In this episode of JCO Article Insights, Dr. Giselle de Souza Carvalho interviews Dr. Hatem Azim and Dr. Ann partridge on their JCO article “Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy,”

TRANSCRIPT

Giselle Carvalho: Welcome to the JCO Article Insights episode for the August issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host. I'm a Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers, and one of the ASCO editorial fellows at JCO this year. Today, I will have the opportunity to interview Dr. Hatem Azim and Dr. Ann Partridge, two of the authors of the POSITIVE trial. We will be discussing their trial on “Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy,” which was published in May this year. 

Hello, Dr. Azim and Dr. Partridge. Welcome to our podcast.

Dr. Ann Partridge: Hi. Thanks.

Dr. Hatem Azim: Hello.

Giselle Carvalho: So, beginning with our interview for breast cancer survivors, in addition to the treatment itself, aging is one of the major contributors to infertility. The optimal duration of adjuvant endocrine therapy in patients with hormone positive early breast cancer ranges from five to ten years, depending on patient and tumor characteristics. This time interval can be critical for women who wish to attempt pregnancy. One of the main concerns in daily breast cancer oncology practice is whether breast cancer recurrence rates are increased either by temporary interruption of endocrine therapy for pregnancy or by the use of assisted reproductive technologies.

Dr. Azim, what about assisted reproductive technology is worrisome regarding breast cancer outcomes? And how do the POSITIVE study results address the concern about worsening breast cancer outcomes either with assisted reproductive technology or endocrine therapy interruption?

Dr. Hatem Azim: So, in the primary analysis of the POSITIVE trial, we tried to address one of these questions, whether temporary interruption with endocrine therapy affects breast cancer outcome. And what we found was that interruption did not appear to have a detrimental impact at the median follow up of 41 months. So in the current manuscript, we addressed the second question, whether assisted production of fertility preservation has an impact as well on breast cancer outcome. And we did not find any worsening of outcomes in patients who underwent these procedures compared to those who had a spontaneous pregnancy. Of course, we have relatively short follow up, but at least the outcomes at the median follow up of around 3 to 4 years appears to be reassuring.

Giselle Carvalho: I see. Thank you. These are really important outcomes regarding premenopausal patients.

So, moving on, results from your study show that after 24 months, 80% of women under 35 years old had at least one successful pregnancy, while the same was true for 50% of women aged 40 to 42. These results are particularly impressive considering that over 60% of women over 35 had undergone chemotherapy. 

Dr. Partridge, other than age, what factors did you find were associated with a successful pregnancy? 

Dr. Ann Partridge: Yeah. The biggest factor, other than age, that was associated with successful live birth pregnancy was use of assisted reproductive technologies. So either having gone through IVF prior to diagnosis and banking eggs or embryos prior to diagnosis and then using them during the study, for undergoing stimulation of the ovaries during the study and then using it during the study. And that's what we also looked at in this most recent analysis of the initial POSITIVE data. 

Giselle Carvalho: I see. Thank you. The group of patients who underwent embryo oocyte cryopreservation at diagnosis were more likely to be nulliparous and treated with chemotherapy. Presumably these represent the patient group most afraid they will be infertile, as they would be receiving chemotherapy, and most desirous of pregnancy, as they had not yet had any children. Fertility preservation techniques are expensive and not easily available for all patients, particularly in less wealthy countries. Is there any group of your breast cancer patients with a high enough likelihood of pregnancy without assisted reproductive technology that you would not recommend this? 

Dr. Ann Partridge: Sure. So we are so glad to have assisted reproductive technologies available in many places, but as you know, they're not available everywhere. And even where they're available for some people, it's either inaccessible for a number of reasons or it doesn't feel right emotionally or ethically. And then finally, sometimes people need fairly quick treatment and they just don't have the time, even though we don't think there are long delays. And so we do and are able to know who can get pregnant after standard chemotherapy. Not perfectly, but we can give estimates. And the gestalt is, the younger a woman is, the less likely she is to become amenorrheic and the associated infertile, although it's not a perfect match in terms of amenorrhea being a surrogate. And then there are particular chemotherapy regimens that are more gonadotoxic than others. The more cyclophosphamide, for example, or alkylating agent, the more anthracycline, the higher the likelihood generally of causing at least amenorrhea and likely infertility. The huge caveat there is that for some of our newer therapies, we have no good information about how they might impact on menstrual status, let alone the actual rates of fertility. So we need to collect those data. But certainly, if someone's very young, they're going to get four cycles of TC or they have inflammatory breast cancer, we often take kind of a let the chips fall where they may approach, because they just aren't able to access it and we'll often do something like ovarian suppression through the chemotherapy to help support them and hope that it improves their menstrual functioning in the long run and/or fertility.

Giselle Carvalho: Thank you for your insight. So you found that pregnancy incidence over time differed by age group, although incidence of menstrual recovery over time was similar across all age groups, which I conclude that menstrual recovery does not translate into fertility. The addition of gonadotropin releasing hormone analogs to chemotherapy was not associated with time to pregnancy. However, of course, such use was not randomized. 

Dr. Azim, if assisted reproductive technology is not available to patients for reasons such as socioeconomic factors, would you recommend using GnRH analogs with chemotherapy for the purpose of fertility preservation? 

Dr. Hatem Azim: Yes. The short answer is yes. Of course, POSITIVE study was not designed to address the question around GnRH analogs, but we do have several randomized studies and meta analyses that have shown clearly that the use of GnRH analogs with chemotherapy reduce the risk of premature ovarian insufficiency. And subgroup analysis of some of these studies have shown a trend towards higher pregnancy rates as well. So, of course, if a patient does not have access to assist reproductive technology, GnRH analogs in combination with chemotherapy represent a very good alternative. 

Giselle Carvalho: I see. Thank you. Thank you for your response. At enrollment, 93.2% of women on POSITIVE trial had stage 1 or 2 disease and 66% had no negative disease. Therefore, one possible bias is that investigators might have been more comfortable with temporarily interrupting endocrine therapy if the risk of relapse was low.

Dr. Partridge, what recommendations would you have for women with stage three hormone receptor positive breast cancer who desire to attempt pregnancy?

Dr. Ann Partridge: Yeah, thank you. That's a really good question. It comes up in our tumor boards and discussions about patient care all the time, and I think, as you know, only a small proportion, about 6%, had stage 3 disease. Those patients are at higher risk of recurrence by nature of their stage. Not that all stage 3 are created equal, because, of course, if someone had a complete pathologic response to preoperative therapy and their stage 3 disease at diagnosis went to a PCR, then that person may have even better outcomes in the long run than someone who had postoperative treatment, and we don't know their likelihood even with stage 1 or 2 disease. But someone that you're concerned about their risk of recurrence, they still remain at risk of recurrence. And while we do not think, based on the POSITIVE data and all the data that we've had from retrospective studies and other data sets collected for other reasons, that a pregnancy would worsen their outcome, we certainly don't believe that a pregnancy at this point in time will dramatically improve their outcome or as a treatment for breast cancer. That's when I have a heart to heart conversation with the patient, really acknowledging they still remain at high risk. And most of my colleagues tend to want the patient to get more endocrine therapy into their system before they take a break. We've kind of discussed this, and we want someone to get more like at least three to five years. That may be a little bit paternalistic, because, as we know, taking the break for people with a little lower risk didn't seem to worsen outcomes. Maybe it's fine. I don't know that a break at five years is any better than a break at two years. I don't know. Hatem, how do you handle this in your practice?

Dr. Hatem Azim: Well, I completely agree with you, Ann. I mean, it's very much decided on a patient by patient basis. The level of uncertainty that some patients accept to take is not necessarily like others. And sometimes we as physicians, we adopt this. I agree with this paternalistic approach. Nevertheless, it's very important for the patient who is 32, is not necessarily counseled like the patient who’s 39, and her acceptance and the feasibility of waiting a bit longer as well in order to attempt pregnancy - the success of pregnancy afterwards is not necessarily the same. So I'm not sure we could adapt a one size fits all approach here. And I do not necessarily tend to factor much the elements around the stage. I think my point to patients is usually, well, you do have give and take this amount of risk of relapse, for example, and whether we accept to take such, what we could refer to as relatively unconventional approach of temporary interrupting endocrine therapy, and when we are comfortable to go ahead with this journey, depending on the feasibility of getting pregnant afterwards as well. So, yeah, I completely agree. It's very customized, based on and tailored according to the patients’ situation.

Giselle Carvalho: Thank you. I really appreciate your response to this. So, moving forward, tamoxifen alone was the most commonly prescribed endocrine therapy, followed by tamoxifen plus ovarian function suppression. The latter was preferred over aromatase inhibitors ovarian function suppression in the selected population. Endocrine therapy prescription changed in the second half of the recruitment period after July 2017 across all continents, likely due to the results of the SOFT and TEXT trials. It demonstrated absolute improvements in all disease outcomes by escalating endocrine therapy, which was more clinically meaningful in patients with high risk disease. Dr. Azim, how do you imagine this change could impact positive outcomes?

Dr. Hatem Azim: Honestly, I'm not necessarily sure that it impacts significantly the way you interpret the data and the way we counsel our patients. So, in our study, some 50% of patients received GnRH analogs and around 15% received AI. And most of the patients, I would say, were recruited in the second half of the study after we had the results from, for example, SOFT and TEXT. Furthermore, as we alluded to earlier, we had 60% of patients who received chemo. So most of our patients had a stage 1 and 2 disease in which you would argue that the absolute difference between the different hormonal therapy options is not necessarily massive. Whether or not this would impact much, I'm not sure. I think the main counseling recommendations would apply, that patients who receive endocrine therapy would be asked to interrupt it for at least three months and then they attempt pregnancy afterwards.

I don't know what you think, Anne, but I'm not sure that if we have more patients, and this is pretty much the case now, we have more patients treated with AI. I tend to do this a lot, especially if I'm thinking of interrupting, so I think I'm giving them maybe the best option first. I'm not sure this is necessarily, I mean, affecting me much, while interpreting that it does not appear that temporary interruption on the short term has an impact.

Dr. Ann Partridge: I completely agree with your strategy. Depending on the patient and their tolerance, if they have enough risk to warrant ovarian suppression with AI or tamoxifen, of course I recommend that. And yet, at the same time, I agree with you in this group that was in POSITIVE, I think the groups are relatively low enough risk. Although 40% had no positive disease, the majority got chemo, so they weren't that low risk. And so I think over time, these kinds of patients are more and more going to get ovarian suppression. I'm doing that more in my practice as tolerated. And I hope that all that means is that their breast cancer outcomes will be better independent of a pregnancy.

Giselle Carvalho: And on the topic of women with higher risk disease, CDK4/6 inhibitors are now used in the high risk adjuvant setting. How do you envision this impacting fertility?

Dr. Hatem Azim: Well, this is a very good question. Of course, this is something, this is an area of research that we have to address. Some analysis from some of the adjuvant studies, for example, the PENELOPE-B, I think they reported on some of the results of their study in which they were evaluating palbociclib in the adjuvant setting and did not appear that there was significant differences in terms of the level of estradiol levels and FSH and anti-Müllerian hormone, for example. I think these were the parameters that were evaluated in this study. So, of course, more information. Of course, palb is not the CDK4/6 inhibitor approved in the adjuvant setting. So we need more information as well about the other CDK4/6 inhibitors and longer follow-up. 

In my view from a counseling perspective, I think maybe you would have a certain level of uncertainty regarding whether or not this could have a mental impact on fertility. But the concept as well of possibly proposing a temporary interruption as we adopted in POSITIVE, would still apply. These patients would be treated as well, often, because if they are receiving CDK4/6 inhibitors in the adjuvant setting, it means that they have a high stage disease, so often they will be treated as well with GnRH analogs. I would counsel them pretty much the same, acknowledging a certain level of uncertainty regarding the data we have today on CDK4/6 inhibitors.

Dr. Ann Partridge: Yeah, if they got a full course, they would generally be further out than many people on POSITIVE, because we treat with, for example, the abemaciclib for two years and then you want to wash out and things like that. In POSITIVE, the average was two years. And so you'd expect people of higher risk to be a little further out, which I think would make everybody a little more comfortable too, because someone who's very high risk, you'd worry about very early bad recurrence, too.

Giselle Carvalho: Yeah. Thank you.

So, Dr. Partridge, regarding adherence to endocrine therapy resumption after the two year break, what was the percentage of patients who resumed treatment and which strategies would you suggest to increase adherence in this case?

Dr. Ann Partridge: That's a really great question. In the study, it was well over 70%, which is actually higher than you see in the general population of breast cancer survivors, especially young women. So in some cases, and I can tell you anecdotally, I experienced in my clinic that patients were more likely to start and take their endocrine therapy when they had the promise of the POSITIVE trial, to take a break to have a baby, because some of them don't want to start it, let alone stay on it, if they're told they have to take a full five to ten years. So it actually promoted adherence, ironically. And then for the people who got back on in the real world, the data suggests that by four years, somewhere close to half to 30% to half are no longer taking it. And so in POSITIVE it was, I think, 74% got back on, and that was only at the time point cut off when we did the initial primary data report. And of course more people will have gone back on because some people were still having babies and in the middle of things. And so I think that it's not as much of an issue with POSITIVE. In part, these are very compliant people, right? They're participating in a clinical trial to share the data with the rest of the world. They could have gotten pregnant on their own and they want to do it with their doctors. And so I think this is a little bit of a different group, but it was very reassuring to see that most people got on hormonal therapy after their interruption.

Giselle Carvalho: And recurrence of hormone receptor positive breast cancer may occur late. How long do you plan to follow patients enrolled in the POSITIVE trial?

Dr. Ann Partridge: So our plan is to follow them for at least 10 years. And it's interesting because we're starting to get close to that. We started enrollment in 2015, so I saw someone earlier this week who will have her 10 year mark next year because she got on in 2015. And that's very exciting. Obviously, it would be great to follow them even longer because ER positive breast cancer can recur many years later. But I do think that we feel as though at least 10 years will give us a good, very evidence-based feeling about the safety.

Giselle Carvalho: Thank you. Thanks for sharing. With enrollment occurring at 116 institutions in 20 countries across four continents, this representation of different races and ethnicities provides strength to support this recommendation for this group of patients worldwide.

Dr. Azim, what are your hopes for future analysis from this study and what future research in the area are you planning or would like to see performed? 

Dr. Hatem Azim: So Ann mentioned, of course, it would be crucial to conduct the long term follow up of these patients, and provide more reassuring evidence on the safety of this approach of adjuvant endocrine therapy. So this is something we're really looking forward to. Other analysis that we are working on is the breastfeeding analysis. So looking at patients who underwent breastfeeding and how far the feasibility of this approach, obviously, but how far as well this had an impact on their breast cancer outcome. So this is something that hopefully we are going to report on soon, expected end of this year. As well, we are working on evaluating, we had a large translation research program within POSITIVE, addressing several questions, including the evolution of ovarian function parameters over time and the ovarian reserve. Also, we are working on reporting on this information. We hope that this could happen maybe in the coming year.

Giselle Carvalho: Great. And finally, what advice do you give young women in your clinic who have been diagnosed with early stage hormone positive breast cancer and who are hoping to attempt pregnancy.

Dr. Hatem Azim: We address these kinds of questions relatively early in their treatments and often they are very much concerned about their chance of future fertility. Usually early on, for example, before going for chemo and so on, I just share the information that this is something that we certainly could discuss and certainly there are the possibility that we could consider in the future that it's not a ‘no go’ at least. And definitely it's something that we could work on once treatment is completed and recover from the adverse events of therapy. And because throughout the journey of treatments as well, women's wishes evolve over time and their perception of their pregnancy project as well evolve and change over time. So I think it's important to acknowledge, in my view, it's very important to acknowledge that this is feasible, this is possible, and because this as well provides an important psychological boost for them. And then as the patient comes over for their follow up after therapy and so on, start understanding, getting a little bit deeper into these kind of questions regarding feasibility, timing. If they are ER positive, then if it's okay to interrupt, not to interrupt, to explain a bit better and to consider a bit better regarding what kind of risk we're talking about. Articulating better, what do we mean by risk? So that sometimes you have a patient that is willing to accept a 10% risk, although others 1% risk for them represent a major threat. Also, it matters nulliparous versus a patient who already has two or three kids. So I think I tend to go a bit more granular in this kind of information as patients are out of chemo and on hormonal therapy and start addressing these matters. But I think it's important early on to share the information that nowadays we do have sufficient information not to discourage women who would like to have a pregnancy in the future.

Giselle Carvalho: Thank you. Thank you. Dr. Partridge, would you like to add some final comments on this?

Dr. Ann Partridge: Yeah, I think this is just such an important issue for our young breast cancer survivors and cancer survivors diagnosed at a young age, regardless of the type of cancer. So I think paying attention to this at diagnosis and through their survivorship is critical, both for their thriving in survivorship as well as for their long term health and cancer outcomes. Getting back to that adherence issue, people, if they're unhappy, won't do all the right things for themselves, sometimes medically and emotionally. And we know that infertility can be associated with long term distress for patients with and without cancer. So we need to pay attention to this and I'm really happy that ASCO is doing a podcast on this and I'm really happy that JCO is doing a podcast on this. 

Giselle Carvalho: Thank you. I really would like to thank you both, Dr. Azim and Dr. Partridge for attending this interview.

This is Giselle Carvalho. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows asco.org/podcast.

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. Azim
Employment Company name: Pierre Fabre, EMERGENCE THERAPEUTICS Stock and Other Ownership Interests Company name: Innate Pharma, Diaacurate Travel, Accommodations, Expenses Company name: Novartis

Dr. Partridge
Research Funding Company name: Novartis Patents, Royalties, Other Intellectual Property Company name: UpToDate

Host Dr. Davide Soldato interviews Dr. Sana Raoof to discuss the JCO article Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.

TRANSCRIPT

Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with others from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Sana Raoof, Physician at Memorial Sloan Kettering, to talk about her article, “Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.”  

Thank you for joining us today, Dr. Raoof.

Dr. Sana Raoof: Thank you so much. It's lovely to be here.

Dr. Davide Soldato: So, Dr. Raoof, I just wanted to start a little bit about the theme of your article, which is really centered around multi-cancer early detection tests. And this comes from the results of several studies that showed their reliability and efficacy in identifying cancer in the average risk population. But I just wanted to ask you if you could give us and our readers a brief overview of how these tests work and how they were designed for this specific population.

Dr. Sana Raoof: Of course. Well, there's an interesting story. The origin of multi-cancer early detection tests actually begins with insights that come from the field of obstetrics and gynecology. So about six or seven years ago, in the peripheral blood of pregnant women, we discovered that you can actually find fetal DNA floating around. And that was an early discovery of cell free DNA coming from the baby into the mother's bloodstream. But in some of those young, otherwise healthy women, we also discovered that there's another clonal signal, unfortunately not coming from the fetus, but coming from an undiagnosed tumor. And that led to the entire field of circulating tumor DNA and all of its applications. 

