments. 

So we had stratified our analysis by treatment type. We looked at radiation therapy, and then we also looked at oncology infusion, so specifically immunotherapy and chemotherapy. And to evaluate these endpoints, we used a couple of different data sources that we linked together. So the first and the primary data source was the electronic health record. So at UNC, we have EHR data for research purposes stored in a data warehouse that we were able to pull from. And then we also linked in UNC Health's portion of the North Carolina Cancer Registry to get that really important information on cancer stage, cancer type, and treatment start date. And then, of course, we pulled in program records from the Cancer Patient Assistance Fund to identify which patients were receiving assistance, how much, and at what time points. And so, essentially, using that data and thinking about missed appointment outcomes in those six months following treatment initiation, we created a couple different models. So we looked at the high versus low no-show proportion using a logistic regression. And then we also looked at just the continuous no-show proportion in the sample to see if there was an effect on that as well.

Dr. Shannon Westin: And what did you find? What was the impact of the fund’s support on your outcomes?

Dr. Caitlin Biddell: For radiation therapy, which I'll start with, the radiation therapy had a higher number of encounters, as we might expect, than immunotherapy/chemotherapy. There were a mean of 37 total radiation therapy encounters in the six-month follow-up period, and about 53% of the sample had one or more no shows. And so, then, when we looked at the impact the Cancer Patient Assistance Fund on radiation therapy missed appointments, we found that receipt of any assistance was associated with an eight-percentage-point decrease in the probability of having a no-show proportion in the highest quintile. 

And then, when looking at continuous no-show proportion, we found it was associated with a 2.1-percentage-point decrease in the overall proportion of no shows, which corresponds to a 51% decrease in the overall mean no-show proportion. So a really substantial effect on radiation therapy missed appointments. And unsurprisingly, when we stratified the analysis by the amount of assistance received, we did see a greater impact of the program among patients receiving higher amounts of assistance. 

Moving on to the oncology infusion cohort, this sample had a lower number of encounters in the follow-up period and less no shows, so only about 14% had one or more no shows. And so it potentially wasn't as surprising that we did not see an impact of the Cancer Patient Assistance Fund on infusion oncology missed appointments, though, of course, with the additional power and alternative analyses, it's not to say that there wasn't an effect, but in our population, we were not able to detect that.

Dr. Shannon Westin: Yeah, and that makes a lot of sense. I mean, radiation is so much more time intensive and having to come back and forth. And when you were describing the fund and saying, like, housing assistance, I was like, “Oh, well, there you go.” Because that, I feel like, is one of the major issues. At MD Anderson, we also kind of take care of a very large catchment area, and it can be a huge burden for patients to have to come for that 15-minute appointment every day. So, yeah, when I saw your results, I thought that was likely what you were hypothesizing was the reason. And certainly, the impact on radiation is so impressive. It’s just a hugely successful study and a hugely successful fund. So congratulations. 

So, I guess, any other variables? You spoke a little bit about the amount of financial assistance received. Was there anything else that impacted the number of missed appointments in your study?

Dr. Caitlin Biddell: Yeah, because of our propensity-weighting design, we really didn't focus as much on other patient-level contributors to missed appointments. So we attempted to control for all of those things through the waiting and then kind of didn't add those into the final model. So that was really the main focus, was looking at the impact of the Cancer Patient Assistance Fund and then, of course, looking by amount of assistance. That was a really important finding and also, of course, needs to be taken in the context that every patient has different needs and so the amount of assistance may differ for every patient. And so there's always a need to kind of really assess what a patient's needs are and base the amount of assistance on that.

Dr. Stephanie Wheeler: It's probably worth saying again that the level at which we dichotomized these results was $180, which was sort of the median level of assistance provided. As you can imagine, there's a long tail, with some people receiving considerably more financial assistance. But I think it's really noteworthy that in the grand scheme of things, $180 per patient is a very small amount of money to provide to assist with things like housing support, transportation support, gas cards, and so forth.

And the program does not have strict rules about how those funds are used. So, in our setting, where we've got a lot of rural patients potentially traveling hours across state in their own vehicles, gas cards are really important for them. But in other settings—more urban settings, for example—having flexibility in how those funds are used could be really helpful for people who need bus assistance or other public transportation beyond kind of having to drive a private vehicle to appointments. 

Dr. Shannon Westin: It is a great point, and it is incredible how much you can do with a fairly little amount of money. And when we were talking about healthcare spending, obviously, that's a lot of money to an individual or a family. But in the grand scheme of what we spend on healthcare, that is a very, very small amount. So really, again, congratulations. 

So I think the last question I'll ask is just kind of what are the next steps? And really should we be making sure that we have these programs everywhere? Do I need to go back and make sure that this kind of situation is set up in my institution?

Dr. Stephanie Wheeler: Well, we also should share a little bit more about the economic evaluation results. Caitlin, why don't you describe that?

Dr. Caitlin Biddell: Yeah, absolutely. And this speaks exactly to what you were talking about in terms of the amount of assistance that can go a really long way for a patient and is a drop in the bucket for a health system. So we did want to look at what the cost-effectiveness, or the cost consequence, of this program was from the health system perspective. And so we conducted a decision tree analysis, which is a method used in economic evaluation research, using kind of a hypothetical cohort of 350 patients, that mean number of radiation therapy encounters, 37 encounters over a six-month time horizon. And we did find that under the current funding of the model, which essentially is that philanthropy covers all of the financial assistance and then UNC Lineberger covers the cost of the staffing and the indirect cost of housing the program, we found that this program was estimated to save the health system $153 per missed appointment averted. 

And then, in kind of an additional threshold analysis we conducted to see how much could the health system chip into this program in some way, whether it's through indirect cost or direct financial assistance, while still kind of breaking even from the perspective of no shows averted, and it was around $100 per patient. So, of course, that would be split across patients in different ways. Not everyone might receive that same amount. But there is opportunity here for health systems to make investments in reducing patient nonmedical barriers to care in a way that will come back in the form of saved revenue from averting missed appointments.

Dr. Stephanie Wheeler: And the only thing I would add to that is this obviously was focused on those no-show appointments, but we anticipate that there's other financial benefits to the health system, like retention in care, patient satisfaction. There's a whole host of quality-of-life and clinical outcomes that are probably also benefited through use of this kind of nonmedical financial assistance program that we weren't able to measure. But I think part of our goal with this analysis is to start to make the case to hospitals and health systems that providing direct nonmedical financial assistance helps their bottom line as well.

Dr. Shannon Westin: We, as clinicians and researchers, always want the benefit to the patients. But I agree, when you're dealing with administrators, we also need to show that. So I think that is super clever and a really nice part of the design. 

So what's next steps for your research?

Dr. Caitlin Biddell: Yeah, so I think we're currently kind of disseminating these findings within our own institution, so disseminating them back to the Cancer Patient Assistance Fund program so that they can use them in additional grant applications, but also really trying to get these findings in front of the health system administrators who might be able to make funding decisions surrounding this program. And then I think we are also thinking about ways to measure other endpoints beyond missed appointments. So we've kind of created this data set that involved some complicated linkages upfront, and now I do think there's opportunities to pull in other endpoints and even potentially some patient-reported endpoints as our electronic health records get better at collecting patient-reported data and even social determinant of health data, opportunities to really think about other impacts of this program. 

And then I'll also add that there is talk among other groups at our institution about using this kind of approach to measure other similar programs. For example, we have a pretty large AYA program that does a lot of similar types of assistance and also psychosocial assistance. And so they're thinking about ways to use a similar methodology to evaluate some of their own work. So I think it's just kind of starting to open the door to thinking about how we can use the data we have within our institutions to really underscore the impacts that the programs that already exist are having on patients.

Dr. Stephanie Wheeler: I would only add to Caitlin's fabulous answer that dissemination of this is really critical because we know that NCI-Designated Conference of Cancer Centers, the vast majority of them provide some kind of direct medical and nonmedical financial assistance, but many of them have restrictions on who can access those funds and eligibility criteria that preclude patients with certain cancers from accessing those funds or patients with still what we would consider to be relatively high financial vulnerability to not be able to access those funds. In addition to that, we know that community oncology practices less often have access to these kinds of financial support resources. And so what often happens—and this is an extremely fragmented space for patients and their caregivers to be navigating—is that when nonmedical financial needs present, people are left to their own devices to have to search out, seek out, and identify programs for which they're eligible in the community. And these are often funded by philanthropic organizations, really wonderful healthcare support organizations. But oftentimes these types of financial supports are not directly provided through the hospital, or if they are, they're in the form of “charity care provisions,” which are often opaque to patients and their caregivers to even find. And then the eligibility requirements for those programs, again, are often preventing access for a number of patients in need.  

So what I would like to see, as a person who does a lot of research in this space around financial hardship, is for that burden to be shifting away from patients and caregivers and more towards the systems that are treating these patients and that are supporting the caregivers so that people can focus on what's important during their cancer care, which is getting treatment that's recommended, staying in treatment, and attaining the best possible health that they can. When patients and their families spend hours and hours and days and weeks trying to understand existing financial support programs in the community and then those disappear or evaporate, as they do when funding and contributions subside, that really has a very detrimental impact on the patient's entire care experience. And I think it's on us, as people who are part of the healthcare system, to ensure that that doesn't happen. And the financial case to hospitals is clear, I think, from this analysis, but the moral case to all of us, as providers, should be clear and should be compelling in itself.  

Dr. Shannon Westin: On that note, I think that's a perfect way to end. Thank you so much. This was such an intriguing discussion, and I really hope people are listening that are making the decisions for their hospitals and will see how they can implement something like this in their institution. 

Again, this was a discussion of “Economic Evaluation of a Nonmedical Financial Assistance Program on Missed Treatment Appointments Among Adults with Cancer,” simultaneous publication in the JCO and presentation at the 2023 ASCO Quality Care Symposium on October 28^th. It was great to have you all here. This was amazing, and I hope our listeners had a good time. And please do check out our other podcast offerings wherever you get your podcasts. 

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the Podcast do not express the opinions of ASCO. The mention of any product, service, organization, patient activity or therapy should not be construed as an ASCO endorsement.

Shannon Westin speaks with Holly Prigerson and Alfred Neugut about their thought-provoking editorial, "You Get (Offered) What You (Can) Pay For: Explaining Disparities in End-of-Life Cancer Care."

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.  

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. And this is where we get in-depth on manuscripts and editorials that have been published in the Journal of Clinical Oncology. As always, I am your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the Journal of Clinical Oncology, and I'm so excited to be here today. We are going to be talking about a very compelling editorial that is called “You Get (offered) What You (can) Pay for: Explaining Disparities in End-of-Life Cancer Care." And this was published on June 20th, 2023, in the Journal of Clinical Oncology as an editorial on an article entitled the "End-of-Life Systemic Oncologic Treatment in the Immunotherapy Era: The Role of Race, Insurance, and Practice Setting." So a very timely topic and very exciting for us to discuss today.

I'm joined by two of the authors of the editorial, Dr. Holly Prigerson, Professor of Sociology and Medicine, the Irving Sherwood Wright Professor in Geriatrics Medicine at the Weill Cornell Medical College and the Director of Cornell Center for Research on End-of-Life Care. Welcome, Dr. Prigerson.

Dr. Holly Prigerson: Great to be here.

Dr. Shannon Westin: And also accompanied by Dr. Alfred Neugut, the Myron M. Studner Professor of Cancer Research and Professor of Medicine and Epidemiology at Columbia University and the former Associate Director for Population Science and Racial Disparities Program for the Herbert Irving Comprehensive Cancer Center at Columbia. Welcome, Dr. Neugut.

Dr. Alfred Neugut: Thank you very much.

Dr. Shannon Westin: Very excited to talk about this topic today, and I like to always start with a little bit of level setting. So I'd love for one of you to discuss: How common is the use of systemic anticancer treatment at the end of life?

Dr. Holly Prigerson: So, based on the article, it looks like the rates within the last 30 days of death, it was 34% on average overall. So that was sort of the—you say level setting—the base statistic. Within 14 days of death, it dropped to 13% overall. So all the associations that are described are really disparities from that level. 

Dr. Neugut: Speaking as an oncologist, I don't think any of my clinical colleagues will be surprised that it's that high. There is an effort made really to, in desperation, try to help. Patients want it. Families want it. So there really is efforts made to try to do that to prolong life or palliate or whatever.

Dr. Holly Prigerson: The design also, which is probably going to be a question that's coming up, does raise a question for me that I'm wondering if Al could enlighten at least me on. They did select patients who were getting treatment for metastatic or advanced cancer starting in 2011 and then who died four years later. Does the selection for the fact that they were getting treatment initially—because everyone, that's how they sampled the study—does that increase the likelihood that they'll get treatment later on so that the rates are somewhat inflated is my question.

Dr. Alfred Neugut: Yeah, no, for sure. People who start chemo tend to continue partially because there is a certain amount of those who do well do well. If you respond to chemo initially, you tend to respond to the second-line therapy, you tend to respond to third-line therapy. If you didn't do well on first-line chemo, you're not likely to respond to a second line or a third line, so you don't have the enthusiasm to continue with it, and the patient certainly tends to lose interest in it. So you're right; there is a certain, call it, momentum or inertia in going forward with chemo once you've started.

