Omission of Radiotherapy after Breast-Co...

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.

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Dr. Jagsi:

Stock and Other Ownership Interests Company name: Equity Quotient

Research Funding Company name: Genentech"