Of course, scientists in the last six or seven years have harnessed the fact that DNA and the methylation patterns on the circulating tumor DNA, as well as other analytes like glycosaminoglycans, proteins, and other analytes, are secreted by tumors into the peripheral blood in order to try and screen for tumors, hopefully at early stages, when there are still curative, definitive interventions that are available. There's several different tests now that are providing the ability to detect cancers at many stages, including early stages. They're in different phases of preclinical to clinical development, and one is even commercialized and available by prescription in the United States.

Dr. Davide Soldato: Okay. So I think that in most of these tests, they really look at the tumor DNA, so they identify mutations or, for example, methylation patterns. But do we also have some tests that integrate some other type of biomarkers that we can identify in the blood? Like, are they integrated all with the others, or are we just relying on circulating tumor DNA?

Dr. Sana Raoof: It's a great question. There's a lot of really fascinating biology that different companies predominantly are using in order to find signs of early cancer. One of the analytes that I find really interesting, other than looking for small variants in circulating tumor DNA and looking at methylation patterns, as you mentioned, is looking at fragment length. So, for example, the company DELFI looks at the different patterns of the length of DNA fragments that are floating around in the peripheral blood. And not only is fragment length tissue specific, so in theory, a fragmentomics based multi-cancer early detection test could tell us what is the tissue that this aberrant signal is coming from, but they can also tell you if there's likely a cancer present, because there's a difference in fragment length patterns in cancer versus non cancer. 

There are also other analytes. I mentioned glycosaminoglycan. There's another company that doesn't yet have prospective data, to my knowledge, that is making a test that looks at these analytes instead. There are other companies, again, without prospective data yet, that are looking at circulating tumor cells. And I'm sure that in the next few years, we're going to start getting prospective data from all of these players and also hear about other analytes that scientists have found can predict cancer from non cancer and maybe even protect tissue of origin based on artificial intelligence.

Dr. Davide Soldato: So you mentioned artificial intelligence. So, basically what you're suggesting, but correct me if I'm wrong, is that when we use this test, we are actually measuring something in the bloodstream, but at the same time, we are actually applying some type of artificial intelligence to actually interpret these results and then give us the definitive results, or what we would call like a positive and a negative of the tests, is that right?

Dr. Sana Raoof: Yeah, absolutely. And it's an important distinction that you're making, we are measuring something in the blood, but we're not just measuring it. We're using machine learning algorithms that have been trained on thousands and thousands of patients with cancer and thousands and thousands of patients without cancer, and have measured various analytes and analyzed the patterns, for example, of DNA sequence, or bisulfite sequencing of methylation patterns of patients with and without cancer, and have been trained to look for the differences between them. And so the analyte that we're looking for is not a specific mutation per se, but is a pattern that looks like patterns that you typically find more so in cancer patients.  

There's many different companies, they are trained on different types of cancer. So some companies, like GRAIL, have a test that looks for a very expanded list of over 50 cancer types. Other tests have a narrower focus and were trained and validated on a smaller list of cancer types. So there's just a great diversity in this space. These tests are trained to look for different types of cancer. They're trained and validated on different populations of interest. So, for example, some of the populations that these tests were trained on are predominantly white, and that will have impacts, potentially on how these tests perform in non-white populations. And that's a really interesting area of future research. These tests may or may not have included cancer survivors in their populations, and that could ultimately impact how these tests perform in those populations. 

So there's just so much to learn, so much data that's going to be coming out in the next few years from all of these different key players in the multi-cancer early detection space. But one thing that I'm sure of is between all of the different analytes, all of the different training and validation studies, and all of the different prospective studies, we're going to learn a tremendous amount about the potential clinical utility of using multi-cancer early detection tests to complement the few standard of care surveillance cancer screening tests that we have recommended today.

Dr. Davide Soldato: So just taking a step back and going back to the fact that we actually use machine learning algorithms to identify a pattern that can give us an idea of whether cancer is present or not, I believe that there is also some room for calibration of these types of tests. And I think that this is one of the key arguments that you make in your paper where you say that we can actually personalize a little bit more these types of tests to understand and then to decide what we are looking for. Is that correct and can you expand a little bit on that?

Dr.Sana Raoof: Yeah, absolutely. This is the central concept of the paper that we're discussing. Because these tests are machine learning based, as I said, they're trained to say cancer versus not cancer, and some of them are further trained to say, coming from this organ or coming from that organ. But what does it mean to say cancer or not cancer? There are specific thresholds that are defined to say, above this threshold of signal detection, we're going to say this is a positive cancer signal detected, and below it we're going to say negative. And so right now, these tests are kind of designed to have this binary output, and the concept that I wanted to put forth in the paper is it doesn't necessarily have to be binary, and the thresholds don't have to be static. So, for example, you can imagine that in an average risk population where the pretest probability of cancer in your lifetime for Americans, it's pretty high, roughly 40% for lifetime. But at any given moment in time when you're getting a test, it's lower. For example, in Americans, 50 to 80, the chance of having cancer at any given moment is just under 3%. So you don't necessarily want a test that is very nonspecific, you don't necessarily want to tell a lot of perfectly healthy people that are asymptomatic screening populations that they have cancer if they don't. And so these tests were designed to have very high specificity, predominantly across the board, across the different companies making them at the cost of, in some cases, having lower or moderate sensitivity in early stages.  

And it's important to keep in the back of your mind that we cannot ever expect the types of early stage sensitivities from multi-cancer early detection tests that we're used to thinking about for single cancer screens that are just optimized for one single organ. They work in a completely different way. So I don't expect a future where the sensitivity of a mammogram, which is only for breast cancer, is going to be analogous to the sensitivity of a blood-based test that's looking for all cancers in your entire body. I don't think it's fair to expect that. But I do think it's possible to imagine a future where we do change the thresholding of these tests that were trained and validated in average risk screening populations, and say, “Let's turn the knob on the dial and let's take the sensitivity a little bit higher, even if it means the specificity drops from 99%, for example, which is the very high number of the gallery test, down to 98%, down to 97%. Let's see how this affects the positive predictive value and the negative predictive value of the test.” And how having a higher negative predictive value by having a higher sensitivity may or may not make it more clinically useful for higher risk populations that have higher pretest probabilities, in which case we are kind of more interested in being sure that we're ruling out cancer. 

Another concept that I talk about in the paper, aside from just turning the knobs, is to make it a continuous variable rather than a binary report. Rather than saying signal detected or not signal detected, I can also imagine a future where we personalize the output of multi-cancer early detection tests to return a score, for example, from 1 to 100 or 1 to 10, and give physicians the ability to use that continuous variable in addition with other clinical findings, physical exam findings, other labs, symptoms, patient’s past medical history, family history, all of that together to make decisions about should we pursue further workup, should we do an invasive biopsy. This is kind of the way that we use other scoring tests in oncology, like the oncotype tests for breast cancer, decipher test in prostate cancer. And I think physicians like having continuous variables to work with and to help them make very personal decisions for patients' diagnostic workups.

Dr. Davide Soldato: To summarize a little bit, what you're arguing in the paper is that we could potentially modify a little bit these tests as they fit the type of population that we are looking for. For example, if we are looking at the average risk person in America, there we just want to be sure that we are just doing additional workout and additional follow ups and additional invasive procedure, for example, biopsy, when we have a very high probability of finding that cancer. At the same time, if we have someone who has a baseline risk which is higher, like cancer survivors, in that case, we are more interested in seeing if there is really cancer at that point, and so we can increase the sensitivity and go down on specificity, but still looking at the overall outcome that we want to have for that specific patient. 

One thing that I was wondering is, do you also see a future where we personalize a little bit more also including additional information that comes from risk factors, environmental or behavioral patterns, type of diet, or these types of risk factors that we already know from epidemiology are associated with a higher risk? So could we potentially customize this test even more, saying, this patient has a higher risk of developing colorectal cancer, so could we look more specifically to that specific cancer type and that specific risk compared to tobacco associated cancers, that for that specific patient, they are not so relevant? 

Dr. Sana Raoof: What you're saying is actually a fascinating and really compelling idea, and it reminds me of the way that noninvasive prenatal testing works. So, again, back to the world of obstetrics and gynecology, you have a woman at the end of her first trimester having fetal DNA testing to look for chromosomal abnormalities. And when you order that test, you actually do put in various features about the woman to help you understand her baseline risk for carrying a fetus that has chromosomal abnormalities, including her age, the status of her other children, and other things in order to help you calculate a pretest probability. And so after that, the non invasive prenatal test takes that into consideration and returns a probability of carrying a fetus that might have those aberrations, and it's not a binary risk. It's, as I said, a continuous variable.

So I think what you're proposing actually goes beyond what I wrote about in the article. I think it's a fabulous idea. And I think that in the near future, I can imagine that as natural language processing is exploding, and in general, large language models and the ability to extract features about a patient from the EMR are exploding, we might have a better stratification in general of patients into average risk, low risk, high risk, and really high risk, using EMR data, using real world data that could help us feed a really accurate picture of a patient's pre-test probability into this test, so that these tests could be further refined and further trained and validated on patients, taking into consideration more factors and help us improve the predictive power of the tests as they're returned in a report to the physician. So I think maybe you should even write an article about the idea just proposed. It's a great idea.

Dr. Davide Soldato: So another aspect that I was really interested in is I've looked at one of the papers that you cited, and I wanted to discuss this with you as you are an expert on the topic. In one of the articles that you cited that used this type of test, they identified some of the cancers that we also normally identified with standard screening procedures, like breast or lung or colorectal. So for those cancers, we add a certain proportion, or like, for example, for breast cancer, a higher proportion identified with conventional screening. But still we had some other cancer that eluded those types of screening and were identified using liquid biopsy tools. So do you envision a strategy where we would use the screening methods that we already add as a complement to those liquid biopsies, or do you think that someday liquid biopsy could potentially completely substitute standard screening procedures? 

Dr. Sana Raoof: I think we're too far from a day where liquid biopsies are going to replace standard of care screens. The scope scans and smears that the United States Preventive Services Task Force has recommended are gold standard screening interventions because, number one, for all of them, except for cervical cancer screening, we have randomized data with definitive endpoints that tell us that there are mortality benefits from doing those screens. We don't have that type of data yet from the world of multi-cancer early detection. And as we talked about earlier in this podcast, those tests are kind of designed with a different approach where they have higher sensitivity and much lower specificity than multi-cancer early detection tests. 

So I think that the molecular cancer screening companies have done a very careful job of creating tests that are really more optimized to be complementary tests rather than a standalone catch all test, to have higher specificity at the cost of lower sensitivity. So I don't imagine a near future, at least not in my career, where we're going to stop doing colonoscopies and mammograms and pap smears. I don't think that that's going to happen. But I do think that whereas right now 75% of cancers that Americans die from, we lack cancer screening mechanisms for them, I think that that number has the potential to really drop. If in the next few years, one of these multi-cancer early detection tests is ultimately approved and covered, then I think that a lot more cancers could be detected by screening rather than by symptoms, and we might ultimately see a big stage shift. 

Dr. Davide Soldato: Yeah, I think you're absolutely right. In the same article that I was mentioning before, there were several of those cancers which can be lethal if diagnosed at an advanced stage, that were diagnosed at an early stage, for example, ovarian cancer, bladder cancer. So I really think that we really have potentially the way to screen, or at least have a signal for cancer that currently we just diagnosed when symptoms associated with higher stage appear. 

But moving on to turning the knobs on this type of test, and so going to the higher risk population, for example, cancer survivors, which is something that you speak a lot about in the manuscript. So you also discuss a little bit the question of whether we should use multi-cancer testing versus single cancer testing. So are we looking at a specific recurrence from that specific tumor, or are we looking at a general risk of cancer in a population that has a common risk factor, like tobacco? And so I was wondering if you think, and this is probably just your perception or just your opinion, that that is another way that the physician should turn the knob. Should we evaluate the risk of those cancer survivors and say, in this specific patient right now, the risk of recurrence is higher so I should use or I should be more in favor of a test that is more centered on the risk of recurrence versus I have a general risk of several cancers that could appear, and so should I use something that is more multi-cancer? This, of course, is merely speculative because we still don't have definitive data regarding the efficacy of this test. But it is just your perspective on this type of approach in the near future or not so near future. 

Dr. Sana Raoof: Well, I think if we're speculating, then I think that the fantasy situation for any oncologist is that you have two types of liquid biopsies. One is a multi-cancer early detection liquid biopsy. And it would be great if you could select whether you want it to be optimized for highest NPV, negative predictive value, or highest PPV, positive predictive value. And then you also have a host of single cancer screening liquid biopsies that can help you specifically figure out if there's a recurrence of a single cancer type that you're suspicious about.  

So, for example, in the article, I talk about how there will be clinical gray areas, and it's not always going to be obvious which test you should reach for. But one example that I think we can all relate to in the oncology community is you have some indeterminate imaging finding, and you don't know what to do about it. So, for example, you have a woman that has a history of breast cancer, has had no evidence of disease for a few years, now, has back pain. You do a spine MRI, you see a lesion. Maybe it's an atypical hemangioma that's causing pain, maybe it's a breast cancer metastasis. You're not sure. What should you do? Should you do a biopsy of that lesion in the spine? Should you wait and see if it grows and do another MRI in two or three months? What are your options? And so in this situation, I think we can all agree that if you had a liquid biopsy that was optimized for really high sensitivity, specifically for breast cancer, and had a very high negative predictive value, and if it came back negative, then in that setting, it might help you avoid an invasive test, like a biopsy in the spine, and give you a little bit more comfort as a physician to say, “You know what? I'm going to come back in two or three months and do another spine MRI. I'm going to see how this woman is feeling, and I don't need to biopsy this right now. Maybe it really is just hemangioma.” 

Dr. Davide Soldato: And in this specific setting, let's take the same patient. So it's a female patient, she had a previous diagnosis of breast cancer. Do you think that there is a difference between tumor-informed tests, really based on the molecular aberration that the primary tumor had for these women, versus just a standard test that gives us information regarding the presence of breast cancer cells or not? And if you think that there is a difference, what would you think would be the advantage of one? And the disadvantages, for example, is a tumor informed essay more complex to obtain? Do we need more time? Is it more expensive versus a commercial test that is already available or something like this? This is my understanding as someone who's not so much in the topic, but I think that this is a point that many oncologists probably wonder about, and probably we should speak a little bit more about with someone who is an expert on the topic. 

Dr. Sana Raoof: Absolutely. And I think that you've actually hit all of the major points on the head. So comparing a tumor informed versus a tumor agnostic test is like really comparing apples and oranges. A tumor informed test where you're starting with a patient's pathology and you are looking specifically for mutations and other molecular features that you know the patient has in their tumor, is going to, of course, result in a test that is, number one, more expensive and harder to make, but also, number two, more sensitive, more specific, more predictive, and in every way probably just more powerful than a test that is, in general, optimized for a single cancer type, but is almost certainly going to be trained and validated on people with a mix of histologies, a mix of molecular features, and will not be as sensitive or specific as a test that is actually informed by that single individual's tumor. One of the things that matters a lot to me is health equity in oncology. There are just huge disparities in outcomes in patients that are advantaged and disadvantaged. And it stems from lots of different things. In no small part, it stems from later stages of diagnosis in disadvantaged patients, and then even once you have a diagnosis, delays to confirmatory workup, delays to starting treatment, disparities in the treatments offered. 

I don't imagine a world where everyone on earth is going to have access to tumor-informed liquid biopsies. I do imagine a future where tumor agnostic liquid biopsies, both for single and multi-cancer screening, should be a lot more economical than they are now, and should be more available for multiple cancer types, and should be more available to patients that aren't at just the Memorial Sloan Ketterings and the Dana-Farbers of the world. And so I do think that those types of off the shelf tests have the potential to really revolutionize the way that we work up suspicion of cancer, not just in advantaged patients, but also in patients that are diverse, in patients that are not at academic cancer centers, but at other cancer centers around the world. And I think it's a really exciting prospect.  

Thinking about the chance of recurrence in the breast cancer patient is a perfect example of when you want to test that is optimized just for breast cancer, because you see something in the spine, you know her history, and you're less worried about a new primary and a new MET from that primary. But there are other situations that are also interesting to consider. For example, patients that have had lung cancer and have a history of smoking, because they've had a history of smoking, they're actually at risk for a dozen different cancers, not just lung cancer. And when you think about what we do to follow lung cancer survivors, we're just doing CTs of their chest and of course, physical exams. But the vast majority of cancers that people with lung cancer history will get may not be present in the field of view of a CT of the chest. They may also get renal cancer, bladder cancer, they might get leukemias, they might get pancreatic cancer. So there are a lot of things that you're not going to catch in a CT of the chest. And so in that situation, you care not only about recurrences, which in thoracic oncology, it's kind of a gaussian probability distribution, where the tail is almost close to 0 after five years, but also a uniform distribution of roughly 3% per year of a second cancer, a new primary cancer that goes on for the rest of their life. And so in that clinical setting, you can imagine that having an off the shelf multi-cancer early detection test may be dialed up for higher negative predictive value, would be extremely useful.

Dr. Davide Soldato: Yeah, I totally agree, but thank you for clarifying these points, because I think that there is a little bit of confusion also in the oncology community, as this type of tests, they're also based on very complicated molecular biology, sometimes could be potentially integrated, and we could potentially integrate them in the clinic. 

And so I wanted to close up with kind of a personal question. I was wondering how you came to be so interested in this field of molecular screening or early diagnosis and prevention associated with molecular data. 

Dr. Sana Raoof: Well, it's an interesting story. I did my MD PhD at Harvard Medical School, and my PhD was in the opposite world from molecular cancer screening. I was designing drug combinations that could be used in advanced oncogene mutant lung cancers. And I thought I would become a medical oncologist and spend my life designing new systemic therapies for advanced malignancies. And what I saw every day in the lab during my PhD is drug resistance emerges and it's a process of evolution by natural selection happening on a cellular level. And although we have some really great slam dunk drugs that come to mind, for example EGFR inhibitors in certain lung cancers, immunotherapy in melanoma, on average, the median overall survival gain from all of the FDA approved drugs in the last 10 years is roughly two months.  

By the end of my PhD, I really started feeling like, is the best use of my life to continue fighting a battle against natural selection in cancer cells, or is it a better strategy, to me, it seemed like a more sensical strategy to just try and find cancers in these patients earlier, when you don't have to engage with the complex signaling mechanisms of a cancer cells biology, and instead can just provide a definitive local intervention, like surgery or radiation, which already is curing many patients with non metastatic cancers. And as I looked around the world, I just didn't see that many people investing heavily in early detection research at the time. It was the very early days of multi-cancer early detection. And so I became involved with all of the groups, the companies, the organizations that were developing these tests, and really fell in love with, number one, just the concept of the tests, the concept of multi-cancer early detection, rather than single cancer screening alone, because no one knows what cancer they're ultimately going to get. But I also really fell in love with methylation biology, fragmentomics. I fell in love with the types of clinical trials that were being designed and the new types of endpoints that we have to think about when we're designing clinical trials for a multiverse of single cancer screening. And it's just such an exciting time in that community, it's the early days. So that's how I came to this space, and it's just the perfect time to be in this space, because everything is exploding. 

Dr. Davide Soldato: Thank you very much. And thank you also for sharing the personal side of the story.