Dr. Shannon Westin: I mean, I think this just always highlights some of the issues we have, right, with any kind of retrospective data is how well can we design a population without—because we can't always do randomized control trials, and certainly not in this kind of setting. That would not be acceptable, I think, to providers nor patients. And I do agree that it can be tricky. Any other kind of, maybe just to help the listeners if they haven't gotten a chance to read this Canavan study, about the design, exactly what they were looking at in this population?

Dr. Holly Prigerson: Basically, they took these patients who were getting systemic therapy and had advanced metastatic cancer prior, and then who died. So there's always a question about the sampling on death issue, that they had to have died to be in the sample. So those are methodological issues, but there’s really very little way around that. If you want to know what treatments people received in the last month of life, they have to die for there to be a last month of life. 

So then the treatments were divided into chemotherapy alone, chemotherapy with immunotherapy, and then immunotherapy with and without targeted therapy. So there were three types of treatment, which is sort of an important update because Al and I had published something in 2015 on chemotherapy and the outcome of what was called palliative chemotherapy at that time. And this was sort of a very refreshing–well, not—I shouldn’t say refreshing, but important update to our study, which had said that there are questionable outcomes of palliating someone with palliative chemotherapy so far along in the disease. And then the question became, well, is it different? Is it different with immunotherapies? Is it different with targeted therapies? And that's why I was delighted to see this paper, because it answered… 

Dr. Alfred Neugut: I'd have to say there are probably differing views on this, but Holly and I are probably relatively nihilistic in terms of thinking that chemotherapy in late stages or near terminal patients is probably not all that helpful. Third-line, fourth-line therapy probably not going to get you very far. And maybe it's best to be thinking more about hospice care and supportive care. And now we have terrific palliative care programs at most or all cancer centers, and we really should be taking advantage of this. I think a real benchmark study was the Temel study from 2010 or 2011, which really—for those of your listeners who haven't read it or seen it, they should really take a look at it. It really changes the playing field and makes you realize that treatment is not really always the best thing for patients, and there are other options. And we go to hospice care or palliative care really, I think, too late in the game a lot of the time, and we really should be thinking otherwise. 

Dr. Holly Prigerson: That is one of the outcomes that we had looked at before. So we had looked at palliative chemo, and not only does it not palliate, and we didn't show that it significantly enhanced survival; we also showed that it resulted in a lower likelihood of earlier enrollment in hospice, a higher likelihood of not dying where your family members thought you would have wanted to die, a higher likelihood of dying in the ICU or getting some kind of aggressive care. So it's not only what the chemo does or doesn't do in terms of treatment or survival or quality of life; it also seems to exacerbate and put someone at risk for very burdensome interventions that having avoided it might have enabled patients to avoid getting very burdensome care that's largely futile. But as Al said, we are probably more the nihilistic type.

 Dr. Shannon Westin: Well, I think you bring up a couple of good points because you've got objective data, and these studies that you're mentioning are just some of them that show that early hospice care and early enrollment and even just a palliative care program or a supportive care program or whatever terminology we want to use, people do better, right? They live longer actually from that piece rather than necessarily the more “aggressive measures” of chemotherapy and things.

Dr. Holly Prigerson: When there was an extra analysis of the Temel data, I believe they had shown that some of the survival advantage was explained by avoiding toxic chemo. So that's directly relevant.

Dr. Alfred Neugut: There is an on the other hand, as always, which is that patients and families often don't want to do that. I mean, they realize that doing that is giving up, so they're reluctant to take hospice care or palliative care as an alternative to another cycle of chemo or another type of chemo. And as you say, you never know; maybe the next one is going to be the winner and there'll be a miracle or there'll be at least some substantial benefit. And then there's always experimental therapy, and now immunotherapy, which is the topic of this article, is the new winner on the block. And it has bright lights around it, and everybody has great hope for it. And it’s the new kid on the block, and everyone hopes that that’s going to be the big savior. 

Dr. Shannon Westin: Right, and I think everyone knows of a story of somebody that was “on death’s door” and got immunotherapy or the newest targeted therapy or the newest ADC, so that definitely colors it. And that also colors, I think, the physicians that are offering it, right? Because, yes, I've definitely heard this, and I'm sure you guys have too: nobody should die with such and such cancer without receiving immunotherapy once or without receiving such and such targeted therapy. I hear people say this all the time, and I don't necessarily disagree. It's more that when are we giving it, right? So we should be thoughtful about when we're placing those things. But you're right; there's so many factors that go into these decisions, and it's not cut and dry around what the patients and the family members and the physicians are going to decide.

Dr. Holly Prigerson: And I think that Al hits on a really key issue when he used the word “hope” because that seems like what the negotiation appears to be all about. You don't want to disparage someone or not offer them hope if there might… No one wants to say that there isn't hope. No one wants to be the bearer of that kind of bad news. And I guess it leads to—I think that that's part of the driver that ends up providing the gas that drives people to getting more aggressive therapies is because no one wants to be the person to be the wet blanket and disparage hope. And so it might affect how treatments are sold to patients or at least communicated to patients.  

There was this one finding in this report that was curious, and it was that patients with undocumented performance status were the ECOG group most likely to get treatment. And so, in terms of what could be done going forward to make people more realistic and not offer hope where it's really, really unlikely, maybe employing more decision rules about requiring the documentation of performance status and ensuring that it's what the ASCO guidelines permit for administering another line of treatment. Because that might be a way to sort of use data to help correct what in psychology we call cognitive distortion, so correct the distortion of this hyper-optimism. It might help correct some of that. We don't want to overcorrect and make people hopeless or depressed, but we want to offer realistic options. 

I think that's part of why this paper is so important, and it sort of informs future research to try to unpack some of the findings that they didn't have data on physician characteristics or communication discussions between patients and their oncologists. And maybe that's where the money is. Maybe that's where offering hope in a realistic way or different forms of hope, what to hope for, might be better communicated through more effective communication strategies and ways to enhance patients’ abilities to understand what they're agreeing to or not agreeing to. 

Dr. Alfred Neugut: And I would add that it's easy for us to sit here and be dispassionate or scientific interlocutors and saying, you know, “It doesn't work, and therefore we're not going to offer it or you shouldn't get it or go on to hospice.” But it's different when you're on the other side of the table. And even us doctors or healthcare professionals or scientists, when you're sitting on the other side of the table and you're the one who's got the cancer or your mother or child, you're not going to be so easily dismissive of getting third-line chemotherapy and having your 5% chance that the tumor will respond to some cocktail of who knows what and you never know. I don't want to say anybody's wrong or that it's stupid. Everybody has to do what they have to do, and we at least have to think about it and know what we're doing and have realistic—at least some idea of the realism of what we're putting people through and the costs and the toxicities and what to expect.

Dr. Shannon Westin: I think you guys brought up some really great points, and I do think that there is a huge impact around the communication piece. And we actually just did a podcast on discussion of goals of care at the end of life for adolescents and young adults and how those conversations can be different. 

I think the other thing that really caught my eye and, of course, caught your eye when you did the editorial around the Canavan study was this idea that the patients with insurance—with all other things being equal, that the patients with insurance were more likely to receive end-of-life systemic treatment. And it's interesting because typically I feel like we think having insurance and having that support is always a positive thing and has a positive impact on our health, and it most certainly does. So that's not up for grabs. But then this particular study showed that it could potentially have been negative because of all the things that you all just said about the negative impact of care in this 30 days or even 14 days near the end of life. What are the opportunities for intervention at the insurance level? You talked a little bit about provider level and communication. Are there opportunities at the insurance level that we could address?

Dr. Holly Prigerson: It does seem like having insurance companies determine what is reasonable and not reasonable to reimburse for. So including things, I would think, like having performance status factored in. What are the criteria for determining whether it's high value care or not? And I'm not an oncologist, so I really am going out on a limb, and I really want Al to respond to that question. But from my perspective, it seems like the ASCO guidelines determine when it's—“low-value care” is how they put. It’s wasteful and futile and burdensome. And they have guidelines of performance status, having not responded to multiple lines of chemotherapy, so that there could be guidelines for when there is value and when there isn't and that it could be more values driven in terms of guidelines of what they would reimburse. Because, as our title implicated, it seems like you get offered what insurance companies are willing to pay for, and that leads to potential disparities in equity if you have different insurance than other people and fairness and justice. Those seem like valid questions to raise.

Dr. Alfred Neugut: I mean, I think if we're following randomized trials and evidence-based medicine, then I think we're in a reasonable area of what should be done and could be done and needs to be done. And almost always, insurance will follow those. You don't usually end up then having to argue with a peer-to-peer call to the insurance company under those circumstances. Where things get sticky is when you want to treat someone off-label or go off the reservation. I don't know if that's to some degree what this paper talked about. And there you probably don't get much benefit from treatment if it's not a data-driven use of the drug. So that's really, I think, where the line needs to be drawn. I don't think there you'll have an insurance problem if you've stated those sorts of guidelines. If you want to use NCCN or the ASCO guidelines, all good and reasonable. The problem is when someone's desperate and you're trying to make them happy, so you give them something even though there's no reason on God's earth why it should work, but just so they feel like you're getting something and you're not being abandoned, which sometimes you do feel pressured to do that, and very commonly you do. And maybe that's where racial disparities save the uninsured from being tortured for something that's not likely to really be very helpful. 

Dr. Holly Prigerson: But as someone who's a disparities researcher as well, it raises the question were Black patients—which these data couldn't answer: were they offered different treatments than the White patients? And I think we all agree that low-value treatments shouldn't be offered or received, but the fact that Black patients receive less of the expensive stuff, the newer cutting edge, is problematic. And I think there does need to be more research into equity in terms of the options presented to patients with similar diagnoses. That was the troubling aspect of it, not that they weren’t getting, in essence, better end-of-life cancer care, but that's beside the point. In terms of ethics, it would be nice to have known whether they were offered the same things and declined it. I think all of us are a little suspicious that maybe they weren't. 

Dr. Shannon Westin: Yeah, that definitely—I like how you said it. It struck a nerve. Like, when I was reading through both the article and your editorial, that was something that caught my eye is this evidence of how implicit bias is impacting what people are offered. And yes, it ended up being an overall benefit to underrepresented minority patients. However, that wasn't necessarily the intention or why that happened. So I would be interested to hear what you all think about what we know about how implicit bias impacts the care of patients with cancer, just for our listeners, and specifically what particular treatments are offered, not necessarily just at the end of life, but just across the cancer continuum. 

Dr. Alfred Neugut: There are estimates—if you read the medical literature on health policy and things like that, there are estimates that we overdo a lot of things in medicine and give—I don't know. I've read that like 70% of what we do in medicine is unnecessary. I'm not saying in oncology necessarily, but screening and wellness care, etc. And so oncology probably is equally guilty of such things. And there are biases in that as well, so, you know, that's what happens.

Dr. Holly Prigerson: And in the article, they had cited, I think it's Penner. There was a study that showed that ratings of an oncologist's implicit bias were negatively associated with Black patients' willingness to undergo their treatment recommendations. So the dynamic between what's offered, what's heard, what's trusted. There's obvious history of Tuskegee and concerns about being denied treatment. So this article kind of feeds into why was the latest and greatest types of treatment not as common? That said, the actual differences, if you look in the tables, the actual differences weren't that disparate. They were statistically significant, but we’re talking like 37% to 34%. So the disparity isn't as wide as to cause serious alarm bells to go off that people are being treated so differently. But it does raise a lot of underlying concerns that you would want to make sure that everyone's being offered the same things. So it does imply—that Penner article implied—it's basically medical mistrust may be interfering with a Black patient's willingness to undergo or accept some treatment offered. So if you follow the logic on that through, then the intervention would be: What are ways to enhance medical mistrust of their oncologist? What are the reasons for it? And how can patients feel that they are being treated by someone who treats them fairly and no differently than White patients? And so efforts in those directions seem like they might pay off in terms of enhancing and addressing implicit bias. 

Dr. Shannon Westin: Well, this has been a really great discussion. I'd love to hear just kind of your last thoughts from each of you around some of the unmet needs. We've heard themes throughout the discussion, but maybe just sum it up for the podcast listeners, bring them back and where we need to go next here. 

Dr. Holly Prigerson: Al and I have been working on a few different projects to address medical mistrust and leveraging things like healthcare chaplains, who might be liaisons within an outpatient oncology setting. We also have interventions that try to enhance clinical communication, like what we call a GIST, so that patients easily get the gist, the essential meaning of things like scan results to sort of level the playing field so that patients have adequate information to know what the harms and benefits of the treatments that they're being offered might be and have a better background to be engaged in those decisions in the first place. 

Dr. Alfred Neugut: My own thing is that you should be telling patients right from the get-go that they have incurable diseases and not letting them meander along thinking that we can actually help cure them in some meaningful way. We know who's incurable, and even if they have two or three years of survival coming to them, colorectal cancer or breast and prostate, etc., it's still fair to tell them that we can't cure them. And then when the time does come two, three, four years later, they're not going to be shocked, and they'll deal with it, I think, in a better way because they've known all along that this day is going to come, and then they don't react badly in the last two weeks, three weeks, four weeks, because they've been prepared for all those years before. I think the real problem is no one ever tells them directly, or many doctors don't tell them directly upfront. And so, when it comes near the end, they don't tell them until they're almost semiconscious. Then it's a shock out of the blue. And then of course they want to be treated more aggressively at the end. And I think that's where some of the issues may come.

