This transcript has been edited for clarity.
Lidia Schapira, MD: Hello. I’m Lidia Schapira, your host for this program, Medscape InDiscussion: Breast Cancer. Our topic for today is clinical decision-making about radiation for early-stage breast cancer. I picked this topic because there have been so many recent advances in the field that, even as a medical oncologist, I find myself discussing options with patients in my practice, and we discuss it at our tumor board.
Before I introduce our guest for this episode, let me share a case from my practice. I saw a fit, 72-year-old woman with minimal comorbidities, who presented with a screen-detected, 2-cm breast cancer that was intermediate grade. Her surgeon performed a lumpectomy with negative margins and a sentinel node biopsy. We can all agree that her prognosis is excellent, but there are various opinions and approaches to designing her postoperative treatment course, and we’ll return to discuss the role of radiation.
It is my pleasure now to introduce Dr Erin Gillespie, radiation oncologist at Memorial Sloan Kettering Cancer Center. Her practice and research are focused on treatment of breast cancer, as well as investigating new strategies to improve access to high-quality, evidence-based cancer treatment for all patients.
Before we begin to talk about this case, can you share with me and with our listeners what motivated you to become a radiation oncologist, and why you chose to focus on breast cancer?
Erin Gillespie, MD: I think I ended up in cancer because of a personal experience, which I think is how a lot of people end up in their field, both in clinical and research. My mom was diagnosed with breast cancer when we were living in Anchorage, Alaska, and it led to a number of uncertainties about where she should get treatment, and how to determine what quality of care you would get from your local [center] vs a large academic center. I think that spurred my interest not only in treating breast cancer, but also in researching this area of care delivery and implementation science, particularly in the early-stage space.
Schapira: Thank you for sharing that. That’s really a phenomenal way to start this and to make it really personal and about the people we treat.
Let me start by asking you: For women of all ages today who have lumpectomy or breast-conserving surgery, what is currently considered the standard for optimal duration of radiation therapy? I hear from patients that they are treated for one to several weeks. What’s considered standard and acceptable?
Gillespie: I think that the standard is rapidly evolving. Since 2018, an ASTRO consensus for the treatment of whole-breast radiation is that hypofractionated, in a 3- to 4-week course, is the standard. And I think that in the US that continues today as really the most common standard option for early-stage disease. We’ve seen in the past year changes. [We’ve started asking,] can we actually shorten that further to 1 week? That was in response to the UK FAST and FAST-Forward trials looking at 1 week vs 3 weeks. The UK has actually adopted that as an acceptable standard or default for their early-stage breast patients. And that’s sort of an ongoing conversation in the US, particularly in the absence of beyond 5 years of follow-up so far. I would say the most common option is going to be whole-breast [radiation] for 3-4 weeks. The other part of your question gets into [the fact that] you can also shorten treatments, potentially, by doing what’s called partial-breast irradiation.
Schapira: Tell us a little bit about partial-breast [irradiation]. And my question in follow-up to that is also, when you go for these shorter sequences, do you sacrifice cosmesis?
Gillespie: That’s a great question. There have been a number of randomized trials now looking at partial-breast irradiation compared with whole breast. There’s a few that I think are particularly informative in a few different ways. The first in my mind to think about partial breast was the IMPORT LOW trial from the UK, which actually compared partial breast with whole breast using the same time course, a 3-week regimen. It actually showed better cosmesis long term and fewer side effects overall from the partial-breast treatment. That helped us understand that by just treating part of the breast doesn’t necessarily affect cosmesis.
The next question becomes, when we treat smaller areas, we generally try to shorten treatments because potentially you don’t need to fractionate over so many weeks. I think at the same time, there were emerging approaches that came from the brachytherapy literature, when catheters or balloons are placed for radiation from the inside out. Those regimens were really short — twice a day for 1 week. That became a normal regimen that was used in a couple of different studies.
The Canadian RAPID Trial is one that people think about as being most concerning for these cosmetic issues with partial-breast irradiation. And there was just another study this year, a randomized trial from Egypt showing that the twice a day compared with once a day was actually three times more likely to have worse cosmesis.
If you get away from that twice-a-day treatment, our outcomes look better, and that leads to what I think people are starting to really adopt, which is this Florence regimen, which was once a day for 5 days in a randomized trial just in this past year as well, which showed slightly better side effects and same recurrence. It’s an evolution with a lot of different factors, but I think we’re getting to a once-a-day regimen in less than 3 weeks that is safe and effective.
Schapira: You started by telling us about your mom’s story and the distance that she needed to travel just to get treated. I imagine that with these shorter courses we are also making [treatment] more accessible. Have you thought about that, or have people been studying that as well?
Gillespie: Yes. Since partial breast was first discussed, as you know, with this focus on the accelerated treatment, there’s been this hope that it would increase access to breast conservation and that women wouldn’t be deterred by what used to be a 6-week course of whole-breast radiation in order to get early-stage breast cancer treated. There’s actually not a lot of evidence yet that that that is actually happening.
It’s a complex sort of research question. I think, anecdotally, that we have lots of people who would say that this has increased their ability to get radiation in a timely fashion. And I think there are a lot of other downstream benefits of shortening treatment, some of those supported by evidence. There was a study from MD Anderson showing that shortening the treatment from 6 weeks to 3-4 weeks reduced trouble meeting family needs, for example.
I think there have been a few other studies to suggest that maybe there’s less fatigue, potentially less financial toxicity associated with shorter treatments. I think there are benefits. But your question is a good one.