Dr. Sana Raoof: Thank you so much. I'd like to thank Razelle Kurzrock, who's an amazing medical oncologist who's worked with me on two really fun papers so far, one on real world data, and this one on turning the knobs on liquid biopsies. It's always great to bounce ideas around about multi-cancer early detection with friends and collaborators, and Razelle did an absolutely amazing job helping write this piece. 

Dr. Davide Soldato: So this brings us to the end of the episode. Thank you Dr. Raoof, for joining us and sharing more on your JCO article titled, ”Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.”  

If you enjoy our show, please leave us a rating and review, and be sure to come back for another 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.

 Disclosures:

Dr. Raoof

Stock and Other Ownership Interests Company name: Illumina Radiopharmaceuticals Honoraria Company name: AstraZeneca Consulting or Advisory Role Company name: Verily Company name: GRAIL Company name: Exact Sciences Travel, Accommodations, Expenses Company name: Grail

Dr. Shannon Westin and her guests, Dr. Emily S. Tonorezos and
Dr. Michael Halpern, discuss their article, "Myths and Presumptions About Cancer Survivorship" recently published in the JCO.

TRANSCRIPT

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

Shannon Westin:Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Social Media Editor of the JCO, Shannon Westin, and also a GYN Oncologist by trade. I'm thrilled to bring a topic that is very close to my heart. We're going to be talking about a Comments and Controversies article published in the JCO on November 16, 2023, entitled "Myths and Presumptions about Cancer Survivorship." I know you all will find this topic as enthralling as I have, and the authors do not have any conflicts of interest. 

I'm joined by two of the authors on this important work. The first is Dr. Michael Halpern, he’s the Medical Officer in the Health Assessment Research Branch of the Health Care Delivery Research Program. Welcome, Dr. Halpern.

Dr. Michael Halpern: Thank you for having us on.

Shannon Westin: We're also accompanied by Dr. Emily Tonorezos, the Director of the Office of Cancer Survivorship, and both of them work in the Division of Cancer Control and Population Sciences at the National Cancer Institute, National Institutes of Health. Welcome. 

Dr. Emily Tonorezos: Thank you for having us.

Shannon Westin: So, let's get right into it. I want to level set first. I would love for one or both of you to speak a little bit about the state of cancer survivorship currently. What's the prevalence of cancer survivors here in the US? Globally? What do we expect as time passes?

Dr. Emily Tonorezos: Thank you for starting with this question. In the Office of Cancer Survivorship, we use a definition of cancer survivor that we got from the advocacy community many years ago. We use a definition that says “a person is a cancer survivor from the time of diagnosis through the balance of life.” That means in the United States, we estimate that we have a little over 18 million cancer survivors, and globally, it's a little more difficult to estimate those numbers. Not every country has a cancer registry to count the number of cases, but we think there are upwards of 53 million cancer survivors diagnosed within the last five years in the world.

Shannon Westin: Wow. And so this is why it's so important, such a large number, and that's just an estimate. And we know this is only going to be growing. I personally learned so much from your manuscript, which is critically based on the understanding that our beliefs as practitioners truly impact the way we care for our cancer survivors. I admit, I definitely held or hold some of these beliefs, and I'm certainly grateful that you're providing that objective evidence to support or refute these claims. 

So, with that being said, let's tackle the first one that you all approached: Shared care results in the best outcomes for cancer survivors. I think first I'd love to hear about what your definition of shared care is. What does that really mean in the context of cancer survivorship?

Dr. Michael Halpern: Shared care is a deliberate process to coordinate and integrate components of survivorship care between specialty, in this case, oncology providers, and primary care providers. And part of the issues with this belief about shared care being the best have to do with the broad practice experience of survivorship care. While the ideal definition is this integrated and coordinated care, shared care can range from one extreme to being essentially oncologist-led care - where the oncologist also sends information to the primary care providers; and to the other extreme - care led by primary care providers and an oncologist is available to answer questions as needed. So part of the issue with the available literature is that there is a tremendous range in terms of the definition of shared care that's being used in studies.

Shannon Westin: So, understanding those limitations, obviously, based on what you just said, what have we seen in some of the studies that have been exploring shared care and what it might mean for cancer survivors?

Dr. Michael Halpern: So there have been some wonderful studies and some very well-done research in shared care. The majority of it indicates essentially no benefits, not any worse, but definitely not any better than other survivorship care models among multiple domains, quality of life, patient preference, clinical outcomes, in some cases, costs. So there isn't at this point a rationale for believing that shared care leads to better outcomes than does other types of models of care. And that's not to say that we don't think that shared care is a valuable model, that it's potentially very useful and beneficial for certain groups of cancer survivors. It's just that at this point, we don't have evidence to say who it is going to have optimal outcomes for compared to other kinds of survivorship care models. 

Shannon Westin: And that makes sense. I mean, I think we're seeing this over and over again in all aspects of cancer care that one broad stroke or one broad plan isn't right for everybody, whether that's therapeutic or surgical or prevention, so it makes sense to me that that's what we're seeing here in survivorship as well. So I see this manuscript as a call to action about what are we missing, what data do we need to generate to really be able to move this care forward. So that makes total sense to me. And I guess in line with that, another belief, and I've heard this all the time from my patients, too, is this idea that primary care providers feel unable to provide survivorship care. They're not comfortable. “Oh, you have a diagnosis of cancer. You have to be seen there at the cancer center.” What does our evidence demonstrate here?

Dr. Emily Tonorezos: This is another belief that was found to be a presumption. So that means that this is a belief that we think was true, but which convincing evidence does not confirm or disprove. So what the available evidence tells us is that primary care providers do have challenges in taking care of cancer survivors, particularly with regards to certain cancer-related care needs. But at the same time, we found lots of evidence that primary care providers are more than willing and able to take care of cancer survivors. They express confidence in their skills. They think that they are capable of taking care of cancer survivors. And especially for survivors of more common cancers, primary care providers, in general, express a lot of confidence in their ability to take care of those patients. What they might lack could be things along the lines of survivorship-specific knowledge. So that is a gap that we identified. But this idea that primary care feels unable to take care of survivors really was not supported by the evidence.

Shannon Westin: I mean, and that makes sense, right? If we're seeing more and more cancer survivors, primary care is going to adapt to that. We adapt to the things we see commonly in our clinics, and that goes across all specialties. So that certainly makes sense. I guess you've already kind of said this, and I'll just highlight it for the listeners. You know, clear guidelines seem to be a clear, nice option to potentially improve this situation. 

So let's discuss this next myth that you all identified, that oncology providers are hesitant to transition survivors to primary care. Now, I understand this one because I definitely, we get this a lot, and I'm a center medical director in GYN, and we've definitely tried to put patients that are free of disease out back in the community to be able to free up space for other patients. And we definitely get pushback because seeing patients that are in this state of being free of disease and they're living their life, it's inspiring. We remember why it is we're doing the things we do. What did the data show us about this myth? And are we creating barriers to this transition to survivorship care outside of the oncology centers?

Dr. Emily Tonorezos: Exactly. So this belief is a myth. We found evidence that this belief is not true, and it seems to be one of those things that feels true, that oncologists want to take care of cancer survivors, that it contributes to the joy of medicine. But that evidence really does not suggest that that's the case. In fact, the opposite is true in the evidence. We found when we looked at the available research Oncologists want to take care of people who are diagnosed with cancer and need treatment. That is really what they think their role is. That's what they feel they're contributing. And so, even though there is a pleasure in seeing a person who has finished treatment, most oncologists say that the amount of time that they spend taking care of people who are done with treatment is appropriate - meaning they're not looking to expand their panel of post-treatment patients. They really want to take care of people who need treatment currently and then perhaps have a little bit mixed in of people who are done with treatment or who are in that survivorship phase.

We found a lot of evidence, also hard evidence, that oncologists are, in fact, transitioning survivors to primary care. There is a lot of evidence that people who have been diagnosed with cancer are being seen in primary care and that that proportion increases over time. So if oncologists were really creating these insurmountable barriers to transition to primary care, we would not be seeing so many survivors in the primary care setting. But the fact is they're there, and they are being moved there by their providers.

Shannon Westin: I love hard evidence. I do have a few patients that have said, "Can I just come see you every once in a while?" And I love seeing them, but I agree, we can't fill our panels with that. So that makes good sense. 

So the next topic centers around finances, and this is the idea that survivorship clinics lose money. What truth did you all discover here regarding reimbursement for this type of care? 

Dr. Michael Halpern: We discovered that this is a presumption. It's a belief that there isn't compelling evidence one way or the other. Part of the issue with this is probably some confusion about what constitutes survivorship care. There are certainly difficulties in obtaining reimbursement for certain survivorship services, such as sexual health and fertility counseling, and wellness and exercise services. It's understandable that there may be problems getting reimbursement or appropriate reimbursement for those. But when looking at overall survivorship care, there are actually very few studies that have done a financial analysis of the cost of providing that care versus the reimbursement. And those that have done more detailed analyses generally show that the reimbursement for survivorship care is greater than the cost. Survivorship care clinics actually do break even or make money. 

Now, it's also true that providing survivorship care likely doesn't provide the same level of reimbursement as providing oncology treatments, which involves administering systemic agents and different kinds of imaging or diagnostic procedures. And so there are other streams of reimbursement possible for that. But overall, there really isn’t compelling evidence to indicate that survivorship clinics lose money. There is a concern that having this widespread belief that they do may be a disincentive for hospitals or healthcare systems to start different kinds of survivorship clinics.

Shannon Westin: I think this is an area where it would really behoove us to do more work so that we can encourage institutions to do this. And, I know in our center, the things that you're mentioning, it's exactly like the problems that these people are having around sexual health and fertility and exercise, wellness in general, I mean, those are the soft things that I feel like it's harder to kind of gain momentum to really develop established programs that really make an impact. And so I was so glad to see that you mentioned that in this paper, and I hope it will encourage people to really move that forward. 

So finally, I was interested in this presumption around the shared electronic health records and how that might help with survivorship care coordination. Is this our solution for smooth communication and care of these people?

Dr. Emily Tonorezos: This one was actually almost something that's sort of funny to think about, how naive we were about electronic health records. We found a number of examples from five or ten years ago where leaders in survivorship research and clinical care were saying, "Well, once we have electronic health records, we will not have these same problems of care coordination or communication." And that has just not been true, unfortunately. So this one was also a presumption, meaning the evidence of a benefit for electronic health records just was not out there. So we know that consolidation and transfer of diagnostic and treatment information can increase knowledge. So you can show that you can increase knowledge about diagnosis and treatment with a shared electronic health record. So the primary care provider is able to look, for example, at the pathology from the original diagnosis. But whether that actually results in anything in terms of improved care is an open question.

Shannon Westin:I think that's what we've learned a lot about electronic health records in general. I remember when we were transitioning to our new system, and everyone thought, "Oh, this is going to be the end all, be all." And it has been good in a lot of ways, but it certainly hasn't been the cure for everything that ails us. 

Well, I'm just so thrilled. Thank you all so much. This has been really educational and so important, given what we've already talked about, about the increasing population of cancer survivors that we're seeing in the clinic and globally. I think just to kind of tie a bow on it, I would just love to hear each of your bottom lines regarding kind of where we are right now with the care of our cancer survivors and what we need to be addressing maybe in the short term to move things forward.

Dr. Emily Tonorezos: So I'll go first. I just want to say it's really important, I think, when we are around other investigators and in our meetings and talking about clinical care, that we think critically about the things that we hear people saying. This idea, especially the one that oncology providers don't want to transition their survivors to primary care, but the others as well. I think the way that we need to address this or carry this forward is to just be aware when we're in those settings and we hear people say things, to ask the question, "Is that really supported by the evidence?" And you may find that there are even more of these commonly held beliefs that really aren't supported by the evidence or that deserve a little bit of a deeper dive.

Dr. Michael Halpern: I very much agree with that. And it's critical that we be willing to question some of these beliefs, be willing to discuss them, and not accept them as facts in order to be able to develop new research programs, hypotheses, to explore really what can help produce the best outcomes for survivors, because that's really what we're all about.  

The other bottom-line issue, I think, one, Dr. Westing that you brought up, is that survivorship isn't a one-size-fits-all. The best survivorship care is the care that is tailored towards the survivor - the individual needs and wants. What kind of supports will be most effective in terms of enhancing their health? So, we really need to pay attention to the individual and, most importantly, what outcomes for survivorship care matter most to the survivor? What do they want to see happen? What do they want their subsequent future to look like? And how do we measure those outcomes to ensure that they get the best care on the terms that they want? 

Shannon Westin: Well, great. I think that's a perfect place to end. I just want to, again, thank my guests. This went by so fast, and I learned a ton, and I hope all of you did as well. Again, we were discussing the Comments and Controversies manuscript "Myths and Presumptions about Cancer Survivorship" published in the JCO on November 16, 2023. 

Thank you again to our listeners for joining JCO After Hours. And please do check out our other 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 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.

This JCO Podcast provides observations and commentary on the JCO article “Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis” by Abu-Sbeih et al. My name is David Oh, and I am an Assistant Professor at the University of California, San Francisco. My oncologic specialty is genitourinary medical oncology and cancer immunotherapy.

While immune checkpoint inhibitors, or ICIs, can lead to durable responses even when other standard therapies have failed, their therapeutic window is often limited by immune-related adverse events or IRAEs which are thought to be autoimmune in nature. Immune-mediated diarrhea and colitis are a frequent IRAE with ICIs, affecting up to a third of patients receiving anti-CTLA-4, approaching half of patients receiving anti-CTLA-4 in combination with anti-PD-1 or anti-PD-L1, and less frequently patients receiving anti-PD-1 or anti-PD-L1 alone. Since there is often overlap between IRAEs and response or survival with ICIs, and IRAEs such as colitis can require interruption of treatment and immunosuppression in patients who may have failed other treatment options, many providers are faced with an important question: is it safe to resume ICIs after patients have initial diarrhea and colitis, and what are the risk factors for another episode of diarrhea and colitis?

To address this question, which has not been well studied, Abu-Sbeih and colleagues in this issue of JCO performed a retrospective multicenter analysis of patients who had initial immune-mediated diarrhea and colitis requiring ICI interruption, and then subsequently resumed ICI from 2010 to 2018. From a starting population of 550 patients with initial diarrhea and colitis with ICI, they identified 167 patients who subsequently resumed ICI for a re-treatment rate of 30%. This represents a notable cohort with this degree of clinical annotation. For their initial therapy leading to diarrhea and colitis, about half of these patients had initially received anti-PD-1 or PD-L1 therapy, and a quarter each had initially received either anti-CTLA-4 therapy or combination. The majority of these patients had melanoma, with a smaller proportion of non-small cell lung and genitourinary cancer patients. At the time of re-treatment, 80% of these patients received an anti-PD-1 or anti-PD-L1 alone, while the others were re-treated with anti-CTLA-4 alone.

An important observation by the authors was that upon re-treatment of the 167 patients, 57 patients, or about a third, experienced recurrent diarrhea and colitis requiring permanent discontinuation of therapy. The grade of diarrhea and colitis most frequently seen was less severe, graded as less than or equal to Grade 2. As expected, 81% of these patients with recurrent diarrhea and colitis received steroids, while 12% of patients required further immunosuppression with either infliximab or vedolizumab which blocks the integrin alpha-4-beta-7.

Univariate and multivariate analyses were used to identify risk factors for recurrent diarrhea and colitis upon ICI resumption. Univariate analysis identified more severe initial diarrhea and colitis as a risk factor for having recurrent diarrhea and colitis on ICI re-challenge. Initial severity was determined either by longer duration of initial symptoms or requirement for initial immunosuppression. Multivariate analysis confirmed initial severity as a risk factor, and also found that a lower risk of recurrent diarrhea and colitis was associated with initial anti-CTLA-4 use, as well as with choice of anti-PD-1 or anti-PD-L1 therapy at the time of re-challenge regardless of their initial therapy. Importantly, even though resumption of anti-CTLA-4 was associated with a higher risk of recurrent diarrhea and colitis, the severity of recurrence, as determined by frequency of immunosuppression and grading of diarrhea and colitis, were actually similar to when anti-PD-1 or anti-PD-L1 were resumed.

Overall, then, despite the limitations of retrospective analysis, this work provides evidence from a substantial patient cohort across tumor and treatment types that recurrent diarrhea and colitis with ICI retreatment following initial interruption for diarrhea and colitis may occur in less than half of patients and is generally less severe. Furthermore, the risk of recurrent diarrhea and colitis is less likely in patients who had less severe episodes of initial diarrhea and colitis, who previously received initial anti-CTLA-4, or who are re-challenged with anti-PD-1 or anti-PD-L1 therapy. Although the choice of anti-PD-1 or anti-PD-L1 for re-treatment reduces the risk of recurrent diarrhea and colitis, the actual severity of recurrent episodes is similar to re-treatment with anti-CTLA-4 therapy. As a practical matter this can provide guidance to providers about whether to consider ICI resumption, and which agents to consider, based in part of characteristics of their initial treatment and IRAE. This will be particularly important for patients who experienced clinical benefit from their initial ICI therapy, or have limited other treatment options. At the same time, this work also prompts a number of questions for further investigation. Why does prior anti-CTLA-4 therapy leading to initial diarrhea and colitis yield a lower risk of recurrent episodes? Is there an association between recurrent diarrhea and colitis after ICI re-challenge and ongoing response to therapy? Finally, do different ICI-responsive cancer types exhibit higher or lower risk for recurrent diarrhea and colitis? These and other questions can be addressed by future studies involving larger and well-annotated patient cohorts at multiple centers.

                                                                                            
This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “PET Score Has Greater Prognostic Significance Than Pre-Treatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK NCRI RAPID Study” by Barrington et al. My name is Brue Cheson, and I am at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. My Hematologic-oncologic specialty is Lymphoma.

Hodgkin lymphoma is clearly one of the most dramatic success stories in modern oncology. More than 90% of patients with limited disease and about 85% with advanced disease are cured using conventional chemotherapy regimens.  As a consequence, current clinical trials are focusing on augmenting or modifying treatment for those at higher risk and decreasing the intensity or duration of therapy for those at a lower risk of treatment failure.

One important question has been: how best to distinguish those disparate groups?  Over the years, various prognostic scoring systems have been devised.  The International Prognostic Scoring System (IPSS) differentiated patients into 6 groups using 7 clinical and laboratory factors.  However, only 7% of patients are in both the most and least favorable groups.  The German Hodgkin study Group (GHSG) and the EORTC each published criteria slightly different from each other for treatment selection.  Nevertheless, it is not clear that any of these schemas remains relevant in the context of current Hodgkin regimens.  More importantly, they do not reliably dictate how to treat patients, nor do they offer therapeutic targets.

FDG-PET scanning has revolutionized our management of patients with lymphoma.  In 2005 we first demonstrated that integration of PET into standard response assessment improved the ability to distinguish between residual tumor and fibrosis in patients with diffuse large B-cell lymphoma, leading to a revision of standardized response criteria. More recent studies have confirmed this observation in Hodgkin lymphoma and other histologies. Patients with advanced Hodgkin lymphoma can be distinguished into high and low risk groups based on PET scan results after 2 cycles of standard ABVD chemotherapy, regardless of their pretreatment IPSS score.  In a number of studies, reacting to the positive interim scan by intensifying therapy achieved outcomes markedly improved over expected.