Dr. Holly Prigerson: And with the immunotherapies, that probably raises a lot more questions, even from the oncologist’s perspective, about what they can call incurable because maybe there is hope, maybe there are these outliers. That's where it seems like it's wonderful that there are advances, but if the rates are so low and people have a misunderstanding of their chances, I think we're on the side of understanding what the best data suggests are the likely outcomes. And I think all the new advances sort of undermine disparaging hope because that's what they're there to do. They're there to offer hope.

Dr. Shannon Westin: And everybody wants to be the tail of the curve, right? They all want to be that person. So that's exactly—you're totally right. When we're trying to communicate, “Okay, this is the most common outcome.  Yes, there are people that are way over here but…” 

Dr. Holly Prigerson: That's going to be me.

Dr. Shannon Westin: Yes. They always say, “That's going to be my miracle.”

Well, great. Well, thank you both so much. This was such a lively discussion, and I know the listeners learned a ton. I know I did. 

Again, thank you all for listening to JCO After Hours. We were discussing "You Get (offered) What You (can) Pay For: Explaining Disparities in End-of-Life Cancer Care," published in the JCO 6/20/23. We're so excited that you took the time to listen. If you're looking for more podcasts, check out our website, or you can find us wherever you get your podcasts. Have a wonderful day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

A variety of perspectives are explored as Dr. Westin speaks with Dr. Jennifer Mack, Dr. Chun Chao, and Mallory Casperson about end-of-life care planning in adolescent and young adult cancer.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare. 

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get down and dirty with manuscripts that are being published in the Journal Clinical Oncology. And I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the Journal of Clinical Oncology. I am so very excited to have a number of guests with us today to discuss a very important paper entitled “Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults with Cancer Approaching the End of Life.” 

And I'm joined by several of the authors of this important paper. The first is Dr. Jennifer Mack. She is the Associate Chief in the Division of Population Sciences, an Associate Professor at Harvard Medical School and Senior Physician in Pediatric Hematology Oncology at the Dana-Farber Cancer Institute. Welcome, Dr. Mack.

Dr. Jennifer Mack: Thank you.

Dr. Shannon Westin: We also have Mallory Casperson. She is the cofounder and CEO of the Cactus Cancer Society. They provide online support programs and resources to young adult cancer survivors and caregivers in the comfort of their own homes. Welcome.  

Mallory Casperson: Thanks for having me.

Dr. Shannon Westin: And then, finally, last but not least, Dr. Chun Chao. She is a Senior Research Scientist in the Division of Epidemiologic Research in the Department of Research and Evaluation at Kaiser Permanente Southern California. Welcome. 

Dr. Chun Chao: Thank you. It's a pleasure being here.

Dr. Shannon Westin: So I want to get right into this. I think that there certainly has been a lot of discussion, at least at our institution as well as at the ASCO level, around advanced care planning across all patients with cancer and anyone with a diagnosis of cancer. And I would love to just start and level set and make sure all of our listeners are all on the same baseline around the incidence and prevalence of cancer in adolescents and young adults. Like, first, define what are the age groups that we're looking at here? How common is cancer in this population?

Dr. Jennifer Mack: Right. For this study, we defined adolescents and young adults as individuals aged 12 to 39. And right now, about 90,000 adolescents and young adults are diagnosed with cancer in the United States each year. Those numbers are also rising, so more and more are diagnosed each year, and because of that, we think it's increasingly important to pay attention to the needs of this population. This population really experiences a whole range of different cancer types, some of which are more common in children, some of which are more common in adults, but the most common ones include breast and gastrointestinal cancers, sarcomas, germ cell tumors, leukemias, lymphomas, and brain tumors.

Dr. Shannon Westin: And your manuscript notes that adolescents and young adults seem to receive medically intensive measures at the end of life. Now, how common is this across this group? And do you all have a sense of some of the reasons that we see this increased use of these measures?

Dr. Jennifer Mack: That's a great question. We and others—actually, the early work that led to this study was done with Chun. We had previously found that most adolescents and young adults receive at least some kind of medically intensive care at the end of life. And that includes things like being hospitalized, being in the intensive care unit, receiving chemotherapy, and spending time in the emergency room near the end of life. And so, if you take all of those together, about two-thirds of adolescents and young adults receive at least one of these near the end of life. 

And we don't know the reasons for this. There are probably complex reasons. Some adolescents and young adults may actually want to receive these kinds of measures, maybe because they're young and they want to do everything they can to live as long as they can. And some patients in this age group are parents to young children, and they may be making choices to prolong life and be there for their kids. But we also know that if we look at older adults, most people who know they're dying don't want to receive this type of care, which is also associated with more suffering and with poorer quality of life. So it's also possible they're making these choices because they don't fully recognize they're approaching the end of life or because they haven't had opportunity to plan for this time through conversations with their medical teams.

Mallory Casperson: I think the conjecture, too, that a young adult is likely to focus on extending life, even in a situation where palliation is the stated goal, is a really great conjecture. This population is really burdened by these unique psychosocial issues that are driven by the extreme disruptions that cancer has on major life milestones. Like Jenny said, they may have young children at home, they may have a new spouse at home, still be trying to advance at work, you name it. So this period of young adulthood is really characterized by constant change. And it's possible that these young adults are being driven to stay present in their lives for really as long as possible to reach some of these goals or even just to support their young families as they reach their own goals.

Dr. Shannon Westin: I really appreciate that context, and I'm going to always bring it back to what I know as a provider of gynecologic cancer care, where we see quite a bit of young people at the beginning of their life, at the beginning of their fertility. And I think it is so important to keep that context in mind as we're designing interventions and studies and things like that. So I really appreciate that, having the ability to kind of see from that standpoint.

So I think you guys have convinced me this is important. We know the reasons. So why don't we just lay out the objectives of this particular study and give our listeners a brief review of how it was designed?

Dr. Jennifer Mack: Great. We wanted to know how often adolescent and young adult patients with incurable cancer have discussions about prognosis and end-of-life care planning before they die. And a secondary goal was to understand whether having earlier discussions would change the type of care that's delivered. So, for example, having those discussions about goals of care earlier in their illness, could that make them less likely to receive intensive measures? 

So, to do the study, we conducted a retrospective review of health records for nearly 2,000 adolescents and young adults who died between 2005 and 2019 after receiving care in one of three centers—the Dana-Farber Cancer Institute, Kaiser Permanente Southern California, Kaiser Permanente Northern California—and looked for documentation of discussions about care planning. For this study, we focused on patients who either had stage IV disease at diagnosis or who had experienced a recurrence because we wanted to ensure that we had a population of young people who were living with advanced disease and not people who might have died suddenly and unexpectedly during treatment, because they might not have had the same opportunity for end-of-life care planning. So we really wanted to focus on those who had the poorest prognoses.

Dr. Shannon Westin: It's a really large group of people and, I think, hopefully fairly representative. I guess my question is, when you're looking at the group that you were able to kind of pull from in this retrospective database, which I think can sometimes be limited, do you feel like it was fairly representative of the population that's out kind of across the States, let's say?

Dr. Chun Chao: So I think it's a real strength that we included two different care settings in this study, so a tertiary cancer center and community-based cancer care. Therefore, patients who seek care in each of these settings are representative in our study. I think this design really increased the generalizability of our findings. And on a further note, in this study, we actually observed very similar care patterns across all three study settings. So that was quite reassuring.

Dr. Shannon Westin: So reassuring. And I think it brings up a point that I wanted to make, and I also agree was a strength of your study, is having that across the academic center and then a large integrated health plan. And I guess I'm just curious how your collaboration came to be to kind of come across different groups and, of course, the inclusion of Mallory from the patient advocate side. I think this is a testament to your powers of collaboration. I'd just be interested in how that kind of came to be.

Dr. Chun Chao: So this goes back to almost 10 years ago. I think, at that time, people started to really recognize that adolescent and young adults with cancer were a very understudied group, but they are also very challenging to study. So, for example, AYA cancers, adolescent and young adult cancers, are fortunately not very common. Although the number is increasing, you do need a large population base to study them. So, at that time, researchers at Integrated Health Systems started to really see that we had an opportunity here to really contribute to this knowledge gap, leveraging the resources that we had at these health systems, especially the ones that have a very large membership and a long-term retention of these members and also a comprehensive electronic medical record system. 

At that time, my colleague and I published a study that demonstrated the feasibility of using these resources to do follow-up studies of long-term health outcomes of AYAs with cancer. And I think that we might have attracted people's attention to utilizing the resources at these health systems to do such studies. So Jenny was the one who really saw the need or the lack of data or the need of high-quality data to really improve care for our AYAs who are at that end-of-life stage. So she reached out to a research network called the Cancer Research Network, who I think that the people there connected Jenny with me because I was also starting to work on long-term health outcomes of AYA cancer survivors, adolescent and young adults. After we talked, we were like, “We have to get this funded. We have to get these questions answered. These questions are so important.” So, as Jenny mentioned, we did a pilot study that really showed there is a lot of burden of medical intensive care at the end of life for our young patients. And, as often is true with research, this opens up a lot more additional questions that we needed answers for. So we have been working together since then. 

Mallory Casperson: I came into this group sort of by accident. My background is in engineering. I was about halfway through a PhD when I needed to leave a couple years outside of my first cancer diagnosis. And I was at ASCO staffing a booth for my organization and just happened to meet a researcher from Kaiser Permanente Northern California, and the rest is history. That introduction sort of got me into this world, and, once you know one person, you get to meet others. And it's just been a really, really wonderful opportunity to help, I think, insert the patient voice. But also, for me, I just love research and data. And so getting to help advance the conversations happening around adolescent and young adult care in this research setting and in these settings where we are getting to look at very large datasets has just been really, really wonderful.

Dr. Shannon Westin: These are my favorite parts of these podcasts, these stories of how things kind of came to be. And, at the risk of taking too much time there, I love the story, and I'm so in awe of you guys. 

I guess, let's get to the bottom line. What did you guys find? Did you find what you expected in regards to advanced care planning and goals of care in this population?

Dr. Jennifer Mack: So we felt that most patients had documented discussions about prognosis, about goals of care, about palliative care, hospice, and their preferred location of death before they died.

Dr. Shannon Westin: So I was actually kind of impressed at that. It seemed like a lot. I was expecting—I don’t know what I was expecting, but I think I was expecting less documented discussions because, in my own practice, I don't necessarily think I do a great job of this. So was that in line? Were you expecting to see such kind of high levels of documentation?

Dr. Jennifer Mack: I really agree with you. I was impressed with the fact that most patients had these discussions. Many of them had more than one discussion about their goals of care. So their providers were going back and having follow-up discussions, making sure that their goals of care were the same and weren't changing over time. So I agree. I was pleasantly surprised with how often these were happening.  

I would say I'd love to see these discussions either happening with everyone or at least offered to all patients so that they can say whether they want to have them or not. So, in this study, 17% of patients never had a discussion about goals of care. And non-white and Hispanic patients had lower rates of discussions than white patients. So there are some potentially important gaps here that need attention. But I also think you're right; there's a lot of good news here. Clinicians are making consistent efforts to talk with patients about their wishes for care, and then they're documenting them, which is an important thing because it allows those wishes to be known by everybody on the care team and helps to ensure that they're going to be carried out.

Dr. Shannon Westin: I was also intrigued by the finding of the younger patients having earlier discussions around advanced care planning and hospice and goals of care. Any thoughts as to why that might be? Again, I felt like it was a little bit opposite of what I was expecting, not having a ton of background in the area. 

Dr. Jennifer Mack: I was surprised, too. We had to check the numbers a couple of times just to be sure because it wasn't what I was expecting. And we don't know for sure what the reason for this is, but I think one possibility is that some of these discussions with the youngest patients, or for the youngest patients, are happening with family members, maybe their parents. And it's possible that clinicians are a little more comfortable or more likely to talk with parents than with the young patients themselves. And so that could actually increase rates of discussions for that group. 

One thing we didn't assess was who was there for the discussions. It's not always documented. There's more to learn there about who was there and more about what was discussed. But that was our guess is that these may be family discussions more so than patient discussions.

Dr. Shannon Westin: That really makes a lot of sense. And then I guess the next natural question is when we have these earlier goals-of-care discussions or when we have these discussions at all, what did you guys see on the impact of those kind of medical interventions that happened after?

Dr. Jennifer Mack: Yeah. We found that when goals-of-care discussions happened earlier, more than a month before death, that adolescents and young adults were less likely to receive some of these intensive measures that we've talked about, so less likely to receive late-life chemotherapy, care in the intensive care unit and emergency room, and less likely to be hospitalized in the last month of life. So, even though these findings were observational, it creates the potential that having discussions earlier can help reduce some of these intensive measures and refocus care on palliation, if that's what patients are looking for.

Dr. Shannon Westin: I think that's a really important point because we often bring our own thoughts and beliefs into the care of our patients and think, “Well, I wouldn't want those things.” And I think making sure we know where the patient is—and Mallory, I'd just be interested to get your thoughts here. How do we best approach those things and try to avoid—you know, we want to give advice where advice is needed, and we want to make it clear what the goals or what the potential successes might be. But I'd be really interested to hear your thoughts around framing those discussions and making sure that people understand what can be gained from those types of intensive treatments.

Mallory Casperson: Yeah. I think it's important with patients in this situation—and it was discussed in the paper, but the idea of timing, how frequently are we having these care preference types of conversations, and how often are we reframing things with the patient based on how goals might be changing? I think that's a huge piece of the equation because, especially when we're talking about 30 days before death, 60 days before death, things might change quite rapidly from week to week and so having some of those things in mind. 

And then it wasn't discussed as much on this paper, but it definitely has been in other work by both of these authors, as well as other just end-of-life research, but this idea of who is in the room for these conversations, I think, is another really important piece of this. Because a caregiver might have different preferences and goals than a patient. If a patient is 15 versus a patient is 25 versus a patient is 39 is also going to change things, and it's going to change the perspective that their caregivers bring to the equation. And so I think who is in the room and how are we doing that very difficult thing of weighing people's opinions in the situation, I think, is very complicated and also very important to figure out.

Dr. Shannon Westin: And I think that that leads to my next question: How do we get more of that information? What do you think are the next steps for this particular work? And also, I would just say, how do we guide that? I mean, I struggle with these conversations. It doesn't matter if my patient is 22 or 82. I think trying to meet people where they are is one of the critical pieces. So what's next for this work? How do we help inform these discussions for the caregivers and for their providers?

Dr. Jennifer Mack: I think you're right that we do think an important next step is promoting earlier discussions about goals of care and advanced care planning, partly because it gives patients time to reflect on what's important to them, to digest the news, and then make thoughtful decisions that are best for them. But from a research perspective, I think, as we do that, we need to understand more deeply what adolescents and young adults want from these conversations. What topics should be addressed, with whom, and how should they be discussed?

And we've also learned from other work, including work that the three of us have done together, that goals of care for adolescents and young adults aren't always as simple as wanting care focused on palliation or prolonging life, this kind of binary thing. Often, there are these other equally important goals, like making sure their loved ones are okay, what's going to help them the most, having opportunities to nurture and deepen their relationships, and finding ways to attain their life goals and meaning while they're living with advanced disease. 

So all of these different aspects, which aren't always a typical part of goals-of-care conversations, could be integrated to help support the kind of wider goals that are held by adolescents and young adults with cancer.

Mallory Casperson: I think, too, adding to that, we've talked about how AYA patients' goals of care have changed over time. So I think timing is a thing that could be added into future work, which is a difficult thing, I think, to gather from some of these records sometimes. But also, I think thinking through what these different words mean to different populations and how we're defining them is really important, too. So just an example outside of end-of-life care: When you tell a 30-year-old who's going through cancer that exercise is important during treatment and you talk to a 70-year-old going through cancer that exercise is different, that means different things, and they themselves have different context around what that word means in their normal life. And so I think when we throw out words like “palliation,” “palliative care,” and just general end-of-life conversations, that the same context applies. When an AYA agrees that maybe palliative care is the goal, what does that mean to them, and what are they bringing to the conversation in terms of their younger perspective than an older population that we're potentially more used to working with? So I think framing these ideas and how they might differ between populations is another thing that would serve as future work in this AYA end-of-life care space.

Dr. Shannon Westin: Great. Well, thank you all so much. The time just flew by. This was such a great discussion of an incredible topic, and I just want to thank you all again for your hard work in this space.  

And thank you to all of our listeners. Again, we were discussing the manuscript “Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults With Cancer Approaching the End of Life.” And this is published in the JCO, so go check it out. And please do go check out our other podcast offerings and tell us what you think on Twitter. We'll see you next time.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, Davide Soldato summarized finding from the original article published in the September JCO issue: “Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort”. The summary provides information regarding the ability of a blood-based panel of 4 biomarkers in improving the identification of individuals at risk of developing lethal lung cancer and potential of combined screening strategies to improve trade-off between potential harms and benefit of the screening process.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Davide Soldato: Welcome to the JCO Article Insights episode for the September issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today I will be providing a summary on one article focused on the refinement of screening strategies for lung cancer. The article, titled "Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort" by Dr. Irajizad and colleagues, investigated the ability of a panel of circulating blood biomarkers in improving the identification of individuals at risk of developing lethal lung cancer. We already know that lung cancer screening based on the use of low dose CT is associated with a reduction in mortality, as already demonstrated by the National Lung Cancer Screening Trial and the NELSON Trial. Furthermore, the US Preventive Task Force has recently recommended an expansion of screening criteria for lung cancer.

Currently, based on this recommendation, screening strategies are recommended for individuals 50 years of age and older with a smoking history of at least 20 pack-years and who are current smokers at the moment of the screening time or have quit within the past 15 years. Despite this positive data and this recommendation, the uptake of lung cancer screening in the US is still low, with reported uptake rates below 15%. The risk of false positive results, the unnecessary follow-up procedures, uneven access to lung cancer screening programs, and fear of cancer diagnosis and treatment have all been identified as potential barriers to optimal implementation and uptake of lung cancer screening. And so, in order to overcome some of these barriers, several efforts have been made in the last years to develop lung cancer screening prediction models with the aim of selecting a higher risk population who would derive higher benefit from lung cancer screening. 

In the present manuscript, the author builds on their previous work where they developed and tested a clinical prediction model and a blood-based prediction model in the context of the PLCO cohort. The Prostate, Lung, Colon and Ovarian Cancer Screening Trial was a randomized, multicenter trial in the US which aimed to evaluate the impact of early detection procedures on disease-specific mortality for the aforementioned cancers. Two lung cancer screening prediction model had already been developed and tested in the cohort. The PLCOm2012 model is based on several clinical and demographic characteristics, including age, race and ethnicity group, education, BMI, chronic obstructive pulmonary disease, personal history of cancer, family history of lung cancer, smoking status and intensity, duration and quit time. In a previous study, this model demonstrated a higher sensitivity and positive predictive value with no loss in specificity for lung cancer diagnosis compared to the National Lung Screening Trial criteria.

Additionally, in the same cohort, the 4MP was a blood-based panel that included the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment. In a previous study, a combination of this blood-based panel and the PLCOm2012 model was associated with a better identification of patients at high risk of developing lung cancer that would consequently benefit from lung cancer screening. In the manuscript that was published in the current issue of the JCO, the authors aim to expand on these previous results and test the ability of the combined 4MP and PLCO model to identify individuals at high risk of developing lung cancer death. The study used prediagnostic sera of 552 individuals that were diagnosed with lung cancer within one year from the blood draw and 2000  non-cases.

In the study, the authors assessed the performance of this combined four 4MP and PLCO model at a risk threshold of 1% and 1.7% of developing lung cancer at six years. Among the more than 500 individuals who were diagnosed with lung cancer, 70% died from it and 18% died of other causes, and the median survival times for lung cancer cases was 2.7 years. The combined 4MP and PLCO model had an area under the curve (AUC) of 0.88 for the prediction of lung cancer-specific mortality. The performance of this combined model using both clinical demographic and also a blood-based panel was higher than the ones of the two models considered alone. Furthermore, the model had similar predictive performance for both non small cell lung cancer and small cell lung cancer-related deaths. 

Subsequently, the authors compared the performance of the combined 4MP and PLCO model with the 2013 and 2021 US Preventive Task Force criteria and observed that the combined model had improved sensitivity, specificity, and positive predictive value for the prediction of lung cancer-specific mortality compared to both types of criteria. Finally, the authors assessed whether the combined 4MP and PLCO model were able to determine the survival probability among individuals who had a smoking history of at least 10 pack-years. Cases and non-cases were classified as either test positive or negative according to model scores at the 1.7 and 1% risk threshold at six years. For both thresholds, the combined 4MP and PLCO model identified a significantly higher number of lung cancer deaths in test positive individuals compared with test negative ones.

So, in conclusion, these studies identify patients who are at higher risk of developing lung cancer-specific mortality using a combination of blood-based biomarkers and clinical demographic characteristics. The combined models showed higher sensitivity and specificity and positive predictive value compared to the standard US Preventive Task Force criteria. The results of this study are important because the identification of individuals at higher risk of lung cancer diagnosis and death offers the opportunity for a more favorable tradeoff between potential harms and benefits of the screening process. And so these results could assist in the design of future screening and intervention studies as well as facilitate the uptake of lung cancer screening, especially for those test-positive patients that have a higher risk of lung cancer death. Application of this model could potentially lead to a higher number of patients diagnosed in earlier stages and thus eligible for curative intent treatment. 

That concludes this episode of JCO Article Insights regarding a summary of the article "Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort" by Dr. Irajizad and colleagues. 

This is Davide Soldato. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.

 The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Mahdi Sheikh and Dr. David Zaridze join Dr. Shannon Westin to discuss how quitting smoking after diagnosis may impact survival in kidney cancer.

TRANSCRIPT 

The guest on this podcast episode has no disclosures to declare.

Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours. This is the podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology. As always, I'm your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the JCO. And I am so excited to be here today. We are going to be discussing the paper, “Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study,” which was published in the JCO on March 29, 2023. And this very intriguing paper, I have two of the major authors from this paper. First is Mahdi Sheikh, who is a scientist and epidemiologist at the International Agency for Research on Cancer, the World Health Organization in Lyon, France. Welcome, Dr. Sheikh.

Dr. Mahdi Sheikh: Thank you very much, Dr. Westin, and thanks for having us.

Dr. Shannon Westin: And then with Dr. Sheikh is Dr. David Zaridze. He is the Director of the Department of Clinical Epidemiology at the N.N. Blokhin Russian Cancer Research Center in Moscow and also the President of the Russian Cancer Society. We are with greatness today.

Dr. David Zaridze: Thank you. Thank you very much. Nice to be with you.

Dr. Shannon Westin: Very nice to be with the two of you. So, let's get started. I first wanted to just level set. Could one of you review just the overall incidence of kidney cancer and what proportion of patients with kidney cancer are known to be smokers at diagnosis?

Dr. David Zaridze: The figures I'm going to present are rates. They are adjusted to standard world population. Why am I saying that? Because in America you sometimes use adjustment to the US population. These figures will be different from what you are accustomed to see. Okay, incidence of kidney cancer in Russia, in men, 14.1 per 100,000. I compare this with the United States of America, men, 16.5. Very small difference. Women in Russia, 8 per 100,000. In the United States of America, 8.8 per 100,000 of population. Exactly the same. Very close. These rates are sort of high-ish, but there are very high rates, for example, in the Czech Republic, where rates are more than 20 and other Central European countries. In Russia, kidney cancer mortality in men is 6 per 100,000. In USA, 3 per 100,000. In women in Russia, 1.9. In the United States, 1.3.

I would say that there is a difference in mortality in men, not much in women. The incidence of kidney cancer is increasing in Russia sharply, sharply. Since 1990 it has increased - it’s tripled. It increased from 5 per 100,000 in 1990 to 14 per 100,000 in 2019. Mortality is stable or declining. This is suggesting that kidney cancer is overdiagnosed in Russia and probably elsewhere. But this is not a problem of our discussion now. The frequency of the prevalence of smoking in kidney cancer patients. It is estimated that 15% to 20% of patients with kidney cancer smoke. In Russia, we have results only from our study. 18% of patients smoked at admission to our cancer center.

Dr. Shannon Westin: Got it. Okay, good. Well, that's really helpful, especially to those of us that don't take care of patients with kidney cancer every day. It helps us just understand.

And I guess the next question is what do we know about the impact of tobacco cessation on the risk of kidney cancer? So you were talking about that increasing incidence. How does tobacco cessation impact that?

Dr. Mahdi Sheikh: Tobacco smoking is a known risk factor for kidney cancer and an estimated 17% of the kidney cancer burden worldwide can be attributed to tobacco smoking. There is a recent meta-analysis of 56 studies that was published a few years ago that clearly showed a dose-response relationship between smoking and kidney cancer, meaning that the more cigarettes a day you smoke, the risk of kidney cancer will go up. For example, the risk that was shown for five cigarettes per day was 20%. It goes up until 70% for 30 cigarettes per day. And also with a duration, the more years you smoke, the risk for kidney cancer will go higher.

However, the good news is that when you quit smoking, there is strong evidence that the risk for developing kidney cancer will be lower compared to if you continue smoking. And there is some evidence that shows again dose-response relationship, meaning that the more years you spend in quitting smoking, the lower your risk would be for developing kidney cancer compared to if you continue smoking. So this is not only about renal cancer or kidney cancer but also true about many other cancer sites as well.

Dr. Shannon Westin: Okay, that's super helpful. And then I guess prior to your study that we're about to talk about, did we have any information on what happens when patients quit smoking after their diagnosis? Any limitations to those data that were available?

Dr. David Zaridze: You mean the data which was prior our study? You know, the negative effect of smoking after diagnosis has been shown nearly three decades ago. The information exists already for thirty years, but it was largely ignored not only in clinical practice but also in clinical trials. And I have to stress that in clinical trials this information is still ignored. I came across these studies and decided to review them some time ago. All they were case-control studies and to my knowledge, none of them assessed the effect of quitting smoking. I decided to review these studies and included this review in my book, Smoking: A Major Cause of Cancer, which was published in 2012 and was dedicated to Professor Richard Doll's anniversary. In fact, this was a stimulus for the study we are discussing. And in fact, the component of this study we are discussing today was built in and baked into the existing cohort study to which we added the active follow-up component for assessing the changes in smoking habit and disease status.

Dr. Mahdi Sheikh: If you review the evidence, before publishing this study just like a few years ago, we find that there are many studies published talking about the effects of smoking cessation on cancer survival. However, as David mentioned when you go deep into these studies, you’ll find a lot of limitations. First of all, most of these studies are retrospective studies, which means that either case-control or retrospective course that patients developed the outcome, and then some investigators came to see their records to assess or ask family members before they developed the outcomes. There are a lot of biases with these types of studies. And with the epidemiologic study, perspective study that we did, has less limitations compared to retrospective ones.