In the paper that accompanies this podcast, Sally Barrington and her colleagues performed a secondary analysis of the RAPID trial to evaluate the role of pre-treatment risk factors and PET results in predicting outcome of patients with early stage Hodgkin lymphoma.  This study accrued 602 patients who were treated with standard ABVD and underwent PET scanning after the third cycle.  Those with a negative scan (a Deauville score of 1-2) were randomized to no further treatment vs involved field radiotherapy.  Despite a failure to demonstrate non-inferiority of progression-free survival in this cohort, the overall survival was the same, thus sparing 90% of patients unnecessary radiotherapy.  Those with a positive scan (defined as a Deauville score of 3-5), the primary focus of the current manuscript, received an additional cycle of ABVD plus radiotherapy.  Only the 21 patients with a Deauville score of 5, defined as an SUV at least 3 times greater than that of the liver, had an inferior time to progression or greater risk of Hodgkin-related death.  Importantly, this finding was independent of pretreatment prognostic factors using either the GHSG or EORTC scores.  Whether this observation can be extrapolated to patients with features not eligible for the RAPID study, such as those with bulky mediastinal disease or B-symptoms, is presently unknown.  Nonetheless, these data support the role of metabolic imaging over standard clinical and laboratory risk factors.

But we are clearly doing this all wrong.  Why do we treat all patients the same and then wait until the disease has demonstrated resistance before we alter therapy?  Several recent papers support the notion that anticipatory, biologically-based, risk-adapted approaches may be feasible. Pre-treatment total metabolic tumor volume (defined as the sum total of all metabolically active lesions) can predict outcome in Hodgkin lymphoma as well as follicular, diffuse large B-cell and primary mediastinal large B-cell lymphoma.  High heterogeneity of intratumoral FDG uptake distribution on PET-CT may be a marker of chemoresistance in solid tumors as well as various lymphoma histologies.  Unfortunately, those tests do not provide a target against which to direct a specific agent.  In contrast, a number of investigators have demonstrated a correlation between bcl-2, p53, FOXP3, CD68, STAT1, pattern of PD-1 expression, mutational patterns derived from next generation sequencing, and other factors in pre-treatment Hodgkin node biopsies and outcome.  Thus, if we are able to predict outcome prior to treatment, why do we expose patients to drugs to which we know they will not benefit? The goal of treatment should be anticipatory, risk-adapted strategies whereby patients with a high likelihood of benefit may receive standard of care, unless there is another clinical question being addressed.  On the other hand, those unlikely to benefit as determined prior to therapy should be spared the waste of time and toxicity and treated with novel regimens directed at specific targets.  Both groups should be monitored during treatment for the emergence of mutations, with treatment altered accordingly.  Yes, we may be a long way from having the appropriate tools for such an approach.  But, to quote the geneticist, molecular engineer and chemist George M. Church, “The best way to predict the future is to change it”.  Anticipatory, risk-adapted strategies could do just that.

This concludes this JCO Podcast. Thank you for listening.

This podcast provides observations and commentary on the JCO article "Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma" by Davis et al. My name is Brian Van Tine, and I am an Associate Professor of Medicine in the Division of Oncology at Washington University School of Medicine. My oncologic specialty is sarcoma.

Osteosarcoma (OS) is the most common type of primary malignant bone cancer, frequently occurring in children and adolescents. It can also be found in older adults around the age of 70, but unfortunately, though rare, can be found in patients of any age. Thus, Osteosarcoma is a disease that not only do pediatric oncologists need to know about, but also adult oncologists. Osteosarcoma occurs primarily at the metaphysis of the bone, in regions of rapid bone growth, in bone-forming cells called osteoblasts. Various risk factors for the development of osteosarcoma include underlying bone pathologies, such as Paget’s Disease, prior radiation treatment, and genetic predisposition due to mutations, such as Li-Fraumeni Syndrome, caused by mutations to TP53, or in retinoblastoma mutation patients.

Currently, in the curative setting, OS is treated with chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (HD-MTX), followed by surgical resection of the tumor.  Patients who relapse with metastatic disease have limited options, regiments such as ifosfamide with etoposide and gemcitabine with docetaxel are used with an expected 4-month PFS of only 12%, but the standard of care for osteosarcoma has not changed in 30 years.

This is where the Sarcoma Alliance for Research and Collaboration, or SARC for short, comes in.  SARC is a non-profit organization dedicated to the development and support of research for the prevention, treatment and cure of sarcoma.  It is a collaborative group comprised of leading sarcoma physicians dedicated to performing clinical trials in rare diseases.  It is their 24th trial and is the subject of the JCO article that accompanies this podcast, where Dr. Lara Davis and colleagues report their findings of a Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma.

This trial took place across 12 US centers between 2014 and 2018 and enrolled 42 patients between the ages of 18 and 76. Once again, the age distribution highlights that osteosarcoma is not just a pediatric disease, and that there is a dedication to rare disease researchers to accrue to rare disease clinical trials at SARC.   In this trial, patients were randomized one to one to either Regorafenib or placebo on a 28-day cycle and responses were assessed using RECIST version 1.1 every 8 weeks.  At the time of progression on placebo, patients were allowed to crossover to Regorafenib.

Following the release of the European REGOBONE trial, a study of similar design that showed a significant benefit of regorafenib in osteosarcoma patients, an independent Data Safety and Monitoring Committee (DSMC) was convened by SARC due to concerns regarding continuing to enroll on a placebo-controlled study. The committee recommended closing the study after enrollment of 42 or the 48 planned patients.   

Here is what they found.  At the time of analysis, they found a progression free survival of 3.6 months for Regorafenib and 1.7 months for placebo with a hazard ratio of = 0.42; a 95% confidence interval of 0.21-0.85, and a p=0.017.  Given the crossover design, there was no overall survival seen with a p-value of 0.62.   In addition, no new safety concerns with regorafenib treatment were identified during SARC024 and adverse events were generally manageable with dose reductions.  Notably, the median dose at the end of blind treatment was 120 mg. Taken together, this makes this the second trial to clearly show benefit for the use of single agent Regorafenib for the treatment of Osteosarcoma

Highlighting the issues with using RECIST to evaluate tumors that make bone in their matrix, only 3 patients on Regorafenib achieved a partial response.  Whether this is a cytostatic response to Regorafenib or part of the bone biology of osteosarcoma will need to be determined in future work. 

There are a number of meaningful observations that come from this trial.  First, and most obviously, Regorafenib is active for the treatment of osteosarcoma and it is oral.  While at this time, it is not listed in the NCCN guidelines, this publication makes the second randomized trial supporting its use.  I would hope the guidelines change to reflect these publications soon.

Next, there was a very important paper published in JCO in 2016 by senior author Katy Janeway. It was a summary of seven negative phase II trials from the Children’s Oncology Group (COG) that established the natural history of unresectable osteosarcoma to have an event free survival (EFS) of 12% at 4 months.  They concluded that, “This evaluation provides a baseline for disease progression in a population of children and young adults with recurrent/refractory osteosarcoma that can be used as comparison for the design of future phase II trials in osteosarcoma.” In the current trial and the REGOBONE trial, the placebo arms of this trial and the REGOBONE study demonstrate similar rapid progression: 10% in 16-week PFS in SARC024 and 0% in 12-week PFS in REGOBONE. These become the 8th and 9th trials with a placebo arm that supports the data of the 2016 JCO publication that stated that the progression free survival of placebo for the treatment of osteosarcoma is well established. To be fair to the authors and to be clear, SARC24 was started two years before the Janeway publication, but are supportive of stopping placebo controls in phase II trials of osteosarcoma in future trial designs.

Once again, the authors are to be congratulated on their findings, which I find practice changing.  Their dedication to rare cancer research is benefitting patients that agree to participate in clinical trials.  Working together they have identified an active agent for the treatment of osteosarcoma.  It will be interesting to see what the next steps are for the SARC team, as they have proposed combination studies based on Regorafenib in their discussion. 

Finally, rare disease research and clinical trials in sarcoma are desperately needed to improve the outcomes of our patients.  Thank you to JCO for highlighting the work from Lara Davis and colleges and the Sarcoma Alliance for Research and Collaboration.  This national organization has sites across the country where sarcoma patients can enroll on clinical trials.  A list of adult and pediatric sarcoma referral centers and the clinical trials that are available in sarctrials.org. 

This concludes this JCO podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study” by Bates et al. My name is Joseph Carver, and I am the Chief of Staff at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, Pennsylvania. My specialty is cardio-oncology.

It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.   It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.  Total dose delivered does not reflect specific cardiac exposure.  This has led to report the mean heart dose that is the percent cardiac volume within the radiation fields.  For most treated patients, discovery of anthracycline cumulative dosing is easily abstracted and straightforward. For modern therapeutic radiation, however, historical mean heart dose or other cardiac dosimetric parameters have not been traditionally reported and may be more difficult to obtain. This has led to a lack of consensus about the cardiovascular risk when the total dose is <30 Gy,

In the article that accompanies this podcast, Bates et al1 enhance our understanding of the association between cardiac volume exposure to different radiation therapy doses and rates of serious cardiac conditions among long term survivors of pediatric cancer and reaffirms the association of cumulative anthracycline dose and subsequent risk for cardiomyopathy.

With data from the Childhood Cancer Survivorship Study, they determined the rates of self-reported grade 3-5 cardiac conditions as defined by Common Terminology Criteria for Adverse Events  v4.03 in 24,214 >5-year survivors who were treated for a variety of cancers at a median age of 7 years.  Evaluation occurred at a median follow-up of 20.3 years with a median attained age of 27.5 years.  Late cardiac risk was compared to 5,046 untreated siblings.  For each survivor, radiation fields were reconstructed on age-specific phantoms to calculate estimated mean heart dose and the percent of heart volume receiving at least 5 Gy (low dose) and 20 Gy (higher dose).  Doxorubicin-equivalent doses were similarly abstracted.

Toxicity parameters were any cardiac disease, coronary artery disease and heart failure.  They found a cumulative incidence of cardiac disease, 30 years from diagnosis of 4.8% (95% CI 4.3-5.2). There was a dose relationship between mean heart dose and all parameters.  Both low-moderate doses (5-19.9 Gy) to a large volume of the heart (>50%) and higher doses (≥20Gy) to small cardiac volumes (0.1-29.9%) were associated with an increased risk of cardiac disease. Heart failure drove the risk of high doses to small volumes while CAD drove the risk of low doses to large volumes.

Similarly, they reconfirm the relationship between cumulative anthracycline dosing and any cardiac disease with an increased risk for those treated at a younger age (≤ 13 years of age).  An increased relative risk for any cardiac disease was also present with any anthracycline exposure (0.1-<250 mg/m2: RR 1.7%, 95% CI 1.1-2.5) compared to siblings.

This study shows that low-moderate dose RT to a large volume of the heart and higher-dose RT to a small volume of the heart increase the risk of late cardiac disease. It also reconfirms the association of cumulative anthracycline dosing and cardiac risk, especially in patients who were treated at < 13 years).  With a 4.8% risk for any cardiac toxicity at 30 years, the study provides an evidence-based long-term realistic risk estimate that can be part of pre-treatment conversations with patients and family as well as survivors.

What are the take-home points of this study?

1. In spite of modern techniques to deliver therapeutic radiation and avoid the heart, a “safe” cardiac dose has not been well-defined.  Two large retrospective, phantom-based studies have shown an increased risk of coronary heart disease of 7.4% per 1 Gy MHD in breast cancer and lymphoma patients. These studies have not only alerted radiation oncologists to the potential risk of even “low” radiation doses to the heart but have also driven them to push RT planning algorithms to optimize one parameter, mean heart dose. The problem with this single metric is that two treatment plans with vastly different dose maps can have the same mean heart dose: 1) low dose spread out to a large volume such as in an intensity modulated radiotherapy plan; or 2) high dose to a small volume (that may include the left anterior coronary artery) with almost no dose to the rest of the heart such as in breast tangents or a proton therapy plan. Even with current image-driven treatment planning algorithms that prioritize a low mean heart dose, it is still possible to deliver higher doses of radiation to cardiac substructures.  The results from this paper have major implications for treatment planning and delivery, informing us to be wary of low dose generic mean heart dose metrics and makes a case for universal adaptation of the quantification of structure-specific dose exposure and attention to the “low-dose cloud” in the rest of the heart.

1. For survivorship and surveillance, there are implications for guideline development evolving one step beyond binary “high risk/low risk” stratification to understand that any exposure to anthracyclines and/or therapeutic radiation is part of a continuum of risk: low risk is not no risk. This continuum informs health care providers to a proactive management approach for the late survivor population that includes aggressive management of cardiac risk factors present at initial evaluation and those that emerge over the decades of survivorship.

1. It is equally as important to reiterate that the late cardiac toxicity due to therapeutic radiation and anthracyclines pales in comparison to the risk associated with untreated traditional cardiac risk factors: (obesity, cigarette smoking, sedentary life style, diabetes, hypertension and the metabolic syndrome) and when they are present in this population, they magnify the 4.8% cardiac event risk defined by Bates.

1. This study also provides additional rationale for the field of cardio-oncology- for greater collaboration between medical and radiation oncologists and cardiologists at every step of the cancer treatment continuum.

I congratulate Bates and colleagues for this potentially paradigm changing contribution and am optimistic that further enhancements in radiotherapy planning and delivery will reduce late cardiac toxicity and improve survival.

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article Durable Tumor Regression and Overall Survival in Patients with Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy by Paul Nghiem, MD, PhD et al. My name is Reed Drews, and I am a member of the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center in Boston, MA. My oncologic specialty is non-melanoma skin cancers.

Merkel cell carcinoma is a rare, aggressive neuroendocrine skin malignancy with high propensity for local recurrence and regional lymph node and systemic metastases. Its incidence rises exponentially with aging and is 10-fold higher in chronically immunosuppressed patients. When Merkel cell carcinoma is advanced and/or unresectable, historical 5-year overall survival rates are low, from 14 to 27%. Cytotoxic chemotherapies, like platinum plus etoposide used in other high-grade neuroendocrine malignancies, have not yielded durable response rates.

The cutaneous cell (or cells) of origin in Merkel cell carcinoma remains controversial. Nevertheless, scientists have identified 2 pathogenetic pathways leading to Merkel cell carcinoma. In 80% of cases, clonal integration of a polyomavirus leads to Merkel cell polyoma virus-positive Merkel cell carcinoma. In the other 20% of cases, ultraviolet light-induced DNA damage leads to polyoma virus-negative Merkel cell carcinoma. Polyoma virus-negative Merkel cell tumors display predominant cytosine to thymine transitions, a signature of DNA damage from UV light, and they have a 100-fold greater mutational burden than virus-positive Merkel cell cancers. For both subtypes, loss of immune surveillance, as with aging or chronic immunosuppression, contributes to Merkel cell carcinoma development, with diminished non-self-antigen recognition of UV-induced neo-antigens in virus-negative tumors and viral oncoproteins in Merkel cell polyoma virus-positive tumors.

Given these factors, investigators have recently studied whether immune checkpoint inhibitors might hold promise for managing advanced Merkel cell carcinoma. To date, 3 antibody inhibitors of the programmed cell death-1 pathway (abbreviated PD-1), including anti-PD-ligand-1 avelumab, anti-PD-1 nivolumab and anti-PD-1 pembrolizumab, have been tested in patients with chemotherapy-refractory and/or treatment naïve Merkel cell carcinoma. The 62% objective response rate from avelumab in treatment-naïve Merkel cell carcinoma was nearly twice that observed in chemotherapy-refractory disease. In 2017 avelumab became the first immune checkpoint inhibitor approved by the FDA for advanced Merkel cell carcinoma. Nivolumab yielded similar results, as did pembrolizumab according to a 2016 report from Nghiem and colleagues of a multicenter, phase 2, non-controlled study with 26 patients.

As reported in this JCO publication, Nghiem and colleagues have now increased their cohort to 50 patients through the multicenter expanded phase 2, Cancer Immunotherapy Trials Network-09/Keynote-017 trial. They administered pembrolizumab 2 mg/kg intravenously every 3 weeks for up to 2 years. Median follow-up time was 14.9 months, with a range from 0.4 to 36.4 months. This represents the longest follow-up to date of any anti-PD-1 pathway inhibitor for first-line treatment of advanced Merkel cell carcinoma. The 50-patient cohort included 43 patients with (stage IV) distant metastatic disease and 7 with stage IIIB recurrent locoregional disease not amenable to definitive surgery or radiation therapy. All patients had normal organ and bone marrow function and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria were previous systemic therapy for unresectable Merkel cell carcinoma, immunodeficiency or systemic immunosuppressive therapy, active autoimmune disease, concurrent second cancer, and active central nervous system metastases.

The median age of enrolled patients was 70.5 years, with 80% age 65 or older. 64% of patients had Merkel cell polyoma virus-positive tumors. For previous management of their primary Merkel cell carcinoma, 42 patients had had surgery, and 35 patients had had radiation treatment. While no patient had previously received systemic therapy for advanced Merkel cell carcinoma, 3 patients had received adjuvant chemotherapy greater than 6 months prior to study enrollment.

Patients received a median of 10.5 doses of pembrolizumab – range 1 to 35 doses—and the median treatment duration was 6.6 months – range 1 day to 23.6 months. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors, version 1.1. Responses were generally rapid and durable with 2.8 months as the median time to response – range 1.5 to 9.7 months. The objective response rate to pembrolizumab was 56%, with complete and partial responses of 24% and 32%, respectively; 10% had stable disease; and 32% had progressive disease.

At time of data analysis, 20 of 28 responses were on-going, and the median durability of response had not been reached. The Kaplan-Mier estimation of response durability at 24 months was 79.1%. Median progression free survival was 16.8 months, and the Kaplan-Mier estimation of progression free survival at 24 months was 48.3%. Median overall survival had not yet been reached. The Kaplan-Mier estimation of overall survival rate at 24 months was 68.7%.

Tumor viral status, as determined by small T-antigen specific antibodies in serum or large T-antigen expression in tumor biopsies by immunohistochemistry, did not correlate with any study outcomes, such as progression free survival or overall survival. However, a trend towards improvement of these outcomes appeared in patients with PD-L1-positive tumors, as defined by cell-surface PD-L1 expression on at least 1% of tumor or immune cells.

The safety profile of pembrolizumab in advanced Merkel cell carcinoma was similar to that in other studies of anti-PD-1 pathway inhibitors: 28% of patients had grade 3 or greater treatment-related adverse events, causing 14% of patients to discontinue treatment. A 73-year old male patient with widely metastatic Merkel cell carcinoma and pre-existing atrial fibrillation died after developing pericardial and pleural effusions 1 day after one infusion of pembrolizumab. Other adverse events were generally manageable and typical of complications of anti-PD-1 pathway inhibitors, including adrenal insufficiency, colitis, hyperthyroidism, hypothyroidism, infusion-related reaction, myocarditis, pancreatitis, pneumonitis, maculopapular rash and thyroiditis.