Another one is that when we go into the study you see, they only assess a small number of patients, small sample size. Some studies just assess 10 smokers, some assess like 30. By this study we try to assess a large number of smokers who quit smoking after diagnosis. Another limitation is that– First, let's see what exposure and what setting we are talking about. We're talking about smoking which is a very dynamic behavior. People quit smoking and they relapse smoking and they quit smoking and so on. So if you access this exposure for only a limited time, for example, for one year, then you may miss what happens after that which results in misclassification of some of the participants. So repeated assessment was not done in other studies that we did here in this study.

Another one, you are talking about special setting patients who are diagnosed with cancer. These patients have special circumstances, they have treatments, they have family support, they might go under the stress of cancer, and all these different stages at diagnosis. And most studies that are available, they didn’t account for this. They didn't adjust or they didn't try to understand the role of these compounding factors, as we call it in epidemiology, on that, the thing that we're trying to address. And a prospective study, as I said, long follow-up time. Even the very few prospective studies that were available for other cancer sites that have only one year or maximum two years of follow-up with this type of exposure, so it is important to follow them for a long time.

Another thing I would say was exposure assessment. Not only did we repeatedly try to assess exposure among participants, but try to call the people– David and his team who did the study in the field, called the participants and tried to ask the family members and sometimes their physicians about their smoking behaviors. When you go to current evidence you see, mostly smoking behavior was assessed using the record that is available like treatment records or patient records, which again has some limitations if you do not assess exposure among qualified participants.

Finally, we're talking about a dynamic behavior in the follow-ups. Some people might change smoking. But there is a very important thing, in this study, we also collect at the time of quitting smoking. There's a very important thing in statistics we call Survivorship Bias, meaning that, if you were assessing an exposure doing the follow-up and if you do not pay attention to this, you will assess an exposure that is a proxy of people who lived longer. Meaning that people have enough time, they have a long time, and those who have longer time, will have more time to quit smoking. And then you will be assessing this, actually, not the exposure, but you're only assessing people who quit smoking, and then whatever you assess, you would end up with a beneficial effect. But if you have the time of quitting smoking and follow up and all these statistical things and lower sample size, you are able to account for this very very important bias in epidemiology.

Dr. Shannon Westin: Before we go further, I'd love for just a bit of a description of exactly how you laid out your study to really add to where this data are so limited around survival and tobacco cessation. So maybe review the primary/secondary objectives, basic design, just to make sure our listeners are all on the same page.

Dr. David Zaridze: The study has classical prospective cohort design that the study, which was basically a basic study, in which the new component was built in. This study used a user’s questionnaire-based exposure assessment and molecular epidemiologic approach. I mean that, in addition to the questionnaire approach, we collected blood and tumor tissues for molecular studies. All patients with kidney cancer admitted to the cancer center were interviewed at admission before receiving any treatment. A structured lifestyle questionnaire was used. Participants were asked about their lifetime smoking history which included questions about the duration and frequency of smoking cigarettes, the average number of cigarettes smoked every day. They were also asked about their lifetime history of alcohol drinking. The questions included questions about exposures to carcinogens other than smoking, and health conditions, including chronic kidney diseases, hypertension, diabetes and so on. Height and weight were measured.

Today, this study generated and continues to generate plenty of results and papers published in most prestigious journals such as Nature Genetics, for example. So, as you know, we started from 2012, we started the follow up of the cohort members, we were focusing on Moscow residents and the follow-up includes regular annual contacts with the patients personally or via telephone or with patients’ household members, etc. Again, we collected information about changes in smoking behavior and disease status. We also used information from the regional cancer registry to confirm the information obtained from patients.

The average period of follow up was eight years. And this is quite a long follow-up. Repeated assessment of smoking status reduces the likelihood that exposure to smoking was misclassified. However, regrettably, the self-reported information on smoking was not supported by biochemical tests, for example, by blood cotinine testing. To my knowledge, this is the only prospective cohort study in patients with cancer, not only with kidney cancer that have collected data on participants' smoking status prospectively for quite a long time. The average follow-up time was eight years.

Dr. Shannon Westin: That was incredible. That definitely caught my eye. And I was looking, I was like, “Oh, how many did they lose?” And you guys kept 80-100% of the patients. I just was so impressed by that. And now hearing the mechanisms in which you did that, it makes sense. You were very diligent, multiple ways to contact patients and confirm the data. So you really are to be congratulated for the work that you're able to achieve.

Dr. Sheikh, I'd love to hear, you talked a little bit about how some of the studies didn't really think about confounding variables. Can you kind of highlight some of the confounding variables that you all controlled for in order to really assess the impact of the cessation on survival?

Dr. Mahdi Sheikh: Thanks to the high-quality data and also the large sample size and the way the study was designed, we were able to adjust for a lot of confounding. So we tried to adjust for all these things. So we used three approaches. The first approach was adjustment. When you ran this in the analysis, we tried a statistical model, we tried to adjust for these confounders like age, sex, treatment, socioeconomic status, smoking intensity, alcohol, and other factors. This is one effect, one approach.

The second approach was stratification, meaning that we come and see the effect within people who have been diagnosed with only earlier stage tumors to see if the effect among people with earlier stage tumors differs with the effect that we see among people with higher stage tumors. But again, if you read the paper, you see that we saw the protective effects of smoking cessation on both groups of people, those who were diagnosed at earlier stages and those who were diagnosed at later stages. And also heavy smokers or mild to moderate smokers, again, we tried stratified analysis excluding those heavy smokers and saw the effect, again, among those who were light smokers or moderate smokers and also with the heavy smokers. I want to say that we tried all these types of analytical approaches and we really saw the protective effects across all patient subgroups.

Finally, I talked again about the survivorship bias. So we used really strict statistical approaches to address this confounding, and because we had the time of quitting, we had the follow up time and all these things. And, again, whatever we did in the study we still could see the effects of smoking and all this is due to the good design, the large sample size, and the good questionnaire data that we have.

Dr. Shannon Westin: That's awesome. I think, of course, now let's get to the bottom line. 40% reported that they quit smoking after diagnosis with none relapsing during the time period. And what did you see was the impact on overall survival as well as cancer-specific survival?

Dr. Mahdi Sheikh: So we tried several outcomes - overall survival, cancer-specific survival, but also progression-free survival. And then because we had the large sample size we could assess all this. Interestingly, we saw the effect on all the three outcomes that we assessed. So the overall survival was better among those during the quitting time and also the cancer-specific survival was also better and also progression-free survival was better among all these participants.

Dr. Shannon Westin: I think most people that have read this paper - and if you haven't read this paper you should run to read it right now - I really was impressed with that kind of clear benefit across cancer-specific mentality across all subgroups regardless of how much they smoked. So I don't know why you get a sense of like, “Oh, if you smoke a little bit you wouldn't see as big of an impact,” but a very clear impact. And I would love to hear why you think smoking negatively impacts these outcomes. How does the cessation help? This is a perfect time for that.

Dr. Mahdi Sheikh: When we review the evidence about how smoking cessation may be beneficial for patients, for the survivorship of patients with cancer, we come to five mechanisms that are suggested in the literature. So the first one can be, is suggested, that is altered cancer biology. Smoke and tobacco smoke contain numerous carcinogens and mutagens. So it has been shown that cancer cells that are exposed to tobacco smoke, they may become more aggressive and the risk of metastasis might go higher and also, angiogenesis and all other effects on the biology of cancer cells. So it may affect the cancer cell biology.

Another suggested mechanism might be altered immune response. So tobacco smoking affects the immune system and then the immune response among those who are exposed to tobacco might be affected by tobacco smoking. So their response to the cancer cells but also other bacteria, viruses, and other things might be affected as well.

The third possible mechanism suggested altered drug metabolism. It has been shown that tobacco smoke and smoking can affect some of the enzymes that have metabolic responsibilities and metabolism of the drugs. So that can affect the washout period for the drug. It might not stay enough in the blood or vice versa as well. It might affect the toxicity. There is some evidence about this.

The fourth mechanism suggested is about increasing treating-related complications or treatment-related complications. People who smoke have delayed wound healing, they have more complications, the surgery, the time they spend at the hospital might be longer. And this is also part of which smoking may affect the outcomes that we saw here.

And finally, that is we are talking about tobacco smoking and patients with cancer are human beings with all these systems. So we know that smoking causes damage to the cardiovascular system, to the pulmonary system and also to the lungs and other things. So this is why we see different outcomes are affected by cancer.

Dr. David Zaridze: I was impressed by the data that exposure to tobacco smoke condensate induces changes in tumor microenvironment. For example, it inhibits formation of interferons, interferon alpha and gamma, inhibits the migration to tumor microenvironment of the immune cells. The number of CD8+ T lymphocytes, T killers, are significantly lower in the tumor microenvironment of current smokers compared to former smokers and never smokers. And even more interestingly, the number of PD-L1+ cells are also lower in the tumor microenvironment of current smokers than former or never smokers. This is probably very important in terms of effectiveness of impairment by smoking of the immunotherapeutic approaches in cancer treatment.

Dr. Shannon Westin: That's very important and we know the microenvironment has a huge impact on just the way the cells respond to treatment and develop resistance and so that makes a lot of sense.

Okay, well, this has been amazing and I think one thing that you just said just struck me, Dr. Sheikh, that you've obviously shown this in lung cancer and you're looking at this in other cancers. I guess the question is: What should we be doing? How should we be implementing tobacco cessation efforts across all cancer diagnoses to help all patients that have really any diagnosis of cancer?

Dr. David Zaridze: Let me first underline the clinical importance of these results. The benefits from quitting smoking are comparable or even superior to those recorded in the clinical trials of modern kidney cancer treatments such as immune checkpoint inhibitors. I refer to the results of pivotal trials in advanced renal cell cancer in the frontline setting and these results were reported at ASCO Meeting 2023 recently in May. If you compare the results of our study with results of these pivotal trials, it is very impressive.

It is clear that our findings strengthen the case for making tobacco cessation treatment a standard part of the routine health care for all people with cancer, however, smoking is still quite high in cancer patients. And I would like to quote Peter Shields who is saying that, in the United States,10% to 50% of cancer patients smoke. As far as Russia is concerned, in our study, 80% of kidney cancer patients smoke, and in our lung cancer study, 58% of cancer patients smoke. 

The barrier is that the oncologists do not believe or are accepting with a great deal of skepticism the results of our study. They don't believe the idea that anything else besides surgical, radiological, or medical treatment could improve the outlook of cancer patients. It's difficult for them to apprehend. Many of them think that smoking cessation after diagnosis is simply a waste of time. Many patients simply don't know that smoking cessation after diagnosis may be beneficial for them. In addition, they are pessimistic and they feel discouraged to quit smoking, as they might think it is too late. I would like to quote my favorite quote: “Smoking cessation treatment has to become the fourth pillar of cancer treatment, one that could affect cancer treatment outcomes as powerfully as surgery, chemotherapy, or radiation therapy.” This is Dr. Fiore, 2019.

Dr. Shannon Westin: Thank you so much. And Dr. Sheikh, anything to add there around cessation efforts?

Dr. Mahdi Sheikh: As we saw the results of these studies that smoking cessation is feasible and it is accessible at a minimum cost for many patients, it should really be integrated in the  management of patients with cancer. It is feasible, it is cheap, it is accessible. But unfortunately, when we review the evidence we see that only less than half of the physicians, like around 40% of physicians, send the patients to tobacco smoking cessation services. And even some do not discuss this issue. And as David mentioned, they do not know the effect of smoking cessation. So when you go through these studies to find the major barriers, in addition to what David had mentioned, we find two important points. First one is lack of education or experience in providing tobacco cessation interventions among those who deal with patients with cancer. So they do not have the education. And second is lack of available resources for referrals. Now we’re not only talking about the United States but also many other countries even high-income countries, we do not see the resources for referrals on smoking cessation services in cancer care settings.

The take home message probably from this study and also from these barriers, would be for three groups. First, for the policymakers, we would recommend sustainable funding should be dedicated to tobacco cessation services. As we saw, the effect is huge and seems to be a very big effect and it is cheap so why not implement this smoking cessation service within cancer care settings. 

And the second one, tobacco treatment training programs for healthcare providers. This is also very, very important that we try to implement this training program in the curriculum of healthcare providers, especially those who deal with cancers and tobacco-related outcomes.

And also for physicians, we recommend that physicians should assess and address tobacco use in all patients with cancer. They should talk about this topic and also show the benefits of quitting smoking. And patients with cancer who smoke should be supported to stop smoking at any time and each visit after diagnosis is not like some time pass, as we saw, all patient subgroups could benefit from smoking cessation. This is important. 

But something also very, very important that we shouldn't forget that cancer itself causes a lot of fear and anxiety and stress. And smoking cessation sometimes may be associated with stress and more anxiety. So it is very, very important to think about this point and provide the psychosocial support to patients who quit smoking. Sometimes they may relapse just because of the fear and anxiety they have. So it's not only showing the evidence, but also supporting these patients, telling them how to do that and also supporting them emotionally and also psychosocially.

And finally for the patients, I would like to give this message that we see and we know that it is never too late to quit smoking. As David said, patients may feel like, “It is too late now I've developed cancers,” but no, it's really not too late. And if you quit smoking at any time after diagnosis, you would benefit a lot from smoking cessation.

Dr. David Zaridze: In the United States there are guidelines, several guidelines for smoking cessation, specifically for cancer patients because smoking cessation in cancer patients is very different from smoking cessation in general population. In the general population, we more or less succeeded, I would say, and we have to look now at this direction to the smoking cessation in cancer patients. And this is a message to WHO, that countries, members of WHO, based on the recommendation guidelines of WHO, develop their own specific guidelines for smoking cessation in cancer patients. And that should be used in all cancer clinics and that should be a must, absolutely important part of anti-cancer treatment. And as I already told, it should be the fourth pillar in cancer treatment, as treatment, as surgery, chemotherapy and radiation.

Dr. Shannon Westin: Thank you both. That was such a great discussion, and I hope that we've convinced everyone that this is a critical effort that they need to be addressing every day. 

I just want to thank everyone who listened. This has been "Smoking Cessation after Diagnosis of Kidney Cancers Associated with Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study", again published in the JCO on March 29, 2023.

Thank you guys again for listening to JCO After Hours. Please check out our other podcast offerings. You can check them out on the website or wherever you get your podcasts and let us know what you think about the podcast on Twitter.

Dr. David Zaridze: Thank you.

Dr. Mahdi Sheikh: Thank you very much.

 The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin and her guest, Dr. Helena Yu discuss the paper "HERTHENA-Lung01, a Phase 2 Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFR TKI Therapy and Platinum-Based Chemotherapy" published in the JCO during the World Conference on Lung Cancer in Singapore. 

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare. 

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. And as always, it's my pleasure to review an incredibly exciting manuscript. 

Today, we're going to be talking about “HERTHENA-Lung01: A Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-mutated NSCLC Following EGFR TKI Therapy and Platinum-based Chemotherapy.” And this is exciting. This is a simultaneous publication in the JCO on September 10th, 2023 at the same time it's being presented at the World Conference on Lung Cancer in Singapore. 

I am joined today by the first author and overall outstanding physician, Helena Yu. She's an Associate Attending Physician, Thoracic Oncologist, and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center in New York, New York. 

Welcome, Dr. Yu. 

Dr. Helena Yu: Thank you. I'm glad to be here, and thanks for having me. 

Dr. Shannon Westin: So we're so excited to have you, and we love doing these simultaneous podcasts because I think not everyone can go to Singapore and be with you today. So it's awesome that we'll be able to give people the data that they want to see as soon as possible. 

So first, let's just level set. Coming from the GYN Oncology standpoint, I always like to get down to the basics of the cancer. So, can you speak just a little bit about the incidence and mortality of lung cancer overall and what have been some recent trends in the treatment of this disease? 

Dr. Helena Yu: Everyone knows somebody that has been touched by lung cancer. It's the second most common cancer that is diagnosed in men and women in the US today. It is the leading cause of cancer-related deaths, with 25% of cancer deaths really being attributable to lung cancer. Historically, prognosis with lung cancer has been poor, with five-year survivals around 10%. What's really interesting is over the last couple of years, there have been some improvements in survival with lung cancer. And I think that that can largely be attributed to the advent of immunotherapies as standard of care, as well as targeted therapies for driver mutation-positive lung cancer. 

Dr. Shannon Westin: So that leads right into the next question: What is the role of the EGFR pathway in lung cancer? How common are these aberrations and how successful have prior treatments targeting this pathway been? 

Dr. Helena Yu: Yes. So we, in lung cancer, have this mutation pie, which really describes the different oncogenes that we see in lung cancer. And probably now two-thirds of patients actually have a detectable driver mutation when their tumors undergo next generation sequencing. EGFR is probably one of the first mutations that was identified. About 15% to 20% of patients diagnosed with lung cancer in the US have mutations in EGFR. It is both activating and sensitizing. So, obviously mutations in EGFR cause cancer and they are sensitizing to different EGFR targeted therapies we have.

Right now, the standard of care for first-line treatment for EGFR mutant lung cancer are EGFR tyrosine kinase inhibitors. And those are oral therapies that actually are very successful at managing EGFR mutant lung cancer. They're not curative, but they do kind of control disease for a long period of time. But unfortunately for all patients, at some point their cancer does progress on these targeted therapies. And the most common one we use today is one called osimertinib, which is a third-generation EGFR TKI. And we do not have any approved targeted therapies after osimertinib. And so that kind of is the setting for this new drug, patritumab-deruxtecan. 

Dr. Shannon Westin: So tell us a little bit about HER3-DXd and why you prioritize targeting this particular part of the EGFR pathway in this population. 

Dr. Helena Yu: Yes. So HER3 is actually part of the HER EGFR family, and it is a protein that, when expressed, really portends a poor prognosis. It kind of tells us cancers that are more likely to recur and cancers where overall survival is shorter. So HER3-DXd is an antibody drug conjugate. There are a slew of new medicines in lung cancer that are ADCs. Historically, we looked at HER3 monoclonal antibodies in EGFR mutant lung cancer and they actually were not successful, not efficacious. And so it's really interesting that using these antibodies as part of an ADC construct has led to better efficacy. 

The HER3-DXd has that HER3 monoclonal antibody, there is a linker and then there is a chemotherapy payload. So for the deruxtecan family of which there are a few ADCs has a topoisomerase 1 chemotherapy, and in part, we know that HER3 is sort of more significantly expressed in these EGFR mutant lung cancers. And because HER3 is part of the EGFR family and heterodimerizes with EGFR, it was sort of a natural initial population to study this drug. 

Dr. Shannon Westin: Why don't you briefly highlight the design of the trial and your key eligibility for our listeners?

Dr. Helena Yu: So this phase II study came off the heels of an initial phase I study that helped us identify the appropriate dose of HER3-DXd for patients with EGFR mutant lung cancer. And so this study enrolled patients with metastatic EGFR mutant lung cancer. All patients had to have received EGFR TKI, most of them received osimertinib and that's first line standard of care globally. And then also patients had to receive platinum doublet chemotherapy, which is really our second line standard of care treatment.

The initial study randomized patients to two cohorts. One, which was all patients received 5.6 milligrams per kilogram every three weeks intravenous. The other cohort was an uptitration cohort, where they actually started with lower doses and then kind of sequentially over cycles increased the dose to see if that mitigated toxicity based on emerging phase I data that really showed that the 5.6 milligram per kilogram had the better efficacy as well as better toxicity profile. Pretty soon after the study started, all patients received that 5.6 mg per kilogram. 

And I think the other important thing to say is that patients with asymptomatic brain metastases were allowed. Lung cancer, in general, has a very high incidence or frequency of brain metastases. But in EGFR mutant lung cancer that number is north of 50%. So having a therapy that is effective in the CNS is especially important for this population.

Dr. Shannon Westin: So let's talk a little bit more about this population. The group that you enrolled and treated, is it representative of the general population that we might see in the community?

 Dr. Helena Yu: Yes, I think so. I think that one thing to highlight are these patients were pretty heavily pretreated. The median prior lines of therapy were three lines prior to study enrollment, but I think that went up to eleven for certain patients. And so that is one thing that I think is unique about this population, where they're able to sort of receive several sequential therapies. I think it was unique in allowing those asymptomatic brain metastases and then EGFR mutant lung cancer has certain demographic tendencies. And so we see women, Asian, never smokers, which may not kind of represent the typical demographic for lung cancer, but certainly is the typical demographic for EGFR mutant lung cancer.

Dr. Shannon Westin: Got it. And let's hear about your primary results. What did you discover?

Dr. Helena Yu: To set the stage, this is really an unmet need where post EGFR TKI and post chemotherapy, we really don't have exciting efficacious therapies. When you look at real world studies, the response rate to third line and beyond treatments are less than 10% PFS less than three months. And so really searching for something in this treatment landscape. And so for the study, the primary endpoint was confirmed overall response which was 30% for this patient population. Duration of response was 7.4 months and the median progression free survival was 5.5 months. Looking at sort of prespecified subgroups, there really did not seem to be a particular subgroup that had enhanced benefit. 

Dr. Shannon Westin: So that is a really impressive improvement in the expected standard of care results. So I congratulate you and I'm so excited. 

I was also really excited to see that you included patients with the asymptomatic brain meds for the recent ASCO-Friends guidelines. Can you speak a little bit about the efficacy in this population specifically?

Dr. Helena Yu: Absolutely. As I mentioned before, for these novel targeted therapies, we really do need to look specifically at CNS efficacy because that is absolutely an area where we often see disease progression. And so having studies that allow those patients really is more representative, of course, of the clinical practice that we actually treat. And so when you look at the subgroup that had a history of brain metastases, which in this group was actually, I believe, 51%, so the majority of patients, the response rate was really similar to the patients that did not have brain metastases. I believe it was 29% response rate for patients with brain metastases and 30% for patients without. 

And I think what is especially useful that we did was we had specific neuroradiologist look for measurable target lesions within the CNS that had not received prior radiation or prior local therapy to look at intracranial response rate. And so there were a subgroup of patients, 30 patients that had measurable target lesions within the CNS and the confirmed intracranial response rate was 33.3% in those patients with measurable target lesions in the CNS and disease control rate was 77%. So, I think, it's really exciting to see that the response rate in the CNS was really comparable to what we see with systemic disease.

Dr. Shannon Westin: That is awesome. I don't think I've ever seen anything quite like that. So really, you and your co-authors are to be congratulated for including this really important population. 

I guess the next natural question is, how was HER3 expression? Did you look at that? How was it associated with response to therapy? And did you find any other intriguing genomic alterations associated with benefit from the HER3-DXd? 

Dr. Helena Yu: That is a super interesting topic because I think in lung cancer we are well familiar with these driver mutations that really are the biomarker for targeted therapy. It is less clear what the appropriate biomarkers are for some of these antibody drug conjugates. We absolutely looked at HER3 expression, pretreatment tissue was required for this point specifically. And actually within EGFR mutant lung cancer, almost all patients have some degree of HER3 expression. And so we're already looking at a population that is enriched for potential response. 

But we actually looked at H-scores, looking at membrane HER3 expression and really did not find differences in the degree of HER3 expression when you compare patients with response versus stable disease versus progressive disease. So I don't think the degree of HER3 expression really is an appropriate biomarker. And I think we're still figuring out with ADCs, I think you actually might need very little of the surface protein for these ADCs to be internalized and be effective. So, right now, the disease population of interest is EGFR mutant lung cancer, where we think there's reasonable efficacy.

Dr. Shannon Westin: And that makes sense. And with this particular drug, is there a bit of bystander effect as well, like we've seen with some of the other ADCs? 

Dr. Helena Yu: There absolutely is a little bit. And I think what is interesting for this drug too is there are a few ADCs that are in development. So there is trastuzumab-deruxtecan, which is already approved for HER2 positive lung cancer; and then there is also datopotamab-deruxtecan, which is a TROP2 ADC. And so I think there really will be a wave of these different ADCs which are studied in slightly different populations. But I think understanding what the biomarker is for these and then, will there be cross resistance because of the similar chemo backbone, is something that we will need to find out in the future.

 Dr. Shannon Westin: Yeah, these are definitely unmet needs in this space.  

I guess one other question just around safety signals, anything unique for this particular agent? Kind of take us through the dose interruptions and dose reductions? 

Dr. Helena Yu: Absolutely. So I think that it is important to remember, and I do remind all of my patients that have consented to this study, that ADCs are a hybrid chemotherapy agent. So they will have some of the typical chemotherapy adverse events like cytopenias. We did see a little bit of alopecia with this as well. So I think there's thrombocytopenia and neutropenia that actually is more front-loaded and actually weren't necessarily associated with significant clinical sequelae like bleeding or neutropenic fever. 

The rate of treatment discontinuation from adverse events was actually pretty low at 7%; but about 20% of patients did require a dose reduction, and many of the side effects do appear to be dose-dependent. So I think those dose reductions are helpful. And then a really important side effect of this class of drugs is ILD or interstitial lung disease or pneumonitis. And we've seen kind of varying ranges of pneumonitis with these drugs. So far it really looks to be the highest with trastuzumab-deruxtecan with an ILD rate north of 15%; but with this drug, the independently adjudicated rate of ILD was 5%. So present, but maybe not as high as some of the other drugs in this class.

Dr. Shannon Westin: Well, that's great news. Well, congratulations on these exciting results and your presentation and your paper. 

The last question I have for you is what's next for this agent? What do you see? Where do you see it going?

Dr. Helena Yu: Absolutely. So I hope that with these promising results in an area of unmet need, that we will get approval for this drug so that we can get access to our patients. The other interesting thing that we are looking at is combining HER3-DXd with osimertinib, which is the standard of care EGFR inhibitor. So the idea of combining this novel therapy with the standard targeted therapy for this type of cancer, I think, is really interesting to see if we'll get even sort of greater efficacy and in particular greater CNS efficacy by combining two CNS active agents. So those are results that I'm looking forward to seeing, too.

Dr. Shannon Westin: That's great. Well, thank you so much for being here, Dr. Yu. And congratulations again on these incredible results and your incredible success in the lung cancer space.  

And thank you all of you for listening in to JCO After Hours, again, discussing the “HERTHENA-Lung01: Phase II Trial of of HER3-DXd in EGFR Mutated Non-Squamous Cell Lung Cancer.” We are always excited to have you. Please check out our other podcasts, reach out and let us know how we did. And until then, we'll see you next time.  