With such impressive rates of durable tumor regression and overall survival, on December 19, 2018, the FDA granted accelerated approval to pembrolizumab for treating patients with recurrent locally advanced or metastatic Merkel cell carcinoma. Today’s standard of care for advanced Merkel cell carcinoma is an anti-PD-1 pathway inhibitor, and the NCCN Clinical Practice Guidelines in Oncology in 2018 recommended avelumab, nivolumab and pembrolizumab as preferred first-line therapy for advanced Merkel cell carcinoma, ahead of cytotoxic chemotherapy.

Future studies must determine what role anti-PD-1 pathway inhibitors will play in the neo-adjuvant and adjuvant settings when managing early stage Merkel cell carcinoma with high-risk features. Prior to immune check point inhibitors, neo-adjuvant and adjuvant chemotherapy were considered case-by-case, absent strong evidence for benefit.  However, now with impressive results from anti-PD-1 pathway inhibitors in advanced Merkel cell carcinoma, adjuvant nivolumab and avelumab are being evaluated in 2 randomized phase II trials. Nivolumab is also undergoing study in the neoadjuvant setting, and researchers presented promising preliminary results of a phase I/II study at the 2018 American Society of Clinical Oncology Annual Meeting. We look to Nghiem, his colleagues and other investigators to keep us informed regarding future advances, including insights into mechanisms of resistance to the immune checkpoint inhibitors.

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article Gonadal Functioning and Perceptions of Infertility Risk among Adult Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study by Lehmann et al. My name is Leslie Schover, and I am retired from the faculty of MD Anderson Cancer Center and currently Founder of Will2Love.com a digital health company in Houston, Texas. My oncologic specialty is cancer-related problems with reproductive health, i.e. sexual function and fertility.

Damaged fertility is unfortunately quite common in survivors of childhood cancer. A variety of chemotherapy drugs, as well as surgery affecting parts of the reproductive system or radiation therapy focused on the pelvis or brain, can damage spermatogenesis, reduce ovarian reserve, or interfere with uterine function. In general, males are more at risk than females for cancer-related infertility. Some survivors do not undergo puberty without hormonal support. For others, fertility may recover over time. However, many young women who have menstrual cycles in their teens or twenties are at risk for premature ovarian failure, leaving a narrowed window of time to become pregnant. Men do not know whether they have normal sperm counts, motility, or form unless they have had a recent semen analysis. People diagnosed with cancer before puberty may never have been counseled about fertility. Even survivors treated as teens or young adults typically do not know their fertility status unless they have consulted an expert in reproductive endocrinology or andrology. Surveys of young survivors suggest that the majority want to have children, particularly those who are childless.

A number of studies have documented markers of infertility or reduced rates of offspring in survivors of cancer, but little has been known about their perceptions of their fertility status. In the paper that accompanies this podcast, Lehmann and colleagues present novel data about the risk perceptions for infertility compared to indicators of actual gonadal function in over a thousand long-term survivors of childhood cancer participating in the St. Jude Lifetime Cohort. None of the participants already had children or a previous pregnancy. The mean age of the sample was 29, with a mean follow-up of 22 years since cancer diagnosis. 85% were white and 32% had at least a 4-year college degree. 52% were married or in a relationship. Only 10% of men and 16% of women had been tested for infertility outside of the study.

Gonadal function was measured by a semen analysis in 56% of men and by a panel of hormones in the others. In women under age 40, status as fertile vs. sub-fertile was assigned by chart review based on menstruation, diagnosed premature ovarian failure, or hormonal assays. Perception of risk for infertility was based on one question with a Likert scale of 5 response options, comparing one’s own fertility to that of peers who had not had cancer. Answers were dichotomized into two categories: perceived at risk for fertility or perceived normal fertility.

62% did perceive themselves as at risk for infertility. Those who perceived their fertility as damaged had characteristics that would indicate potentially more knowledge about cancer and fertility, including being older, white, in a relationship, having a college education, a history of gonadotoxic treatment, having tried unsuccessfully to conceive, or having sexual dysfunction.

In actuality, 24% of women and 56% of men had evidence of impaired gonadal function. However, actual medical status had no significant relationship to perceptions of risk. The most common discordance was that the survivor believed him or herself to have damaged fertility when medical tests appeared normal. This included 20% of men and 44% of women. Inaccurate perceptions were more common in respondents who were white, had more education, had more gonadotoxic cancer therapy, were very concerned about their fertility, and had sexual dysfunction. In contrast only 16% of men and 5% of women overestimated their fertility potential.

In terms of clinical implications, it is common for young survivors to overestimate their risk of infertility. Such beliefs can diminish quality of life. A young person who feels like “damaged goods” may be distressed about the future and perhaps reluctant to date or to enter into a committed relationship. For women, risky drinking was another factor associated with overestimating fertility risk. Risky drinking, and the notion that pregnancy is impossible, may contribute to findings in other studies of excess rates of unintended pregnancies and failure to use consistent contraception in young adult female survivors. Those unaware of their damaged fertility maybe in for distress and disappointment if they try for a pregnancy. Clearly a greater effort should be made to inform young survivors about risks to fertility and to refer them for testing at intervals of fertility status.

It appears that women are much more likely than men to perceive themselves as potentially infertile, despite the fact that men are more likely to be infertile. However, the measures of gonadal function used in women were not sensitive enough to predict the likelihood of diminished ovarian reserve in the future. Many young survivors of cancer can conceive in their teens or twenties, yet have a steeper than normal drop-off in ovarian reserve with aging, so that their menopause occurs far before the average age of 51. In fact, women’s fears in this study that they will have trouble getting pregnant in the future may be more accurate than they appear. Age at first pregnancy has steadily increased in our society, with women postponing childbearing until they have completed educational goals or established a working life. More cancer survivors are likely to run out of time before they are ready to have a child. One solution may be commercial egg banking before age 25-30, if fertility preservation was not accomplished before starting cancer treatment. Egg banking is expensive, however, and does not guarantee a future pregnancy.

This survey adds to our knowledge of the informational needs of survivors of cancer in childhood or teen years. Both medical and counseling support should be more readily available. Survivors with lower health literacy would be particularly good targets for such services.

This concludes this JCO Podcast. Thank you for listening.

This JCO podcast provides observations and commentaries on the JCO article entitled "Indeterminate Pulmonary Nodules at diagnosis in Rhabdomyosarcoma: Are they clinically significant?"  A report from the European Pediatric Soft Tissue Sarcoma Study Group by Bas Vaarwerk, MD et al.

My name is Alberto Pappo and I am the head of the division of solid tumors at St Jude Children’s Research Hospital in Memphis, TN. My oncology specialty is pediatric oncology. 

In this report, Bas Vaarwerk, and investigators from the European Pediatric Soft Tissue Sarcoma Study Group evaluated the significance of indeterminate pulmonary nodules at diagnosis in children with rhabdomyosarcoma defined as the presence of less than 5 pulmonary nodules measuring less than 5mm or 1 pulmonary nodule that measured between 5 and 9 millimeters.

This analysis included 316 patients who were enrolled on the EpSSG RMS 2005 study for non-metastatic rhabdomyosarcoma from September 2005 through December 2013 and for whom chest computed tomography scans were obtained at diagnosis and were available for review. Treatment in the EpSSG RMS 2005 study was stratified according to risk group, pathology, post-surgical stage, site, nodal involvement, size and age. All patients received multi agent chemotherapy with ifosfamide (except for low risk patients), vincristine and actinomycin D (IVA chemotherapy). High risk patients were randomized to IVA or IVA with doxorubicin and after 9 courses if in complete remission, were eligible for a second randomization between end of therapy and additional maintenance therapy with 6 courses of vinorelbine and cyclophosphamide

Local control was determined by risk group, tumor site, age and response to therapy and radiotherapy was given at week 13 in doses ranging from 36 to 51.4Gy. All chest computed tomography scans were reviewed by the local radiologist at the treating center. Data was obtained and recorded using case report forms.  All computed tomography scans were performed with minimum slice thickness of 3 to 5 mm. 

The median age at diagnosis for the 316 eligible patients was 5.4 years and the median follow up time for the cohort was 75 months.  There were 249 (78%) patients who did not have a pulmonary nodule and 67 (21%) who had at least one indeterminate pulmonary nodule. Patient and treatment characteristics were similar between the 2 groups; 80% of the patients presented with Group III  unresectable disease, 54% had high risk disease, and 71% had favorable histology tumors such as embryonal histology tumors.  Twenty four percent of patients received maintenance chemotherapy and 77% were treated with local radiotherapy

A total of 100 nodules were identified in the 67 patients. Nodules ranged in size from 1 to 8 mm.  69% of the patients presented with one pulmonary nodule, 92% of the patients had nodules that measured less than 5 mm 85% of the nodules were unilateral. The 5-year event-free survival for patients with indeterminate pulmonary nodules was 77% and for those without nodules 73.2%. These differences were not statistically significant with a p value of 0.68. The 5-year overall survival rates were 82% for patients with indeterminate pulmonary nodules and 80.8% for those without nodules. The differences between these 2 groups were not statistically significant with a p value of 0.76.   There were no significant differences in outcomes based on the number or size of the nodules.  Similarly, there were no differences in clinical outcome based on histology, fusion status, age and type of chemotherapy received. Lung metastases developed in 3% of patients with indeterminate pulmonary nodules and in 1.6% of patients without nodules a value that was not statistically significant. The authors conclude that the presence of indeterminate pulmonary nodules in newly diagnosed children with rhabdomyosarcoma as defined in this report does not adversely affect the outcome of these patients and these children can be adequately treated with non-metastatic risk-based clinical protocols.

This report highlights the challenges of assigning risk and therapy based on the presence of a limited number of small pulmonary nodules in children with newly diagnosed rhabdomyosarcoma when they are detected using newer imaging modalities such as thin cut computed tomography of the chest. The authors have successfully demonstrated in this retrospective study that newly diagnosed patients with rhabdomyosarcoma who present with indeterminate oligometastatic disease to the lung which in this study was defined as the presence of 4 or fewer pulmonary nodules measuring less than 5 mm or one nodule that measures 5 to 9 mm, have similar outcomes to patients who present without pulmonary nodules. More importantly, these patients can be treated with less intense trials that may include the use whole lung irradiation which is known to significantly increase the risk of breast cancer in childhood cancer survivors. The authors have implemented a standardized definition for indeterminate oligometastatic lung disease which is highly reproducible and easily implemented.  Their results are thought provoking and deserve further validation in a well- designed prospective clinical trial.

Because of the lack of pathologic correlation with imaging findings in this report, it is not possible to determine which patients truly had oligometastatic disease to the lung. It is conceivable that some of the 67 patients with indeterminate nodules did not have actual metastatic rhabdomyosarcoma in the lung, or alternatively these results may also indicate that current risk-based therapies for localized disease are effective at eradicating small oligometastatic disease. It is important to point out however, that in this report, about one fourth of the patient population was assessed using reconstruction widths of ≤ 1.25 mm, which might have identified a larger number of small nodules of uncertain significance. In addition, 69% of the patients with indeterminate nodules had only one nodule, 92% had nodules that measured less than 5 mm and 85% had unilateral disease.  All of these factors have been associated with a significantly lower likelihood of identifying biopsy proven metastatic disease in pediatric patients with sarcomas. These findings raise questions as to whether thin cuts < 5mm in thickness are of any value in the assessment of pulmonary metastases in children with rhabdomyosarcoma.

In summary, this report opens new areas for clinical research that could lead to a uniform strategy for defining metastatic pulmonary disease in pediatric rhabdomyosarcoma and a more precise method for  risk-stratifying disease in this patient population.  

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Tamoxifen pharmacogenetics and metabolism: Results from the prospective CYPTAM study” by Sanchez-Spitman et al. My name is Vered Stearns, and I am a Professor of Oncology and Co-Director of the Breast and Ovarian Cancer Program at the Kimmel Cancer Center at Johns Hopkins in Baltimore, Maryland. My oncologic specialty is medical oncology.

In the paper that accompanies this podcast, the authors report results of a prospective clinical study designated CYPTAM, which was designed to correlate endoxifen serum concentrations and outcomes of women prescribed adjuvant tamoxifen. The investigators enrolled 667 women with breast cancer who were initiating tamoxifen or who have been on tamoxifen for fewer than 12 months. The investigators obtained blood samples for CYP2D6 genotyping using the Amplichip CYP450 Test, and measured steady state concentrations of endoxifen with a high-performance liquid chromatography-tandem mass spectrometry. Co-primary endpoints included association of recurrence-free survival with endoxifen concentrations and with CYP2D6 genotypes. The patients were censored at the time of tamoxifen-discontinuation in case of a transition to an aromatase inhibitor. Several additional endpoints included disease-free survival, complete relapse-free survival, complete disease-free survival and overall survival. The statistical analysis plan was designed as a gate-keeper analysis for the co-primary objectives. Only if an association was found with a p-value below 0.05, were the remaining objectives considered.

The authors were not able to demonstrate an association between endoxifen concentrations and recurrence-free survival on tamoxifen. They also were not able to demonstrate an association either when exploring endoxifen concentrations in quartiles or when considering other thresholds. Likewise, there was no association between CYP2D6 genotypes and recurrence-free survival.

Almost two decades ago, researchers recognized that the absence or inhibition of the CYP2D6 enzyme is associated with very low concentrations of endoxifen, a potent and abundant anti-estrogen metabolite of tamoxifen. Whether low concentrations of endoxifen predict an inferior survival outcome has not been definitively determined. Multiple retrospective and small prospective studies evaluated CYP2D6 genotypes and survival outcomes and have provided mixed evidence. Clinicians have, therefore, wondered whether CYP2D6 genotype testing or endoxifen monitoring will assist in treatment recommendations. The CYPTAM investigators attempted to prospectively correlate endoxifen serum concentrations and outcomes for women taking tamoxifen.

The CYPTAM study is associated with several limitations, and, therefore, it does not provide a definitive answer to the controversy. For example, women were enrolled in the study either before starting tamoxifen or up to 12 months after initiation of the drug. This strategy could have led to incomplete baseline data and to the exclusion of individuals with early recurrences. In addition, about two-thirds of study participants transitioned to aromatase inhibitors following a short course of tamoxifen. The sequential administration of tamoxifen and aromatase inhibitors is superior to tamoxifen alone. Some of the patients who transitioned to aromatase inhibitors could have suffered a recurrence had they have stayed on tamoxifen alone. Furthermore, the authors did not have information regarding concomitant CYP2D6 inhibitor use. CYP2D6 inhibitors are commonly co-administered with tamoxifen and can contribute to misclassification of the CYP2D6 phenotype. 

The challenge moving forward is that single agent adjuvant tamoxifen is rarely used. Most postmenopausal women with hormone receptor-positive breast cancer are recommended an  aromatase inhibitor instead of, or in sequence with, tamoxifen. Premenopausal women with high risk hormone receptor-positive tumors are recommended ovarian suppression with tamoxifen or an aromatase inhibitor. Women prescribed tamoxifen alone are usually at extremely low risk of recurrence, and a prospective study in this group of women will require a large number of participants to demonstrate differences between phenotypes. Given current practice, it may not be feasible to fully determine the role of endoxifen concentrations and CYP2D6 genotypes as predictors of tamoxifen efficacy.

Retrospective analyses that used samples obtained through large prospective studies, such as the Arimidex, Tamoxifen, Alone or in Combination and the Breast International Group 1-98, failed to demonstrate an association between CYP2D6 phenotypes and survival outcomes. Taken together, the data at present are insufficient to recommend CYP2D6 testing or analysis of metabolic profile in women for whom tamoxifen is considered. Indeed, clinical guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network do not recommend CYP2D6 genotyping. Moving forward, prospective studies of altered metabolism due to single nucleotide polymorphism, or administration of inhibitors, should be considered in clinical trials of standard and novel agents as these can lead to differences in drug efficacy and toxicity.

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients with Favorable Histology Wilms Tumor: A Report from the Children's Oncology Group” by Mullen et al. My name is Dr. Meredith Irwin, and I am an oncologist and Professor at the Hospital for Sick Children and University of Toronto in Toronto, Canada.  My oncologic specialty is pediatric solid tumors.

Wilms tumor is the most common pediatric kidney tumor. With current therapies, the 5-year overall survival for newly diagnosed patients is 90%. For the 15% who relapse, most commonly in the lung or abdomen, the cure rates still often exceed 50%. The likelihood for cure is based on a number of risk factors, including histology, stage and previous therapies. Thus, similar to many pediatric cancer patients, those with Wilms undergo surveillance imaging during and following completion of upfront therapy in order to potentially discover recurrences sooner with the hope that early identification of lower disease burden will translate to higher salvage rates. However, to date, several small studies have failed to demonstrate that early detection of recurrence by surveillance imaging is associated with better prognosis for pediatric cancers including medulloblastoma, lymphoma and neuroblastoma. Moreover, with increasing awareness of the potential risks from imaging-associated ionizing radiation exposures and associated financial costs, there is significant interest in generating evidence to determine optimal surveillance strategies and limit cumulative exposures.

To address these issues for Wilms tumor, the study by Mullen et al was designed to determine whether, compared to relapses detected by surveillance with chest x-ray and ultrasound, those detected with cross-sectional CT imaging were associated with improved survival rates. To do this, four authors retrospectively reviewed flowsheets and imaging reports for patients who recurred on the 5th National Wilms Tumor Study (NWTS-5) between 1995 and 2002 to determine whether their relapses were identified by signs/symptoms or scheduled surveillance imaging.  If by imaging, they recorded the modality- CT, ultrasound and/or chest x-ray. The study cohort included the 281 patients who recurred following initial diagnosis of favorable histology unilateral Wilms. All patients underwent imaging at specified time intervals, but the modalities varied.

The 5-year overall survival for this cohort post-relapse was 67%, which is similar to other studies. 48% of recurrences were detected with routine surveillance by chest x-ray or ultrasound, 25% by surveillance with CT, and 25% presented with symptoms between scheduled imaging, most commonly pain or abdominal mass. Certain characteristics differed among these groups. The CT-detected patients were more likely to be stage 4, and in the symptoms group, more relapses were extrapulmonary and occurred post-treatment.  The authors asked whether the specific method of detection of relapse impacted prognosis. Although recurrences detected by symptoms were associated with an inferior 5-year survival of 55%, versus 76% for the imaging-detected group, there were no differences in survival for patients based on the imaging modality used for detection at any point during or following therapy. There was also no significant advantage to CT over u/s or x-ray for abdominal and chest relapses, respectively. Although a higher number of foci detected at recurrence and larger relapse size correlated with inferior outcomes, analyses failed to find a significant advantage for CT use in the subgroups of lung-only relapses or advanced-stage patients.

The authors also examined financial burden and radiation exposures. To determine the economic impact, the authors predicted costs based on US Medicaid/Medicare reimbursement rates.  For patients with stage III disease, more than 200 imaging studies (with estimated costs between $20,000 and $45,000) were required to identify one relapse. For stage IV, between 158 and 190 studies costing more than $15,000 were needed. Estimated radiation exposures from these surveillance protocols varied between 9.4 and 83 mSv, depending on the total number of CTs. Although it is difficult to quantify how cumulative radiation doses may impact future cancer risks, expert groups have estimated that there is a 1 in 1,000 increased risk of future cancer deaths for every 10mSv exposure at age 10, and these risks are higher for patients exposed at younger ages. Other potential negative consequences of surveillance imaging not examined by these authors include the associated psychological stress for families, which is termed “scanxiety,” and possible adverse neurological effects of anesthetic agents for young children.  

The significance of this report is that it is the first study to compare the utility and cost of different imaging methods for the identification of Wilms tumor recurrences. In comparison to x-rays or ultrasounds, there was no advantage to using CT, which is costlier and resulted in higher radiation exposures. It is possible that an advantage to CT was not identified in part because only the best prognosis patients, those with favourable histology, were included. The authors excluded those with bilateral disease, who often have germline predisposition syndromes, and patients with anaplastic histology, which has a higher relapse rate

Ideally, a prospective RCT design would be performed to determine whether cross-sectional imaging would be superior to ultrasounds/x-ray combinations. However, given the overall excellent survival for Wilms tumor, the number of patients required to detect a significant survival advantage would likely be very large. In addition, given the cost and potential late effects of radiation exposures, engagement from oncologists, radiologists and families might be challenging.

 In conclusion, the findings in this manuscript support the recommendations by Mullen and colleagues that surveillance post completion of therapy for favorable histology unilateral Wilms does not need to include CT scans and can instead be based on symptoms and ultrasound and/or x-rays. These authors did not specify whether duration of surveillance could be limited; however, a recent publication in Lancet Oncology by Brok and colleagues supported consideration of a cut-off of two years. Their SIOP study reported that the detection of one relapse 2-5 years post-therapy required 500 scans. Importantly, it remains possible that for rare patient subsets with anaplastic histologies or other biomarkers of unfavorable disease, which may include 1q LOH, surveillance protocols might need to be adjusted. This may be similar to strategies for other tumors, such as neuroblastoma, where, in comparison to patients with high-risk disease, those with low or intermediate-risk disease with survival rates of more than 80-90% are increasingly undergoing surveillance regimens without frequent CT scans, which, in part, is determined based on clinical and biological risk factors. These approaches to risk stratification of imaging are increasingly being used. Thus, clinicians may begin to modify surveillance based on the risk of recurrence for a particular subgroup of patients, similar to precision medicine approaches for treatment. However, it will be important to perform studies similar to the accompanying manuscript to generate evidence to inform and support precision surveillance imaging recommendations that are specific to different tumor types.

This concludes this JCO podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article, "Impact of Baseline Steroids on Efficacy of PD-(L)1 Blockade in Patients With NSCLC" by Arbour et al. My name is Deepa Rangachari, and I am an Assistant Professor of Medicine at the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts, USA. My oncologic specialty is thoracic cancers.

For decades, the management of advanced non-small-cell lung cancer has relied on use of cytotoxic chemotherapies with a median overall survival not exceeding one year.  As this longstanding therapeutic approach has been limited by modest efficacy, finite durability, and significant treatment-associated toxicity,  evolving better tailored, more effective, and less toxic care strategies has long been an unmet need. Beginning in the mid-2000s with the identification of actionable oncogenic driver mutations in the epidermal growth factor receptor, the landscape for personalized care in advanced non-small-cell lung cancer has been permanently transformed. Today, the evidence-based standard of care for upfront therapeutic stratification in all patients with advanced stage disease relies on mandatory genomic and immunologic profiling, with emphasis on identifying subsets of patients who will experience better outcomes and  less toxicity through the use of disease-specific therapies.

It is in this landscape that the use of immune checkpoint inhibitors has flourished for patients with lung cancer. Since 2015, 3 different immune checkpoint inhibitors—Nivolumab, Pembrolizumab, and Atezolizumab—have all gained approval from regulatory agencies for management of patients with advanced stage non-small-cell lung cancer on the basis of phase III studies showing improved overall survival with more durable responses, less toxicity, and better quality of life with checkpoint inhibitors when compared with chemotherapy.[1-5]  This benefit has been seen in both previously treated patients regardless of tumor programmed death ligand 1 (hereafter referred to simply as “PD-L1”) status and in upfront management of patients with high tumor PD-L1, defined by a tumor proportion score >/= 50%. Combined chemoimmunotherapy for patients with non-squamous disease regardless of tumor PD-L1 status is also now a vetted approach.[6]

With widespread use of immune checkpoint inhibitors now the standard of care for many patients with this disease, important pragmatic concerns regarding concurrent use of checkpoint inhibitors and corticosteroids have emerged. Specifically, as many patients will present with refractory anorexia, nausea, fatigue, pain, brain metastases, and/or dyspnea for which corticosteroids are often used as helpful adjuncts to cancer-directed therapy for symptomatic palliation, what if any are the consequences of concurrent use? How do we balance these symptomatic issues against the need for delivering effective cancer therapy?

Due to concerns for the immunomodulatory effects of corticosteroids on T-cell activity and function, nearly all clinical trials leading to approval of these agents have excluded patients requiring the equivalent of Prednisone 10-20mg daily or more prior to initiation of checkpoint inhibitor therapy. In contrast, there is now an emerging body of evidence suggesting the safety of subsequent corticosteroid use, once checkpoint inhibitors have been started, for management of immune-related adverse events , without jeopardizing any previously achieved therapeutic benefit.[7, 8]

But what about those patients being newly initiated on checkpoint inhibitors who have been previously maintained on palliative corticosteroids?

In the article that accompanies this podcast, Arbour and colleagues present important insights into this question.  This is a retrospective analysis of 640 patients with advanced non-small-cell lung cancer with immunotherapy-naïve disease treated with checkpoint inhibitors at the Memorial Sloan Kettering and Goustave Roussy Cancer Centers from 2011-2017. Data regarding steroid dose, mode of administration, and indications for use were collected along with efficacy of checkpoint inhibitors as assessed by an independent team of radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. At the time of checkpoint inhibitor initiation, 90/640 (14%) of patients were receiving the equivalent of Prednisone 10mg/day or more; an additional 17 patients (or 3% of the total study population) were receiving <10mg of Prednisone/day and were analyzed as part of the “non-steroid” group in subsequent assessments.

The most common indications for steroid use reflect those seen in routine clinical practice: dyspnea/respiratory symptoms (33%), fatigue (21%), and brain metastases (19%).  Clinicopathologic characteristics between the steroid and no steroid groups were generally well balanced.  As might be expected, however, there were more patients with poor performance status and history of brain metastases in the steroid group.

Amongst the Sloan Kettering cohort, steroid use of >/= 10mg/day was associated with statistically significant reductions in objective response rates (6% vs. 19%), median progression free survival (1.9 vs. 2.6 months), and median overall survival (5.4 vs. 12.1 months) in the steroid vs. no steroid groups, respectively. Similar findings were seen in the Gustave Roussy cohort.  Pooled data from both cohorts confirmed the same detrimental impact of baseline steroid use >/= 10mg/day.  On multivariable analysis, the findings of inferior response rates and worse progression free and overall survival in those receiving Prednisone >/= 10mg/day were upheld. Further, a similar decrement in checkpoint inhibitor efficacy was observed in patients receiving >/= 20mg/day of Prednisone as compared to those receiving lower doses of 10-19 mg/day.

Patients receiving and then discontinuing steroids 1-30 days prior to initiation of immune checkpoint inhibitors had intermediate progression free and overall survival as compared to those receiving steroids on the same day and those not receiving any steroids within 30 days of starting a checkpoint inhibitor.

The authors do additionally note that 6 patients achieved a partial response to checkpoint inhibitor therapy, despite steroid use at treatment initiation and with durable responses for most of these patients lasting >15 months.

Notable strengths of this investigation are the analysis of real world clinical scenarios where steroid use is often a pragmatic reality and the availability of highly relevant details regarding steroid dose, indication, duration, and initiation/discontinuation relative to checkpoint inhibitor therapy. Outcomes with immune checkpoint inhibitors seen in patients receiving <10mg/day of Prednisone are concordant with what has been seen with these agents in day-to-day practice and in the published literature to date.

Limitations of the study include its retrospective nature and overall low incidence of steroid use.  With the advent of combined chemoimmunotherapy regimens, finite duration steroid use concurrently with each cycle of treatment for prevention of chemotherapy-related nausea and rash has become standard.   However, as patients in this study were treated with immune checkpoint inhibitor monotherapy, the impact of these finite, repeating courses of steroids is not explored here. Further, though multivariable analysis confirmed the independent association between steroid use and inferior outcomes with checkpoint inhibitors, a mechanistic explanation for this has not yet been elucidated. Lastly, immunologic profiling results (i.e. tumor PD-L1 status and tumor mutation burden) were not reported.

In my own practice and consistent with the observations made by Arbour and colleagues in this analysis,  I try to minimize or avoid the use of daily palliative steroids for patients in whom immune checkpoint inhibitor therapy is shortly anticipated.  Whenever possible, steroid-sparing alternatives should be considered and used. However, in those patients who require steroids and without reasonable alternatives (i.e. those with brain metastases and intracranial edema), medically necessary steroid therapy should not be deferred or discontinued until it is clinically safe to do so. 

Arbour and colleagues should be congratulated on their important contribution to this highly relevant clinical issue. 

This concludes this JCO Podcast.  Thank you for listening.

References:

1. Reck, M., et al., Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med, 2016. 375(19): p. 1823-1833.
2. Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med, 2015. 373(17): p. 1627-39.
3. Rittmeyer, A., et al., Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet, 2016.
4. Brahmer, J., et al., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med, 2015. 373(2): p. 123-35.
5. Herbst, R.S., et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016. 387(10027): p. 1540-50.
6. Gandhi, L., et al., Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med, 2018. 378(22): p. 2078-2092.
7. Horvat, T.Z., et al., Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol, 2015. 33(28): p. 3193-8.
8. Schadendorf, D., et al., Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials. J Clin Oncol, 2017. 35(34): p. 3807-3814.

In this JCO Article Insights episode, Alexandra Rojek provides a summary on two long term follow studies: "Long-Term Follow-Up of Rituximab Maintenance in Young Patients With Mantle-Cell Lymphoma Included in the LYMA Trial: A LYSA Study" by Sarkozy, et al published on December 18th, 2023 and "Long Term Follow Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma," by Kahl, et al, published January 9, 2024.

TRANSCRIPT

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

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing two clinical trial updates published in the March 1st issue of JCO, focusing on the long-term outcomes of rituximab therapy for patients with lymphoma. The first paper discusses the use of maintenance rituximab for mantle cell lymphoma patients in the LYMA trial, and the second paper addresses rituximab dosing strategies for low tumor burden follicular lymphoma in the RESORT study.

The first article by Sarkozy et al. for the LYSA group is titled "Long-Term Follow-Up of Rituximab Maintenance in Young Patients with Mantle Cell Lymphoma Included in the LYMA Trial: A LYSA Study." The LYMA trial was designed to answer whether the addition of the CD20-targeting monoclonal antibody rituximab provided additional benefit for patients with mantle cell lymphoma who achieved a response to induction chemoimmunotherapy, followed by consolidative autologous stem cell transplant in randomized patients, maintenance rituximab for three years versus observation alone. The primary analysis of the LYMA trial was published in 2017 and showed that the primary endpoint of four-year event-free survival or EFS was met at 79% in the maintenance rituximab arm compared to 61% in the observation alone arm. Additionally, there was a four-year overall survival or OS benefit of 89% versus 80% in favor of maintenance rituximab. Thus, on the basis of the LYMA trial primary analysis, the use of maintenance rituximab after consolidative autologous stem cell transplantation has become the standard of care in the field for these patients. 

The long-term safety and efficacy data presented in this clinical trial update for the LYMA study continue to demonstrate ongoing EFS and OS benefit for patients randomized to maintenance rituximab. Patients were initially enrolled between 2008 and 2012, and 240 patients were randomized to either arm. EFS in this study was defined as absence of disease progression, relapse, or death, severe infection, or allergy to rituximab. The data cutoff for this updated analysis was April 2019, with a median follow-up from randomization of seven years for living patients with a note that this is prior to the COVID-19 pandemic. For those in the maintenance rituximab arm, the seven-year EFS was 76% compared to 46% for those under observation. For those on the rituximab arm, the majority of relapses occurred within three years of randomization and thus while on maintenance rituximab, which the authors suggest does not show an increase in incidence of relapse after the end of maintenance therapy. The seven-year overall survival was 83% for those on the rituximab arm compared to 72% for those on the observation, with a log-rank p-value of 0.08. There was no difference in causes of death between the treatment arms noted. 

Notably, the patients who received maintenance rituximab after induction and transplant experienced a shorter second OS after relapse therapy, with a median OS2 of 1.1 years compared to 4.6 years favoring those on the observation arm, without impact of the type of salvage therapy received. Although this study was conducted before BTK inhibitors were approved in France and thus used at a low rate for patients who relapsed after initial therapy. This suggests that those who relapse after maintenance rituximab were those with the most aggressive disease biology. The authors also identified a group of patients who experienced progression of disease within 24 months of initial therapy or POD24 and showed that a Ki-67 score greater than 30% and high MIPI score were prognostic of POD24 events. For those who experienced POD24 within the rituximab arm, they also experienced a shorter OS2 compared to those on observation, again suggesting that those whose disease relapses after maintenance rituximab tend to have more aggressive and difficult-to-treat. 

While the interpretation of post-relapse outcomes and therapies needs to be interpreted in the light of a different era of available therapeutic options in more recent years, particularly the newest generation of BTK inhibitors, this updated follow-up of the LYMA study provides additional strength to the standard of care established through the trial's primary analysis of the benefit of maintenance rituximab after induction therapy and consolidative autologous stem cell transplantation for patients with mantle cell lymphoma. Although the extended follow-up was conducted prior to the COVID-19 pandemic, during which increased risk of infection was shown for those undergoing B-cell depletion with agents such as rituximab, this extended follow-up of the LYMA study continues to show that the optimal therapy for mantle cell lymphoma should include maintenance rituximab after transplant. Studies since the design of the LYMA trial have sought to address whether consolidative transplants are necessary when BTK inhibitors are added to induction therapy, and ongoing studies in this era of newer treatment agents will continue to challenge and potentially redefine this now well-established standard of care.

The second article by Kahl et al. is titled "Long-Term Follow-Up of the RESORT Study: E4402, a Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma." The RESORT study, conducted by the Eastern Cooperative Oncology Group, was designed to address whether rituximab-responsive low tumor burden follicular lymphoma patients benefit from maintenance rituximab until progression versus a rituximab retreatment approach at the time of progression. The primary analysis of the RESORT study, published in 2014, did not show a difference in the primary endpoint, which was defined as time to treatment failure. The five-year risk of treatment failure for those on a maintenance strategy was 53% compared to 50% for those on a retreatment dosing strategy. At the time of the primary analysis, letters were sent to participants and providers, and thus the data was locked for further primary endpoint analysis in late 2011. The data lock for long-term follow-up presented in this paper was continued through 2021. 

The authors looked at several endpoints in this long-term follow-up. They found that freedom from first cytotoxic therapy, at a median follow-up of almost nine years, favored the maintenance group over the retreatment group, with 83% versus 63% of patients free from chemotherapy or radiation at year seven. When looking at response duration, the analysis also favored a maintenance over retreatment approach, of 66% versus 30% for 10-year response duration, with a median follow-up of 12 years. However, when looking at overall survival at 10 years, there was no difference between rituximab dosing strategies, with a 10 -year overall survival of 83% for those receiving maintenance versus 84% for those receiving retreatment. While this extended follow-up of the RESORT study was not able to assess the long-term follow-up of the primary endpoint, the secondary endpoints suggest that while a maintenance dosing strategy was superior for prolonging time to first cytotoxic therapy and response duration, this again did not translate to an overall survival benefit. The authors conclude that they continue to recommend a rituximab retreatment strategy for these patients instead of a maintenance strategy, in the absence of a survival benefit, particularly with the high response rates observed with next-line treatment strategies for follicular lymphoma patients. 

Similarly to the LYMA study discussed in the first paper, the treatment arms of the RESORT study were completed prior to the COVID-19 pandemic. B-cell depletion, such as with prolonged rituximab therapy, is known to negatively impact the ability to combat viral infections such as SARS-CoV-2. Thus, the authors conclude that, in light of current and future infectious concerns, the extended follow-up of the RESORT study does not support the use of maintenance rituximab for patients with low tumor burden follicular lymphoma. Other studies have also evaluated modified and abbreviated maintenance rituximab dosing strategies for this same population and have also not shown a survival benefit, thus further strengthening this recommendation of favoring a retreatment approach over maintenance therapy.

Together, the extended follow-ups of the LYMA and RESORT studies, while addressing different questions regarding the use of maintenance rituximab in mantle cell lymphoma and follicular lymphoma, support the primary endpoints of each respective study. There is a clear role for the use of maintenance rituximab therapy to promote improved event-free and overall survival, as the LYMA study has shown for mantle cell lymphoma patients. However, this does not extend to low tumor burden follicular lymphoma patients in the RESORT study. The updated analyses of these two studies provide additional strength to the nuanced and targeted application of this stalwart of lymphoma therapy that is rituximab, in the modern treatment era. While ongoing studies will aim to address how we optimize therapies with new agents for each subtype of lymphoma patients, the LYMA and RESORT studies continue to guide best practice and standards of care. 

This is Alexandra Rojek, thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. 

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.

Read the related article "First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2–Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial" by Rimawi et al on JCO.org.

Transcript:

This JCO Podcast provides observations and commentary on the JCO article ‘First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in HER2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial’ by Rimawi et al.  My name is Sara Tolaney and I am Assistant Professor of Medicine at Harvard Medical School and Senior Physician at Dana-Farber Cancer Institute in Boston, Massachusetts.  My oncologic specialty is breast cancer.

Since the seminal report of the benefits of adding trastuzumab to chemotherapy, we have seen an improvement in survival for patients with metastatic HER2-positive disease from approximately two years to now almost 5 years.  This dramatic improvement in outcomes can be attributed to the use of continued anti-HER2 therapy beyond progression as well as the introduction of new HER2-directed therapies.  The largest improvement in survival has come from the addition of pertuzumab to a taxane and trastuzumab as seen within the CLEOPATRA study.  This resulted in an impressive almost 16-month improvement in overall survival and established this regimen as a first line standard in the metastatic setting. While chemotherapy and dual anti-HER2 therapy is the current first line treatment approach, we are now left with the question about how best to optimize therapies available to us, and whether or not there are other first line approaches we could consider in order to lessen toxicity. 