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gregory H. Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled  “The Childhood Cancer Data Initiative: Using the Power of Data to Learn From and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer”. Dr. Reaman introduces us to the initiative, its goals and structure, and what has already been achieved since its launch.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

 Emily Zabor: Welcome to this JCO Article Insights episode for the August issue of JCO. This is Emily Zabor, JCO's Biostatistics Editorial Fellow. And today I am interviewing Dr. Gregory Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled “The Childhood Cancer Data Initiative: Using the Power of Data to Learn from and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer.”

Dr. Reaman, welcome to our podcast.

Dr. Gregory Reaman: Thanks very much, Emily. Appreciate the invitation.

Emily Zabor: Dr. Reaman, could you start by introducing yourself and describing your involvement in the Childhood Cancer Data Initiative?

Dr. Gregory Reaman: I'm Gregory Reaman. I'm a Pediatric Oncologist. And I guess my involvement with the CCDI began shortly after the initiative was announced at the State of the Union media address in 2019, which was followed shortly thereafter by the formation of a working group by the NCI's National Cancer Advisory Board Board of Scientific Advisors. Given my role at the FDA at that time as Associate Director for Pediatric Oncology in the Oncology Center of Excellence, and the fact that I was the founding Chair of the Children's Oncology Group, I was an ex-officio member of this working group. So from very early on, I had involvement. I formally joined the NCI in November, left the FDA to assume the position as Scientific Director of CCDI.

Emily Zabor: That's great. So you've really been involved from the start. I had not really been familiar with the initiative until I read this paper. And as a cancer biostatistician, I was really excited to learn about this initiative, which sounds like it will ultimately create a very valuable data resource to be used for research purposes, among other things. So I think it's a really interesting project. So for our listeners who may not be familiar, could you describe the motivation for and goals of the Childhood Cancer Data Initiative?

Dr. Gregory Reaman: As I mentioned, this really is a very unique initiative, venture, if you will, on the part of the Cancer Institute and in large part driven by this fortunate infusion of funds to support childhood cancer research. And given the fact that pediatric oncology is very much a collaborative enterprise, it really does sort of follow that data sharing and using the power of data, its ability to be used by multiple investigators, irrespective of the source, aspirationally can improve outcomes for children cancer.

The three primary objectives– actually, this working group that I mentioned earlier put together a white paper that had 24 specific recommendations to the NCI. But there were three foundational objectives or goals. One was to learn from every child diagnosed with cancer, irrespective of the institution where they were diagnosed to receive therapy, to develop an ecosystem that would enable the submission, aggregation of data, and harmonization in a federated system that could then be accessed and used by investigators and analyzed to ultimately improve outcomes.

And then one objective, which was a little bit more specific, and that was to really focus on the opportunity to genomically classify tumors from newly diagnosed pediatric cancer patients, because this was something that obviously is much more widespread in the adult population, given the advent of targeted therapy and precision oncology and its more widespread use in medical oncology than pediatrics. And although many large academic institutions do have resources, the majority of smaller institutions do not. And when it's necessary and preferable to accurately and timely identify or diagnose a child's cancer that may actually provide information on treatment recommendations, the ability to do that and have it covered by insurance is sometimes problematic. So developing a program that would not cost patients or institutions anything and then make that data available to patients, families, and providers, as well as making it available for secondary research use, was a major goal and objective.

Emily Zabor: Yeah, that sounds like such an important initiative. The Molecular Characterization Initiative, which I understand has already enrolled and characterized the genomics of 751 participants just in the first year, I think is what the paper reported?

Dr. Gregory Reaman: That's correct. That was in the first year. We're now beyond the first year and we're approaching 2000 patients that have had their tumors genotyped and about 1500 results that have been returned to patients and providers.

Emily Zabor: That's fantastic. So with this linkage to the clinical data, that's going to be an extremely important data source. And I understand that the participation is currently limited to members of the Children's Oncology Group, which consists of over 200 children's hospitals, universities, and cancer centers. Can you describe in more detail what information it currently provides and how this initiative is going to be advertised and implemented to ensure complete participation across all of these member sites? Because that sounds like a really big challenge.

Dr. Gregory Reaman: Limiting the participation to the Children's Oncology Group initially was in no way meant to be exclusionary, but really provided an opportunity for linkage to clinical data. Since the Children's Oncology Group really represents nearly all of the pediatric cancer programs in the United States and some programs even outside the US, in Canada, and a couple of European sites, Australia and New Zealand, it was felt that given the resources that currently exist within the COG for specimen procurement, specimen submission, and then DNA and RNA extraction through the COG's Biopathology Center at the Nationwide Children's Hospital would really facilitate having the sequencing done at a single site, single institution, using a single platform. And also it provided an opportunity for some clinical data, including demographics, diagnosis, radiographic data, and treatment data that could be collected somewhat longitudinally from patients enrolled on the MCI.

Looking to make this as broad as possible since the objective of the CCDI is to learn from every patient, and every patient that we're concerned about not being able to capture adequately within the Children's Oncology Group are older adolescents and young adults with cancers that are more frequently seen in the pediatric population. So we are looking at ways to work with the COG's Biopathology Center to see if we can create systems that we can actually have specimens submitted from patients seen at institutions outside of the COG and molecularly characterized the same way. And that will be important as we launch another new planned initiative called the Coordinated National Initiative for the Treatment of Rare Pediatric and Young Adult Cancers.

Emily Zabor: Okay, that makes sense. So those adolescents and young adults are harder to capture since they're not being seen at those COG member institutions. Okay, well, that sounds like a big challenge to find those patients at their institutions and get them involved, but I think it's an important piece of this for sure.

Dr. Gregory Reaman: I should also point out that there were opportunities for some of the larger well, for all of the NCI-designated cancer centers, the pediatric programs associated with those cancer centers, to submit genomic data on newly diagnosed patients. That was something that actually transpired early on in the history of CCDI. So those data are in the CCDI's ecosystem.

Emily Zabor: Oh, that's great. So you collected the existing data.

Dr. Gregory Reaman: Right. 

Emily Zabor: That kind of leads into my next question about aggregating data sources. With these disparate sources of pediatric cancer data, it seems like the aggregation is a lofty and important goal, but once that's complete, you're going to have this data ecosystem, which you said was one of the main goals of this initiative. I was wondering if you could tell us who will have access to this data ecosystem and what will be required for individuals to gain access.

Dr. Gregory Reaman: All of CCDI was predicated on this really being a community initiative if you will, so multidisciplinary and community-based. So patients, families, advocates, clinical researchers, physician providers, basic and translational researchers, researchers in public health and epidemiology. So there will be different levels of data that will be available to specific individuals. Patient-level data will be deidentified through a system of APIs that will be used that will enable the association of clinical data to existing molecular data and outcome data that might be available in the ecosystem. Those data will be- there are many data in the ecosystem that will be open source and available to anyone who is interested. This includes data from the NCCR in the Childhood Cancer Data Catalog, which is basically a listing of some close to 300 pediatric cancer databases that are available. The patient-level data will be sort of a controlled access. So there will be a requirement for individuals, investigators who wish to access that data, to sort of be certified, if you will, utilizing NCI and NIH data sharing requirements.

Emily Zabor: That makes sense. Yeah, you mentioned deidentification, but especially when we're dealing with these kinds of rare diseases, patient privacy does seem like it could be a concern. So what exactly are you doing to ensure that that is not something that gets violated through this process?

Dr. Gregory Reaman: I think there's every attempt to eliminate any PPI, HPI, obviously. So, again, most of the clinical data that are being provided currently are data that's coming from the Children's Oncology Group, where for every patient enrolled or registered through the COG and enrolled on a clinical trial, there is a COG ID number that is associated and that will be available only to the NCI and the CCDI to link it to unique specimen identification numbers, which are the only numbers that will be available to any investigator. So no one will be able to make the connection from the specimen identifier to the unique patient identifier in the COG.

Emily Zabor: That's great. And that way, you can really get access to all of the detailed data without concerns about privacy.

Dr. Gregory Reaman: Correct. And then being able to link all of these disparate data sets will really require the identification or the development, I should say, of a participant index. So that is one of our highest priorities right now in developing a CCDI participant index so that we would be able to link the identifier or clinical data with any research data or biologic data that may be available on patients to facilitate research plans and programs.

Emily Zabor: And through that process, is there also some method involved for identifying duplicated data? Because I assume some of these patients may get seen at different institutions over time, and that could be a concern that they end up in the database multiple times.

Dr. Gregory Reaman: That's exactly why I think developing the participant index is so critical to, number one, link, and number two, to avoid, prevent duplication, because you're absolutely right. There may well be the same patient data in multiple data sets, which are, of course, disparate. And the only way that they're going to be really utilizable and made interoperable is by linking them to the specific patient or individual patient.

Emily Zabor: Great. And do you have an idea of the timeline when that part would be complete and this data ecosystem would be available to researchers?

 Dr. Gregory Reaman: The ecosystem is already available to researchers. We launched several months ago the CCDI hub, which is sort of the entryway or entry point, if you will, for access to the ecosystem. We hope to actually have the participant index up and running, and it's something that we've been working on for over a year, but actually available and utilizable within the next several months. 

Emily Zabor: That's fantastic. We'll have to go check out the CCDI hub that's already out there then. Before we end, is there anything you'd like to share with our listeners that we haven't already discussed?

Dr. Gregory Reaman: Well, I think the one program that I mentioned just briefly, the Coordinated National Initiative for Rare Pediatric and Young Adult Cancers, we see there's a real opportunity to address a major unmet need. Fortunately, all pediatric cancer is rare, but there are some cancers that are extremely rare and for which there are, in many cases, no defining standard of care, and in many cases, there are no treatment protocols because of the difficulty mounting studies with such small patient numbers. So we see this as an opportunity to actually develop a registry that will provide, hopefully, natural history data that will inform clinical trials. All of these patients will be enrolled on the Molecular Characterization Initiative. So there will be the opportunity to hopefully learn if there are specific molecular drivers of some of these cancers that could inform the use of targeted drugs in a therapeutic approach to some of these. And we're looking to do this international collaboration with colleagues in the EU as well. So that is something that we just launched a task force  to develop a listing of core critical data elements to collect on patients and then developing the registries for a number of these rare cancers.

Emily Zabor: That sounds like it's going to be a really valuable resource for planning and designing future clinical trials, so I'm glad to hear about that.

Dr. Gregory Reaman: And we would invite anyone who's interested to find out about the CCDI, to find out more about the CCDI, which they can do through cancer.gov/ccdi. There is an opportunity for people to register for newsletters. We have a series of webinars, many of which are designed now to actually provide training on some of the resources and platforms that are available currently through the ecosystem and things that we have all planned for future developments and use. So as I said, this is a community venture and we look to expand the community in every way possible.

Emily Zabor: That sounds great. So hopefully our listeners will take note of some of those resources in addition to this paper being out there, which will guide some people in the right direction to learn about this really great initiative for childhood cancer. 

So, Dr. Reaman, it has been a pleasure speaking with you. And thank you so much for joining me today on this episode of JCO Article Insights.

Dr. Gregory Reaman: Thank you very much. It's been great to be here. Appreciate the opportunity. 

Emily Zabor: This concludes this episode on the article, “The Childhood Cancer Data Initiative Using the Power of Data to Learn from and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer.” Thank you all for listening and please tune in for the next issue of JCO Article Insights. 

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin, Dr. Abbas M. Hassan, and Dr. Leticia Nogueira discuss the impact of heatwaves on cancer care delivery and what can be done about it.

TRANSCRIPT

The guests on this podcast episode have no disclosures to declare.

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. I'm so excited to be here today to discuss a very thought-provoking manuscript. This was published on June 10, 2023, in the Comments and Controversies section of JCO, and it’s entitled “Impact of Heatwaves on Cancer Care Delivery: Potential Mechanisms, Health Equity Concerns, and Adaptation Strategies.” 

And I am thrilled to tell you I am joined today by two of the authors of this very important manuscript. Dr. Abbas Hassan is an intern in the Division of Plastic Surgery, Indiana University School of Medicine. Already reaching for the stars, publishing in the JCO as an intern, that has to be a record. Congratulations and welcome, Dr. Hassan.

Dr. Abbas Hassan: Thank you for having us. Appreciate it.

Dr. Shannon Westin: And with Dr. Hassan is Dr. Leticia Nogueira. She is now the Scientific Director of Health Services Research at the American Cancer Society. Welcome, Dr. Nogueira. I'm so excited to have you.

Dr. Leticia Nogueira: Excited to be here.

Dr. Shannon Westin: Let's get right to it. This topic is very timely. We are currently enjoying several weeks of greater-than-100° weather here in Texas, where I am, and across the United States. Why don't we start by just defining heatwaves in general and what their global impact is on morbidity and mortality?

Dr. Abbas Hassan: Yeah. So, I mean, it's the Texas heat, right? It's hard to ignore it when you're sweating buckets, right? So this kind of extreme heat isn't just a Texas problem. It's happening everywhere, so from Australia to Europe and across the US. And what we're experiencing, my friends, are heatwaves. They're like the unwanted guests at a barbecue, showing up uninvited, hanging around for at least two straight days. Now, defining a heatwave isn't straightforward as it might sound, with various different definitions across studies and policies. But one thing that is clear: heatwaves aren't just about discomfort. They're deadly. They're claiming more than 5 million lives globally every year. 

Now, let's just imagine for a moment the year 2020. Not exactly a walk in the park. And on top of that, everything else, heatwaves cost over $4.5 billion in damages in the US. And that's probably just the tip of the melting iceberg, considering the tricky task of identifying exact heatwave periods.