One potential alternative approach for patients with hormone-receptor positive, HER2-positive disease could be to consider the use of hormonal therapy.  There has been some concern that hormone-receptor positive tumors that are also HER2-positive may be relatively resistant to hormonal therapy.  One reason for this may be that activation of HER2 can result in direct phosphorylation and activation of the estrogen receptor.  This potential HER2 and ER bidirectional cross-talk has provided justification for combinatorial therapy targeting both of these pathways concurrently.  There have been at least three trials that have examined the addition of single agent HER2-targeted therapy to hormonal therapy.  The TAnDEM trial randomized a little over 200 patients with hormone-receptor positive, HER2-positive breast cancer to either anastrozole alone or in combination with trastuzumab as first line therapy and found a 2.4-month improvement in progression free survival, but no difference in overall survival.  The dual EGFR/HER2 tyrosine kinase inhibitor, lapatinib, has also been investigated in combination with hormonal therapy.  A phase 3 study in the first line metastatic setting found that adding lapatinib to letrozole improved progression free survival from 3.0 to 8.2 months, and another trial that looked at adding lapatinib to fulvestrant found an improvement in progression free survival from 3.3 to 5.9 months.  These three studies suggest that single agent HER2-targeted therapy adds modestly to endocrine therapy, and there has therefore been interest to see if dual HER2 targeted therapy added to hormonal therapy would result in a more significant improvement in outcomes.

Since data from CLEOPATRA had suggested that the addition of pertuzumab and trastuzumab to chemotherapy led to significant improvements in disease-free and overall-survival, In the article that accompanies this podcast, Rimawi and colleagues were interested in exploring if adding pertuzumab to trastuzumab and hormonal therapy could offer additional benefits.  The PERTAIN study was a multicenter phase 2 trial that  enrolled 258 patients with locally-advanced or metastatic hormone-receptor positive, HER2-positive breast cancer who had not previously received systemic therapy in the advanced disease setting, outside of endocrine therapy, and randomized them to receive trastuzumab plus an aromatase inhibitor or trastuzumab plus pertuzumab and an aromatase inhibitor.  Patients were allowed to receive induction chemotherapy with a taxane for 18-24 weeks in combination with trastuzumab (with or without pertuzumab) at the treating investigator’s discretion; this was decided prior to randomization and patients were stratified by whether or not they had received induction chemotherapy.  The trial demonstrated an improvement in progression free survival from 15.8 months to 18.89 months with the addition of pertuzumab to an aromatase inhibitor and trastuzumab, meeting its primary endpoint.  This improvement in progression free survival was not associated with a significant improvement in objective response rate (63.3 vs 55.7%).  It is important to note that 57% of patients in the trial received induction chemotherapy, and subgroup analyses demonstrated that amongst those who did not receive chemotherapy, the addition of pertuzumab improved progression free survival from 12.45 months to 21.72 months.  In contrast, amongst those who received induction chemotherapy, the median progression free survival was similar for those who received pertuzumab compared to those who did not, 16.89 and 16.85 months respectively.  This group of patients who received induction chemotherapy had more visceral disease and a shorter medial time since initial breast cancer diagnosis.  Grade 3 and 4 adverse events were more common in those patients receiving all three agents (50.4% vs 38.7%) and the most common toxicities were diarrhea, alopecia and nausea.

The PERTAIN trial represents the first randomized trial to investigate the addition of pertuzumab to trastuzumab with an aromatase inhibitor and suggests that endocrine therapy with dual anti-HER2 therapy may be a reasonable treatment approach for some patients with hormone-receptor positive, HER2-positive metastatic breast cancer.  There is also data looking at a different dual anti-HER2 therapy approach with endocrine therapy from the phase 3 ALTERNATIVE trial.  This study looked at the benefits of adding lapatinib to an aromatase inhibitor and trastuzumab and demonstrated a 5-month improvement in progression free survival, but no improvement in overall survival.  These studies suggest that upfront endocrine therapy with dual anti-HER2 therapy may offer a novel treatment option for patients that is likely less toxic and associated with a better quality of life than chemotherapy-based treatment.  One must weigh the pluses and minuses of each treatment approach when choosing the appropriate first line therapy for patients.  Endocrine therapy with dual anti-HER2 therapy has not yet been shown to be associated with a survival benefit, and is associated with lower objective response rates than that seen in the CLEOPATRA study, so it may not be the best approach in a patient with significant visceral disease at presentation, but may be an optimal approach in patients with limited tumor burden, or those who are not optimal candidates for chemotherapy.  Work is also ongoing in the PATINA trial to see if adding cdk 4/6 inhibition to endocrine therapy and dual anti-HER2 therapy, after induction chemotherapy, will have even further benefit.

This concludes this JCO Podcast.  Thank you for listening.

Read the related article "Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group" on JCO.org

This JCO podcast provides observations and commentary on the JCO article “addition of vincristine, irinotecan to vincristine, dactinomycin and cyclophosphamide does not improve outcome for intermediate risk rhabdomyosarcoma a report from the Children’s Oncology Group by Hawkins, et al.” My name is Alberto Pappo and I am a pediatric oncologist and Head of the Division of Solid Tumors at St Jude Children’s Research Hospital in Memphis, Tennessee.

Investigators of the Children’s Oncology Group (COG) developed a prospective randomized study to improve the outcome of patients with intermediate risk rhabdomyosarcoma by comparing the addition of the doublet vincristine and irinotecan (which will be called the irinotecan arm) to standard vincristine actinomycin D and cyclophosphamide (which will be called the VAC arm) to VAC chemotherapy only. Intermediate risk disease comprises the largest subgroup of patients with rhabdomyosarcoma and comprises patients with embryonal histology who present with tumors that are non-metastatic and unresected and arise in unfavorable sites as well as patients who present with non-metastatic alveolar histology tumors. The authors nicely review prior failed strategies that were aimed at increasing the outcome of this group of patients including dose intensification of active agents as well as the  addition of novel agents such as ifosfamide, etoposide and topotecan. 1-3

Irinotecan is a prodrug that is converted to its active metabolite SN38 and inhibits topoisomerase I. In a front-line trial for patients with metastatic rhabdomyosarcoma demonstrated a high level of activity with a 70% early response rate and an 8% disease progression rate.4 Based strong preclinical and clinical data, this agent was incorporated into an upfront randomized trial for rhabdomyosarcoma testing the benefit of adding vincristine and irinotecan to standard VAC in intermediate risk rhabdomyosarcoma.

Eligibility criteria included patients with embryonal rhabdomyosarcoma who had stage II and III clinical Group 3 disease and any alveolar rhabdomyosarcoma without evidence of distant metastases.  During the first 12 weeks the two treatments were identical in duration of schedule with the exception of the substitution of irinotecan for dactinomycin and cyclophosphamide at week 4 and for cyclophosphamide at week 7 and 10 in the irinotecan arm.  During the next 30 weeks irinotecan replaced actinomycin D and cyclophosphamide at weeks 16, 19, 25, 31 and 37 in irinotecan arm.  Patients were evaluated for response at week 15, 30 and at the end of therapy.  Radiation therapy unlike the prior COG D9803 trial  started early at week 4 instead of 12 and the dose was determined by the clinical group and histology with doses ranging to 36 Gy for those with clinical group I and II to 50.4Gy for those with Group III disease. The study was designed with an 80% power to detect an overall increase in the long term event-free survival from 65% with VAC chemotherapy to 76% with the doublet VAC VI with a sample size of 486 patients.

Between December 2006 and December 2012 there were 481 patients enrolled on the study of whom 33 were ineligible.  Of the remaining 448 eligible patients 222 were randomized to VAC and 226 were randomized to the irinotecan arm.  The patient’s characteristics were similar between both arms and to other COG trials. There was a slight predominance of males, 61% of patients were between 1 and 10 years of age and 71% were Caucasian.  Embryonal rhabdomyosarcoma was the predominant histology seen in 53% of the patients and 86% had clinical Group III disease. The most common primary site was parameningeal followed by bladder prostate, extremity and retroperitoneum. 

With a median followup for surviving patients of 4.8 years the estimated 4 year event-free survival was 63% for the VAC arm and 59% for the irinotecan arm.  The estimated 4 year overall survival rates was 73% for the VAC arm and 72% for the irinotecan arm. There were no differences in radiographic response among clinical Group III patients as assessed by institutional report by week 15 and no evidence of differences in outcome by treatment arm in the histologic subgroup analysis.  When compared to the previous trial D9083 which had slightly different eligibility criteria, there were no differences in event and overall survival for patients with alveolar rhabdomyosarcoma. However, patients with embryonal tumors had an inferior 4 year event-free survival in this trial when compared to patients in D9803 although the 4 year overall survival rates were similar.  The vast majority of treatment failures were due to tumor progression or recurrence. The 4 year local failure rate was 22.4%, the 4 year regional lymph node failure rate was 5.7% and the 4 year distant failure rate was 18%.  Hematologic toxicity and febrile neutropenia were more commonly observed in the VAC arm whereas diarrhea and mucositis were more prevalent in the irinotecan arm. Hepatopathy was more common in the VAC arm and patients in the irinotecan arms who developed grade 3 4 diarrhea were more likely to carry the UGT1A1  7/7 genotype.

 The authors conclude that the addition of vincristine and irinotecan to a VAC backbone failed to improve the outcome of patients with intermediate risk rhabdomyosarcoma. However, the lower cumulative doses of cyclophosphamide in the irinotecan arm which could potentially reduce the risk of infertility in selected patients and the lower rates of hematologic toxicity in this regimen have provided a rationale for the COG to use a VAC irinotecan backbone in their current up front randomized trial for intermediate risk rhabdomyosarcoma.  

This trial highlights the lack of significant advances in the therapy of pediatric rhabdomyosarcoma despite the fact that irinotecan showed significant preclinical and clinical activity in metastatic patients with this disease.5,6 Similarly, in a previous study, the addition of another camptothecin, topotecan failed to improve the outcome of intermediate risk patients despite promising clinical activity in newly diagnosed metastatic patients 7suggesting that identification of novel agents based on their activity in  phase II window studies for high risk rhabdomyosarcoma is not an optimal method for selecting active compounds that could be incorporated into front-line studies for intermediate risk disease. As suggested by the authors of the paper just discussed, other novel mechanisms of drug testing such as randomized phase II studies in recurrent disease might offer alternative more effective strategies for identifying agents to be tested in intermediate risk patients. In contrast to this results, the European Pediatric Soft Tissue Sarcoma Study Group has recently reported at the ASCO 2018 meeting improved outcomes for a similar population of patients when maintenance therapy with low dose cyclophosphamide and vinorelbine is added to a backbone of vincristine, ifosfamide and actinomycin D (VAI). 8  In this trial, patients with non metastatic incompletely resected embryonal rhabdomyosarcoma arising in unfavorable sites and localized alveolar rhabdomyosarcoma without nodal metastases who achieved a complete remission after 9 cycles (27 weeks) of VAI with or without doxorubicin were randomized to stop treatment or receive maintenance chemotherapy with six 28 days cycle of vinorelbine and cyclophosphamide.  The study was initially designed with an 80% power to detect an increase in the 3 year EFS from 55% to 65% with a hazard ratio of 0.67 but was then amended to allow detection of a relativity reduction rate in the relapse rate of 50%.  This trial accrued 670 patients of whom 371 were eligible and 186 were assigned to the standard arm and 185 to the maintenance arm.  The clinical features were well balanced between the two groups. With median follow up of 5 years in surviving pts, the 3 year event-free survival and overall survival in the maintenance arm and the standard arm were  78.4% vs 72.3% (p value 0.061) and 87.3% vs. 77.4 (p value = 0.011).  The investigators concluded that the addition of maintenance therapy is a novel strategy that improves the outcome of this group of patients with rhabdomyosarcoma and establishes the new standard of care for patients in Europe.  The results of this trial however, need to be interpreted with caution and cannot be generalized. The follow-up of patients is relatively short and only those who achieved a complete radiographic response after chemotherapy were eligible to be randomized, no information was provided regarding outcomes of patients who were randomized to receive doxorubicin, there are only 9 cycles of chemotherapy given prior to randomization to maintenance therapy whereas the COG studies give 14 cycles of therapy and finally, there are slight differences in the eligibility criteria when compared to the previous COG  trials.   

In conclusion, the addition of an irinotecan backbone to standard VAC chemotherapy does not improve the outcome of patients with intermediate risk rhabdomyosarcoma. However, the irinotecan containing regimen offers potential advantages such as outpatient administration of chemotherapy, reduced hematologic toxicity and cumulative cyclophosphamide exposure and has therefore become the standard backbone for patients with intermediate risk rhabdomyosarcoma in the United States.  This concludes this JCO podcast.  Thank you for listening.    

Intensifying therapy in children with pediatric B-ALL and IKZF1 deletions leads to improved survival.

Read the related article "Intensifying Treatment of Childhood B-Lymphoblastic Leukemia With IKZF1 Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study" on JCO.org

Discussion of a recent study that evaluated prospectively psychosocial well being measures in breast cancer patients before and after receipt of CPM.

Read the related article "Prospective Study of Psychosocial Outcomes of Having Contralateral Prophylactic Mastectomy Among Women With Nonhereditary Breast Cancer" on JCO.org

This podcast discusses the important risks and potential benefits of PD-1 immune checkpoint blockade in patients with thymic epithelial neoplasms.

Read the related article "Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial" on JCO.org

GRAALL-2005 study shows no overall benefit for cyclophosphamide intensification in older adults with ALL, despite a general improvement in outcomes for the younger adults.

Read the associated article by Huguet et al on JCO.org.

Highlighting the importance of BCMA-CAR T therapy for patients with relapsed refractory multiple myeloma and discusses future avenues of clinical investigation.

Read the related article "T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma" on JCO.org

This podcast includes commentary upon a large case control series that examined the incidence of cardiac injury in association with radiation dose to distinct segments of the left ventricle and coronary arteries.

Read the associated article by Taylor et al on JCO.org.

This is an evaluation of PCI in stage III Non-Small-Cell Lung Cancer.  While the incidence of symptomatic brain metastases is reduced, neurological toxicity is increased and no effect on survival is demonstrated. This trial reconfirms that routine administration of PCI is not a current standard of care.

Read the associated article by De Ruysscher et al on JCO.org.

This JCO Podcast provides observations and commentary on the JCO article 'Prophylactic Cranial Irradiation (PCI) Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer (NSCLC): A Randomized Phase III NVALT-11/ DLCRG-02 Study' by De Ruysscher et al. My name is Everett Vokes, and I am the Chairman and Professor of Medicine at the University of Chicago in Chicago, United States of America. My oncologic specialty is head and neck and lung cancer.

De Ruysscher et al present a randomized trial evaluating the role of prophylactic cranial irradiation, referred to as PCI in this podcast, in patients with stage III non-small-cell lung cancer treated with curative intent. In doing so they have addressed an important issue. Brain metastases are a frequent site of treatment failure and can occur in isolation from additional system disease. It has been postulated that PCI could prolong survival and disease-free survival. In localized small-cell lung cancer, PCI has already been shown to decrease the incidence of brain metastases by about 50% with an impact on long-term survival. However, it is well established that PCI can lead to neurocognitive decline associated with reduced quality of life. Specifically, the authors initially staged patients with a contrast enhanced brain CT or MRI and randomized patients to observation or PCI after concurrent or sequential chemoradiotherapy with or without surgery.

Patients were randomized 1:1; PCI was designated to start at a maximum of 6 weeks after the last chemoradiotherapy and could be given as 36 Gy in 18 fractions, 30 Gy in 12 fractions or 30 Gy in 10 fractions. Patients were then monitored for disease progression including symptomatic brain metastases within 24 months from the time of randomization as primary endpoint. Quality of life measurements were performed as well. Key symptoms were defined as signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures and focal neurological symptoms. MRI or CT was triggered by such symptoms.

The initial goal was to randomize 300 patients. However, accrual was slow and was decreased to 175 randomized patients overall. Between 2009 and 2012, 195 patients were registered, 175 were randomized, 87 to PCI and 88 to observation. The proportion of patients developing symptomatic brain metastases two years after therapy was 7% in the PCI group and 27% in the control group. This compares to a historical average of approximately 30%. PCI thus did decrease the cumulative incidences of symptomatic brain metastases. However; neurological adverse events were also increased. In particular, grade I-II memory impairment and cognitive disturbance were significantly increased in the PCI arm. Non-neurologically events such as alopecia, fatigue and headache were also significantly more frequent in the PCI group.

When evaluating patient reported adverse events, headache was reported to occur significantly more frequently in the PCI arm. Of interest, neurological side effects tended to increase over time after PCI whereas non-neurological adverse events were highest during PCI and decreased over time.

Overall survival at median follow-up of 51 months was not improved, with a hazard ratio of 0.9. PCI did significantly increase time to develop brain metastases, and the median progression-free survival was slightly longer at 12.3 versus 11.5 months in the PCI group, but again this was not statistically significant..

Overall, this study does demonstrate that PCI can significantly reduce the incidence of symptomatic brain metastases in patients with stage III non-small cell lung cancer. However, this comes at the cost of increased neurological adverse events even though most of these were mild in nature. Furthermore, an impact on overall survival was not demonstrated. It could be argued that this study was somewhat small and that a larger study could have shown a more pronounced effect, especially on progression-free survival, which did show a trend favoring PCI. On the other hand, symptomatic brain metastases nowadays can be treated at the time of recurrence with SBRT and other modern radiotherapy techniques. In addition, the recent durvalumab trial (PACIFIC) demonstrating that consolidation durvalumab can increase progression-free survival also demonstrated a reduction in brain metastases in durvalumab treated patients, suggesting that improved systemic therapy may emerge as a better approach to tackling the clinical problem of brain metastases in stage III NSCLC.

So is PCI a recommended standard of care for patients with stage III NSCLC? While I congratulate the authors on conducting this ambitious and randomized trial addressing an important key question, my answer is no. Treatment with durvalumab is an evolving new standard and neurological side effects of PCI are not to be ignored. Treating patients with cranial radiation at the time of actual progression seems like the better approach in the meantime.

This concludes this JCO Podcast. Thank you for listening.

The public perception of medical marijuana has outpaced medical knowledge. Oncologists encounter an increasing number of patient questions and interest regarding its use. This study highlights the beliefs, attitudes and knowledge of medical oncologists regarding the therapeutic use of marijuana.

View the related article Medical Oncologists’ Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study by Braun et al on JCO.org.

This JCO Podcast provides observations and commentary on the JCO article ‘'Medical Oncologists' Beliefs, Practices and Knowledge Regarding Marijuana Used Therapeutically: A Nationally-Representative Survey Study' by Braun  and colleagues. My name is Kimberson Tanco, and I am an Assistant Professor at the University of Texas MD Anderson Cancer Center in Houston, Texas. I am a Palliative Medicine physician.

Medical marijuana is one of the fastest growing medical issues nationwide, so much so it is now legal under certain conditions in more than half of the country, with additional limited indications in certain “non-legal” states for pediatric refractory epileptic conditions.1  Most of the current trials are directed towards non-cancer conditions. In contrast, in the article that accompanies this podcast, Braun and colleagues highlight a variety of key issues that face oncology practitioners regarding cannabis and its potential uses and toxicities.

As healthcare professionals, it is inevitable that we will be asked by our patients and/or their caregivers about the use of medical marijuana, either in a legalized or a non-legalized state. This study does a good job of recording clinician beliefs and practices from different regions of the nation. It also points out a very important fact that the interest and curiosities about the use of medical marijuana far outpaces our knowledge base as demonstrated in their results. It was very interesting to know that up to 80% of oncologists conducted discussions and 46% recommended medical marijuana for clinical use  as compared to only 30% feeling sufficiently knowledgeable enough to make informed recommendations. This is quite a change from 2010, when they cited that only 20% of family practitioner respondents in Colorado would recommend medical marijuana and <1/3 believed it had any medical benefits. Colorado has since legalized marijuana for medical and recreational use since 2012. One of the concerns of any study assessing beliefs and attitudes is the time it takes to complete it, which can make it difficult to assess their current day impact on the product's perception by physicians and patients.  . One of the strengths of this study is that data was collected in a relatively short period of time (3 months) that reduced any bias or opinion changes. The variations in the region and work setting seen in the study also demonstrated how state and institutional policies and regional socio-political beliefs may affect clinician belief and practices.

The authors highlighted key points from the study including the need for expedited clinical trials exploring potential medicinal effect of marijuana in oncology, the need for educational programs about medical marijuana and policies to incentivize the training of clinicians on this issue. In the next few minutes, I would like to discuss these points.

Their first point about the need for clinical trials is certainly a key step into understanding the pharmacology and effects of cannabis, which would help improve educational programs and open up federal, state and institutional policies. However, there are a variety of challenges faced in conducting medical marijuana research.2 In spite of changes in state policy and increasing prevalence of cannabis use, cannabis is still not legalized by the federal government and remains a Schedule I substance. Furthermore, an investigator must navigate through the National Institute on Drug Abuse or NIDA, Food and Drug Administration, Drug Enforcement Administration, state departments, state boards, institutional review boards, and funding sources among others. Additionally, supply of cannabis for research purposes is only available through NIDA and is sourced from the University of Mississippi, which has been the sole cultivator since 1968. An important point is that federal supplies of cannabis may also have been harvested earlier and stored in freezer, and may have lower potencies than those sold in state-regulated markets. Hence, investigator results may have to be taken with caution as they relate to appropriate dosing of cannabis products, particularly when they will be taken from state dispensaries. Additionally, there are drug delivery challenges in inhalation, vaporization or ingestion as well as what the author perfectly described as “entourage effects” in where the effect may be different after administering the whole plant vs. isolated cannabinoids.

On the other hand, as a benefit of conducting more standardized trials, we can also compare through head-to-head trials the benefits and toxicities against currently available oral cannabinoids such as dronabinol and nabilone. The study also demonstrated that oncologists believed that medical marijuana can be beneficial for certain symptoms like anorexia, nausea, and anxiety. Standardized trials would allow us to discover and outline indications, dosages, mode of delivery and more for these symptoms that plague cancer patients.

The second key point is about improving educational programs and is reflected by the results of the study showing only 30% of oncologists feel that they have sufficient knowledge regarding cannabis. In my personal experience, I have been noticing increasing sessions about medical marijuana in various national conferences. Although this is good to see, educational access needs to spread faster and broader. Key concepts including pharmacology, potential uses, adverse effects, and drug interactions should be continued into local, institutional and even into medical school level.

While there was no consensus by respondents regarding the comparative effectiveness of marijuana as a treatment for pain, majority supported using it as an adjunct to standard pain management strategies, which is an especially relevant issue in the setting of an opioid crisis. Cannabinoids may have inhibitory activity in certain cytochrome enzymes and glycopeptides. For example, it has potential inhibitory activity on CYP2D6 and CYP3A enzymes while inducing CYP2E1. These activities may affect levels of certain opioids such as fentanyl, methadone and other drugs like anesthetic agents.3 It may also have potential inhibitory activity to P-glycoprotein which may increase drug levels of certain agents like paclitaxel and etoposide. Further research is needed to be able to better understand these interactions.

A key finding this study demonstrated is the perception of oncologists that medical marijuana has a lower risk than opioids for addiction, overdose and death. With the ongoing opioid epidemic, similar to any national movements or epidemics, there is a natural trend to react and use other substances over opioids, which is still the gold standard for cancer pain treatment. Recent studies have shown decreases in opioid prescribing rates in states that legalized marijuana use.4,5 One wonders if the national and media scrutiny of the dangers of opioid use coupled with the increased excitement over the potential uses of marijuana downplay any of its potential adverse effects. It is also reasonable to consider whether we are opening a can of worms by substituting one addictive substance with another, or whether we are addressing the addiction issue by simply replacing the substance involved. These are important arguments that we do not have time for in this podcast and would be better discussed in another forum.

The third key point is development of policies. Statewide, we have seen increasing legislation to legalize cannabis not only for medical use but also for recreational purposes. Unfortunately, even in legalized states, several institutions do not have policies and guidelines that deal with this issue.6 Clinicians are left to make medical decisions regarding patients using cannabis by themselves or try to deflect the topic altogether.

The debate of medical marijuana is only starting. Clinical trials are needed to better understand its pharmacology to arm oncologists and other clinicians to better care for their patients. As the public perception of cannabis has blossomed over recent years and state-regulated dispensaries have provided medical marijuana to patients, the medical field has an opportunity to learn from what can already be observed and advance this into more standardized and scientific testing.

This concludes this JCO Podcast. Thank you for listening.

Dr. Shannon Westin and her guests, Dr. Herbert Duvivier and Dr. Richard Schilsky, discuss the paper “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study” 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 into articles published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. As always, it is my pleasure to serve and bring this information to you. 

Today, we will be discussing, “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” And this was published in the JCO on August 10th, 2023. 

None of the authors have any conflicts of interest to disclose. 

Joining me today are two of the authors, Dr. Herbert Duvivier, the principal investigator of this arm of the TAPUR trial. Welcome.

Dr. Herbert Duvivier: Thank you. 

Shannon Westin: And then, of course, many of you know Dr. Richard Schilsky, who is the former CMO and Executive Vice President of ASCO and a principal investigator on the TAPUR study.  

Dr. Richard Schilsky: Thank you, Shannon. 

Shannon Westin: So, let's get going. I think the first thing would be great is to level set and make sure everyone knows exactly what this TAPUR basket trial is, the Targeted Agent and Profiling Utilization Registry study. Can you guys give the audience a brief description of the objective of TAPUR and maybe how it came to fruition? 

Dr. Richard Schilsky: Sure. This is Richard Schilsky. Maybe I can start with that. The TAPUR study is a prospective, phase II, multi-basket, multi-center genomic-matching trial. Its primary objective is to identify signals of drug activity for targeted agents that are already marketed. But in the TAPUR study they are being used outside of their FDA-approved indication. The study, as you may know, was conceived in 2014, launched in 2016, and is still enrolling patients across the country. Really, the genesis of the study came from the fact that it began at the time where genomic profiling of patients with advanced cancer was becoming more commonplace. Genomic alterations that could be targeted by already marketed drugs were being identified. However, patients and doctors were having difficulty accessing these drugs because they were not used on label and were unlikely to be covered by insurance. And moreover, even if they could access the drugs, there was no organized mechanism to collect outcome data and report on the results of the patient experience receiving that treatment. 

So those factors led to the development of TAPUR, which attempts to solve both the drug access problem by having collaborating pharmaceutical companies donate their drugs to the trial so they’re available to patients at no cost, but also implements a structured data collection mechanism so all of the relevant clinical outcomes with the patients can be collected and ultimately reported. And that’s how TAPUR came about.

Shannon Westin: Well, it was so necessary, and I think we do so much of our oncology treatments off-label, but as we get more and more expensive drugs when we move away from chemotherapies and more targeted immunotherapies, it’s very hard to get those drugs off label. So this was such a relevant and necessary trial that had to happen, and it's a great example of leadership that you had the vision to put this together through ASCO. 

I think the natural next question for me is having not put patients on the TAPUR study, how does a patient join this study? How do they get started? Walk us through that.

Dr. Herbert Duvivier: At our institution, normally, all the physicians are aware of the TAPUR trial through internal conversations. When they have patients who have been treated with multiple lines of standard therapy, usually the next step for them is to get NGS testing. We have a research team that reviews all NGS testing for these patients and knows the open arms of the TAPUR trial. And if there happens to be a particular patient who may match with one, they will inform the physician. It is then up to the physician to speak to the patient about that option. 

Shannon Westin: Do you have people come looking for the TAPUR trial or are these generally more established patients?

Dr. Herbert Duvivier: From my perspective, I think it is usually established patients.

Shannon Westin: I think what I love about this trial, and I have spoken about this trial in lectures around baskets, it’s such a pragmatic design making it as straightforward as possible to really implement across different centers, whether academic or community, or wherever they are. I guess one of the questions always around these targeted therapies is the molecular selection. How do you make sure that people are being appropriately molecularly selected and how do you decide which testing to utilize? 

Dr. Richard Schilsky: As you pointed out, Dr. Westin, the goal of the study from the beginning was to have a very pragmatic design, in a sense to have this study attempt to replicate the way oncologists were deploying precision medicine in their practice. The study has broad eligibility criteria, it has minimum necessary data collection, it uses conventional clinical evaluations, there are no additional clinical evaluations required that are not part of routine clinical care. And it just makes it easy to embed the study into the clinical workflow. The study is based largely at community sites, about 85% of the 268 participating sites are located in smaller communities. The study has a set of genomic matching rules that are listed in the protocol and baked into the IT platform for the study as a rules engine. For every treatment available in TAPUR, there is a set of genomic inclusion and exclusion criteria. 

So in essence the way it works, the physician determines that NGS testing is appropriate for their patient and can use any NGS test they want, as long as the test is performed in a CLIA certified, CAP, or New York State-accredited laboratory. They select the test, they select the biospecimen to be tested, they get the results, they look at the results, and they determine if there is a genomic alteration in the patient's tumor that is targeted by one of the study treatments in the TAPUR study. They can enter that into the rules engine, the rules engine will confirm or not that the appropriate alteration of treatment has been selected. If it is confirmed, then the patient can immediately be enrolled in the study if they meet the clinical inclusion and exclusion criteria. 

If the rules engine does not confirm the treatment match is appropriate, or in some cases there are multiple possible treatment matches, if there are multiple alterations that can be targeted, or another case is the doctor is simply uncertain about which alteration is best to target, then the clinical site can send that patient case to the TAPUR molecular tumor board. A group of experts convenes weekly that reviews the clinical history, the pathology report, genomic test report, the prior therapy the patient has received, and they make a determination as to whether or not there is an appropriate therapy that’s available on TAPUR for the patient. And if not, then are there other potential therapies  that are available that could be considered. That information is sent back to the treating physician who determines whether or not here she feels that treatment option is appropriate for their patient, and if so, the patient can then be enrolled and receive the therapy.

Shannon Westin: So awesome. I love the idea. If we don’t have an arm for you on our trial, we can help assist you potentially determine an option for your patient outside of that. That’s so clever. 

Okay. So let’s get into this particular arm. Obviously, our audience is quite savvy and are aware of the role of immune checkpoint inhibition across a number of solid tumors. Could you describe what you sought to determine in this particular arm of the TAPUR study? 

Dr. Herbert Duvivier: I think one of the most important things to remember about this study is that this study was opened and accruing prior to pembrolizumab becoming FDA approved in, I think, June of 2020. So prior to June of 2020, there was no indication for pembrolizumab in high TMB tumor types and the goal of the study was to determine if pembrolizumab had any overall response rate, duration of responses, progression-free survival, or overall survival advantage over what would be considered standard chemotherapy at that time in patients with high TMB.

Dr. Richard Schilsky: Yeah, that's exactly right. And in this paper that we're discussing, we're reporting on two different groups of patients. So there's a group of 28 patients, all with colorectal cancer, all of whom had high tumor mutation burden, as defined by the protocol. And that's one group. Then there's a second, larger group of patients, which is a very heterogeneous group of solid tumor patients. And the reason that that group is reported is there were patients who were being enrolled with multiple different tumor types with high tumor mutation burden. Each tumor type determined a specific, tumor-specific cohort in the study, and they were enrolling at different rates depending upon how common the particular tumor type was. But once the FDA approval for pembrolizumab, for any tumor with a high tumor mutation burden, was granted, then all of those cohorts essentially had to close to new enrollments because there was no longer an off-label use for pembrolizumab in that setting - everything was now on the label. 

The result was that we then basically collapsed all of the open cohorts that were not then going to be able to complete into this one large, heterogeneous cohort that's being reported in this paper. And going back to the colorectal results, in the paper, we describe a disease control rate of 31%, an objective response rate of 11%. There were three patients who had partial responses lasting 12, 27, and 97 weeks each. And I think it's important to point out that in this particular cohort, essentially all of the colon cancer patients were microsatellite stable. So that's an interesting nuance here because we know that pembrolizumab is active and has an FDA approval in microsatellite high tumors. But this particular group of patients was essentially all microsatellite stable, suggesting that even in that population, if the tumor also has a high tumor mutation burden, the patient has the potential to respond and benefit from the treatment.

Shannon Westin: I found that very intriguing. And, of course, as a gynecologic oncologist that treats endometrial cancer, I'm always thinking about MSI and microsatellite stability. So I was very intrigued by this. We are not seeing a ton of TMB high in our population, but there are some patients that do have that. 

So let's talk a little bit about the results for the collapsed all solid tumor group. What did you find there?

Dr. Herbert Duvivier: In the histology pool cohort, there were 47 patients representing 21 different tumor types, with a median tumor mutational burden of approximately 13 mutations per megabase with a range of 9 to 228. 40 of 47 patients had MSS disease, microsatellite stable disease. 6 of the 47, MSS was not reported, and 1 case was ambiguous. The disease control rate was about 45%, and the objective response rate was 26%. There were 3 complete responses: 1 in bladder, 1 in parotid, and 1 in squamous cell carcinoma. 9 partial responses and 9 stable disease 16 plus weeks. Of interest in the patients that were responding, 10 out of the 21 patients had POLE or POLD1 mutations, and 9 of the 21 patients had BRCA1 or BRCA2 mutations, although most of those mutations were classified as variants of uncertain significance.

Shannon Westin: That's really interesting. We've seen pretty good data for POLE and benefit from immunotherapy, although at least in the GYN tumors and especially in endometrial cancer, those patients usually do well no matter what you do with them. And so they don't often make it to get immunotherapy because they have a complete response up front to their surgeries. So very intriguing to see that driving benefit. I'm just interested to see because it seems like there's a range that you were quoting of what was considered to be TMB high. So did you see a correlation for response to therapy based on how high the tumor mutational burden was in a given tumor or tumor type?

Dr. Herbert Duvivier: Yes, actually we did see a moderately negative correlation between maximum percent change from baseline in a tumor and increasing TMB, which indicated an association between a higher TMB and greater shrinkage of tumor lesions.

Dr. Richard Schilsky: I should point out, by the way, that when we introduced this arm into the TAPUR study, this high tumor mutation burden arm, as Dr. Duvivier has already pointed out, it was prior to, of course, the FDA approval, and the FDA approval is for tumors that have at least 10 mutations per megabase. It was also prior to the adoption of that threshold of 10, based on work by Friends of Cancer Research and others as sort of the convention for what defined a high tumor mutation burden. So when we put this into TAPUR, we essentially consulted with some of the testing laboratories. We consulted with Merck, the sponsor for pembrolizumab and actually in the TAPUR study, we defined a threshold of 9 mutations per megabase as defining high tumor mutation burden. 

Now, as Dr. Duvivier said, there's a broad range of tumor mutation burden represented in this population, and there does seem, if you look at, if the readers want to look at figure 4 in our paper, there does seem to be a general correlation between best response and number of mutations per megabase, which also holds true in a modest way for both progression-free and overall survival. So, TMB is somewhat predictive of favorable outcomes. It's not a perfect biomarker by any means, but generally speaking, if you have enough patients, you can define this sort of trend to support the notion that the more mutations, the greater the likelihood of benefit.

Shannon Westin: That makes a lot of sense. One other thing that I just wanted to comment on before we kind of bring the podcast to a close is I was really struck by the high proportion of underrepresented minorities in this arm of TAPUR, and I just would love to hear your thoughts on how the design improves recruiting in this population of patients.

Dr. Richard Schilsky: This was a goal of the study, very intentional. When you look at the overall study demographics, there are about 2800 patients now that have been enrolled on TAPUR overall. Almost 12% are black, about 6% are Hispanic, about 4% Asian. The median age is about 64. So it's a slightly older population. The goal always was to enroll a population of patients in TAPUR that was broadly representative of the patients that oncologists treat in practice. In the way we accomplished what we've accomplished, we still have work we can do to improve it. But the clinical sites were carefully selected and vetted. We focused on sites that served a significant fraction of minority patients. We made the eligibility criteria simple and broad, so many of the eligibility criteria that might typically exclude minority populations or older patients from clinical trials are not exclusion criteria in TAPUR. We made the operations of the trial simple, so patients really aren't asked to do much more than what they would normally be asked to do in the course of their routine cancer care. So I think all of those things together have made it possible to attract and enroll a more representative patient population in the study. And we're very gratified by that because when you look at many of the registration trials for many cancer drugs, minorities and older people are terribly underrepresented. So we feel that TAPUR is adding value there and adding useful information.

Shannon Westin: I think it's so generalizable and really the way people are practicing, and so to see similar results or concordant results, despite not as much of the rigorous testing and potentially exclusion of certain patient populations is really reassuring and certainly very exciting. 

The last question is what's coming next? What other arms are coming soon? And can sites still join? Is this something where it's ongoing enrollment and participation?

Dr. Richard Schilsky: So sites can still join. There's a place on the ASCO website where sites can find more information about TAPUR, and there's essentially a form available where sites can indicate their interest in joining the study. And then those sites are then evaluated by the TAPUR study team to determine if they meet the minimum necessary requirements to qualify to join the study. There's a lot more data coming out, many more papers that are in press and being written. There are two abstracts that will be presented in April at the AACR meeting. There are three abstracts that have been submitted for the ASCO annual meeting. So a lot more data to come. 

This is a study that, at least hypothetically, could continue in perpetuity as long as we're able to continue to attract new drugs and new treatment combinations onto the TAPUR study platform. So the TAPUR team is always on the lookout for drugs that are about to get an FDA approval and that could be appropriate for the TAPUR study and continue to talk to many pharmaceutical companies about their interest in potentially putting their drugs on the platform.

Shannon Westin: Well, great. Thank you both for taking the time. I know you're both incredibly busy. 

Again, this has been “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” I'm your host, Shannon Westin, and I'm so grateful that you joined us on JCO After Hours. Please check out our other offerings 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.

Duvivier's COIs: Speakers' Bureau Company name: Guardant Health Company name: AstraZeneca Company name: Regeneron 

Schilsky's COIs:

Leadership Company name: Clarified Precision Medicine Company name: Leap Therapeutics Stock and Other Ownership Interests Company name: EQRx Company name: Leap Therapeutics Consulting or Advisory Role Company name: Cellworks Company name: Scandion Oncology Company name: Bryologyx Company name: Illumina Company name: EQRx Company name: Syapse Company name: Zephyr AI Company name: AADi Research Funding Company name: AstraZeneca Company name: Bayer Company name: Bristol-Myers Squibb Company name: Genentech/Roche Company name: Lilly Company name: Merck

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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.

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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:

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Research Funding
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