Dr. Shannon Westin: And you said it's really hard to define, so I imagine that that makes it really difficult to study. Hopefully, I think we've already gotten our first call to action is coming up with some type of consistent definition so we can truly look at this in a scientific fashion. I guess I'm asking you to predict, but I'll do it anyway. What do we expect to happen over the next 30 years in regards to the climate change we're seeing and maybe overall temperatures across the globe?

Dr. Abbas Hassan: The way things are going, we're probably going to need a lot more sunscreen and a lot more ice cream. In all seriousness, the outlook is pretty stark. By 2023, we're looking at 8.1 million of our fellow Americans facing temperatures hotter than 125°F. And fast-forward to 2053, the number skyrockets to like 100 million. So that's a 13-fold increase. Remember when we thought 2014 was hot? And then 2015 came in, then 2016, and now all the way to 2020. Each year seemed to outdo the last, making the past seven-year span the warmest we've ever experienced. So we're not just dealing with a few off years. We're in the midst of a trend that's heating up our planet and impacting our health at an alarming rate.

Dr. Leticia Nogueira: Yes, I would like to add to that, exactly what Dr. Hassan said. We don't really need to worry about or focus on what temperatures are going to be in 30 years. It is here now. The threats of climate change are here now, threats of extreme heat, no matter how we define it, right? Because it could be number of days above a certain temperature threshold, and that threshold is usually established by the previous 30 years. And we've already seen these jumps in temperatures in the previous 30 years, especially in most recent years. So these hazards, these threats, are already here. No future projections necessary to understand the hazards and the detrimental consequences of exposure to extreme heat due to climate change.

Dr. Shannon Westin: Well, let's talk a little bit about that. And specifically, I would love to hear kind of what we've been seeing as far as the impact of heatwaves on health outcomes. I think our group would be interested in knowing, what are some of the things that you're seeing and you’re experiencing? And then further, what are the things that make people more vulnerable, let's say, to the climate hazards?

Dr. Abbas Hassan: Yeah, let's dive in a bit more into what makes us vulnerable to these heatwaves. When you think about vulnerability, the key elements are, one, increased exposure; two, increased sensitivity; and three, decreased ability to adapt. So think about it this way: Let's say you’re—not sure if you guys play this—let’s say you're playing a game of tag, and the sun is it. Now the sun is pretty good at tag, so anyone spending a lot of time outside—that's increased exposure—is more likely to get tagged. Then you have some players who are, for various reasons, they’re slower or less agile. So this can be due to age, health conditions, or other factors that make them more sensitive to heat. They're not able to dodge the sun as quickly. So that's increased sensitivity. And finally, imagine some players are dressed up  in heavy clothing, unable to change into something cooler. They don't have the resources to adapt. So that represents that decreased adaptive capacity. While everyone playing this game can feel the burn, there are some who are more at risk. 

So, for example, individuals with cancer are particularly at risk because they have various physical, psychological, socioeconomical consequences of their diagnosis, treatment, and even their path to survivorship. And this can include everything from weight loss to tumor, compromised immunity, side-effects from medications, and even financial stressors, making their game of sun tag especially challenging. So when we talk about the impact of heatwaves on health, it's not a one-size-fits-all issue. Our vulnerability is a complex combination of various factors that can leave some of us more at risk than others. And it's this understanding that can help shape our approach to tackling the challenges that climate change brings.

Dr. Shannon Westin: That was very well stated, and I think I want to dig in a little bit deeper on some of the broad factors you covered, especially as it relates to patients with cancer, who obviously fit in the category of vulnerable to really all those pieces. So I'd love to dig in a little deeper. So let's talk a little bit more about age. I know that certainly patients with cancer can be any age, but it does seem to affect patients that are older or more elderly. How might that impact sensitivity to these heatwaves?

Dr. Abbas Hassan: Okay, so dig a little deeper here. The reality is that getting older comes with its fair share of challenges, and one of them is increased sensitivity to heat. So as we age, we become more susceptible to heat. And this is particularly true for individuals over the age of 65, many of whom are also dealing with a cancer diagnosis. In fact, the number of seniors with cancer is expected to nearly double by 2060. So heat sensitivity in this group is due to several factors. First, our body's ability to regulate heat, or thermoregulation, declines with age, much more like an old car cooling system not working as it once did. So this means we're less able to handle extreme heat, making us more vulnerable during heatwaves. And this vulnerability is especially concerning for older cancer patients because some cancer treatments can cause additional complications, such as kidney injury, which can impair our cooling systems even further. 

Additionally, these treatments can lead to dangerously high levels of hypernatremia and hyperkalemia, and this can lead to serious complications like cardiac arrhythmias. So in other words, the aging process coupled with cancer and its treatment can make older folks more susceptible to the harsh impacts of heatwaves.

Dr. Shannon Westin: That makes sense. So you started to touch a little bit on comorbidities with discussing heart disease and arrhythmias and how that might impact. Are there other comorbidities that are certainly quite common in patients with cancer that can impact health conditions related to climate change?

Dr. Leticia Nogueira: Yes. So, in addition to, as Dr. Hassan mentioned, some chemotherapy drugs inhibiting thermoregulation makes it harder for people to control their body temperature, several cancer treatments also impact kidney function, and kidneys are important organs for body temperature regulation. Even some cancer treatment drugs also lead to cognitive impairment, which makes it harder to recognize heat stress and heatstroke symptoms. It could also impair mobility and the ability to go look for a cooling, safe space. There are several other cardiorespiratory comorbidities that can also impact sensitivity to extreme heat. And we cannot forget that cancer diagnosis treatment comes with socioeconomic consequences as well, because it impacts the ability of individuals to remain employed or maintain the same level of income. And these socioeconomic consequences also impact the adaptive capacity that Dr. Hassan was mentioning, such as installing air conditioning or improving insulation during a heatwave or throughout the year, which makes individuals diagnosed with cancer more vulnerable to these threats.

Dr. Shannon Westin: You had mentioned some of the economic challenges here. I'd love to speak a little bit more about that, and I think we certainly see this in vulnerable populations just in general, being able to receive their cancer treatment or make it on time for their treatments. In addition to that, are there limitations around accessing resources or things that would help protect people during these heatwaves?

Dr. Leticia Nogueira: Yes, we see a lot of barriers in access to resources in communities that have been targeted for marginalization or they are experiencing barriers in access to resources. Right? We can start with some of the ways that our urban centers are built. Concrete and asphalt trap heat in urban centers, leading to this effect called the urban heat island. So you see almost a 20° difference between urban centers and more suburban or rural areas when it comes to these hot days. And that, of course, increases exposure to extreme heat, which is one of the components of vulnerability. 

Then you have sensitivity. If there are barriers in access to healthy resources, healthy foods, places to exercise, and there are, for example, an increase in targeted advertising for tobacco or alcohol outlets in the neighborhood, that has been shown to be associated with an increased prevalence of several chronic health conditions. And as we were discussing, these chronic health conditions also increase sensitivity to climate hazards. 

And then, of course, there is adaptive capacity. We were mentioning the challenges faced by people who have been diagnosed with cancer in being able to afford some of the infrastructural updates that are necessary to cope with extreme heat. And the same challenges apply for people who are experiencing other types of socioeconomic distress, making it harder for these communities to prepare and respond to the challenge posed by heatwaves. 

Oh, there's one more thing. I just wanted to mention that this is a concern, the adaptive capacity, not only for these communities that are facing barriers in access to resources. With climate change, there's been an increase in power outages. So, even if you can afford to use AC, it does not mean you're going to be able to use it during a heatwave because these power outages are becoming more frequent, especially as people turn up their AC and overwhelm the electric grid. So this is a concern for all US residents, not just people from lower socioeconomic levels or cancer patients.

Dr. Shannon Westin: You are speaking my language, coming from Texas, where our grid is a constant source of--

Dr. Leticia Nogueira: I lived in Texas for a while. Yes.

Dr. Shannon Westin: I know you did. I saw that in your bio. Okay, well, I think we got the scope. I'm appreciative of the level of detail that you all were able to cover in such a short period of time. So I think now let's move towards the kind of action items, like what can we do? How can we mitigate some of these issues, or all of these issues? Start wherever you think your lowest hanging fruit is, I would say.

Dr. Abbas Hassan: Okay, absolutely. So addressing the challenges that climate change presents, especially for vulnerable groups like cancer patients, is, I would say, a lot more like putting together a jigsaw puzzle. It requires us to work on multiple fronts at once and fit all the pieces together to form a complete picture. So let's walk through this puzzle together. So picture this: Our first puzzle piece involves upgrading our healthcare infrastructure. We need to gear up our systems with surveillance, monitoring, and even staffing to swiftly detect and respond to heatwaves. The second part of the puzzle is that our healthcare workers, or providers, need to become more aware of climate change. They need to provide guidance to their patients that suits their cultural context and language, discussing things like what they need to wear during a heatwave, the best way to travel, even what changes to make in their diet. But how would our healthcare providers turn into these warriors? Well, that brings us to our next piece, like continuing medical education. So, by providing education opportunities into medical and public health curriculums, we can create a force of well-prepared healthcare providers and professionals ready to fight the challenges of climate change. 

And also considering how heatwaves can affect our medications. As temperatures rise, we need to think about developing thermostatic medications that can withstand the hotter conditions. It's like equipping our medications with their own little heat shields. Lastly, I think, which is perhaps most importantly, we need to be stewards of our own environment with our own healthcare systems. This includes reducing our carbon footprint and advocating for heat equity. So a concept that ensures that everyone, irrespective of their socioeconomic status, has access to and protection from heatwaves’ related risks. So, just like that jigsaw puzzle, every piece plays a crucial role. By working on those front lines simultaneously, we can build a more resilient, equitable healthcare system ready to face the rising temperatures.

Dr. Shannon Westin: Okay, you absolutely win on JCO After Hours for the best examples. The puzzle pieces. I’m just—I am, like, obsessed. This was—you're amazing.

Dr. Leticia Nogueira: Playing tag, right? He's a natural.

Dr. Shannon Westin: Playing tag, the sun exposure. I was like, this is like… I have to say you are very well suited for this type of work.

Dr. Abbas Hassan: You're too kind. Thank you.

Dr. Shannon Westin: And honestly, I think when you put it like that—sometimes these kind of problems seem so big and overwhelming, but when you kind of break it down into those chunks, it does seem doable. And I think almost every time on this podcast I bring this up, but I'm going to do it again. What can we do to change policy, right? We need a policy change. Like, some of what you mentioned is medical education, things like that. But really, what about lawmakers? What do we need to be talking to our lawmakers about so that we can get broad-based policy changes that will help us enact some of these strategies that you just so well described?

Dr. Leticia Nogueira: I also wanted to add something I think is relevant to both here, and that is that the United States healthcare system is the second largest industry when it comes to emissions in the US. Emissions from the US healthcare system alone surpass emissions from the entire United Kingdom. So there is a big component of this strategy here to recognize that it is anthropogenic, manmade emissions that are causing climate change and leading to these detrimental health consequences. In our role, there are only so many Band-Aids we can put on this side before we start evaluating how we’re actually contributing to the problem. 

And here is where this jigsaw puzzle and the policy and “I'm getting overwhelmed” kind of all comes together because there are several different efforts that are both climate mitigating and also improve climate adaptation. For example, switching towards clean energy sources that are generated on-site at healthcare systems can decrease the emissions of these institutions and also make them more resilient to power outages that, as we talked about, are only becoming more frequent. And there are several other examples. And you were asking about policy. I think that one of the recent advances when it comes to policy-level interventions comes from the Inflation Reduction Act, where we have a lot of incentives for shifting towards more clean energy sources and decreasing our environmental impact with our professional activities that we need to keep in mind as we're trying to protect the health and safety of cancer patients.

Dr. Shannon Westin: Great. Thank you so much. And I guess that we're getting towards the end of this. It's gone by very fast, and I personally am writing down my to-do list of things I need to do tomorrow. What is next for you all for your work in this space?

Dr. Leticia Nogueira: I think that, as a researcher, there’s a few different things that we can do. Similarly, as you are a clinician or a psychooncology or any of these other professions. One of them goes back to Dr. Hassan was saying surveillance and measuring the effects because that increases awareness and provides the background evidence that's necessary for developing and implementing solutions, right?

And then, of course, being champions within our own institutions so that we are both trying to solve the problem when it comes to protecting the health and safety of patients. Is it possible to use electronic health records to identify those who are most vulnerable? Can we expand on data sharing and information sharing so we can build on lessons learned from previous heatwaves and do better next time? And then how, of course, can we contribute to reducing the emissions from our own institutions so we stop contributing to the problem we're trying to solve?

Dr. Shannon Westin: Well, this was so educational, and I am so pleased that we had an opportunity to talk to you about this really important paper. I just want to thank, again, Dr. Hassan and Dr. Nogueira for taking the time to review this and really for thinking through this very important problem. And I hope it inspires all of you to look at what your institutions are doing and determine what strategies you might be able to utilize to start to mitigate some of these problems. 

Again, we were discussing the Comments and Controversies manuscript “Impact of Heatwaves on Cancer Care Delivery: Potential Mechanisms, Health Equity Concerns, and Adaptation Strategies,” which was published in the Journal of Clinical Oncology June 10, 2023. If you haven't read it, run, don't walk, to do so. And please do check out our other JCO After Hours podcasts on our website. And if you have any problems, reach out to me on Twitter. I'd love to chat. Have a great day.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

 Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.