Schapira: What is the standard recommendation for a person walking into Memorial Sloan Kettering these days? A 50-year-old woman who has an early-stage breast cancer — how long will her treatment be and what nodal groups, if any, will you cover?
Gillespie: A 50-year-old woman — at this point, it depends on a lot of different factors. I think for a node-negative patient with a small tumor, we will do whole-breast or partial-breast irradiation if they’re a good candidate for partial breast. You had asked earlier about omission, which is an emerging area for younger patients. We do have a trial open for those patients. It’s called the DEBRA trial, for 50- to 70-year-olds who have low oncotype. The idea is using these genomic risk scores to try to better identify the patients with really low-risk recurrence and actually potentially omit radiation. But in a 50-year-old after a lumpectomy, that would still be investigational.
Schapira: Tell us a little more about this customization and using some of the new genomic-profiling studies to customize the field and select patients who perhaps have such a good prognosis that they may even be counseled to consider not getting treated. Tell us about no radiation.
Gillespie: The story with no radiation has been a challenging one because we know from both the CALGB and PRIME II trials that in older women (defined as over 65 or 70 years old), depending on which study you look at, there’s no overall survival difference with or without radiation, so that was the first, most important thing. And there really also was no difference in subsequent mastectomy rates. So that’s another sort of hard endpoint that that signals an important potential outcome to prevent.
However, the studies do show that if you don’t get radiation — and again, these are all-comers over that age range, so 65-70 with ER-positive small tumors — the recurrence risk is about 10% at 10 years without radiation and 2% with radiation. We saw that a lot of patients still, when you tell them those numbers, will prefer treatment because they say they don’t want to go through this again.
I think there’s certainly a lot of debate about how to deal with that from a patient decision-making perspective. As we’ve moved into what we really need to do, which is identify the people who really have lower risk and who really just don’t benefit — kind of like we have now with chemo in early-stage patients — once you eliminate the benefit of a toxic treatment, it becomes a no-brainer.
Schapira: I’m curious to know if you can share what radiation oncologist are using as cutoffs for considering perhaps that omitting radiation is safe, in terms of MammaPrint or Oncotype, the tests that we’re all very familiar with. Or is it too early to ask this question?
Gillespie: I think it’s a little early. We still kind of lean more in the elderly group on age and performance status. And then in the less-than-70 group, which is what we’ve used in the US, there’s really not any evidence just to use that in your decision-making. I think if someone has a low Oncotype score, it’s a great opportunity to offer them this DEBRA trial that would allow them to be randomized to either the standard radiation or omission of radiation.
Schapira: I’m on the medical oncology side of this conversation. If a patient is willing to take 5 years of adjuvant endocrine therapy, we all feel that we have a more robust discussion. But as you very well know, adherence to endocrine therapy is not great, and it’s very difficult at the onset when you’re having these conversations to predict who is going to discontinue endocrine therapy. We tend to think of completing the local therapy of radiation as a check; if the endocrine therapy piece then falls off, then the patient is more protected. Is that the kind of reasoning that you and your group also have when you approach these situations where the benefit of either therapy or to combine therapy is borderline?
Gillespie: I think you’re bringing up an important point that I didn’t mention, which is that even in the elderly group, the omission of radiation relied on taking hormonal therapy. There is certainly a lot of question as to whether that is always the right choice. I think for patients who, like you said, aren’t going to likely be compliant with hormonal therapy, then radiation is a good fallback.
At Memorial Sloan Kettering, we’ll treat patients up to about 6 months after surgery. That’s a little bit beyond where — it’s around where the data suggest that it’s probably okay, although most of the time we try to treat by 3 months in order to give people a 3-month trial period. Interestingly, not a whole lot of patients come back, at least anecdotally, with that approach, since I do think the medical oncologists are pretty good at identifying from the outset who doesn’t want to take it at all or who’s likely not to stick with it. But I think if hormonal therapy is not likely to work for the patient, then they probably are better off getting radiation.
Schapira: Let me switch now to early stage but node positive. After ACOSOG Z0011, we know that we don’t need to target the axilla for women with one to two positive nodes. But can you summarize for our listeners how the science has evolved for deciding how to include or target the axilla, when it’s needed, and what your thinking is?
Gillespie: The Z0011 trial was really critical, as well as AMAROS, in showing us that for upfront surgery with one or two positive nodes, you don’t need an axillary dissection. And that element of de-escalation of treatment has been really helpful for reducing lymphedema risks. For patients getting a lumpectomy, they will still get whole-breast irradiation. The exact design of those fields is your exact question, which is: When you have a positive node, do you need to actively treat the supraclavicular nodes above the clavicle or the internal mammary nodes behind the sternum? And that is definitely an area with not a lot of consensus. I think there was a consensus statement made a couple of years ago, or out from the professional organizations, that we kind of agree to disagree in that there are studies showing that potentially any positive node could benefit. But as systemic therapy has gotten better, we really want to try to risk-stratify patients. And how we do that, I think there are a lot of centers using various risk factors to say, “If you’ve got a couple of risk factors — younger age, lymphovascular invasion, or triple-negative histology — then those kinds of factors might bump you up in the risk and consider you a better candidate for treating the node.
Schapira: A lot of our conversation centers on minimizing toxicity [and] de-escalating therapies. While we’re on that topic, there’s an increasing number of breast cancer survivors — now almost 4 million in the country. Tell us a little bit about how you think of the risk for lymphedema and what your approach is to prevention of lymphedema or treatment of lymphedema. And I say prevention, if there is such a thing.
Gillespie: The number of people that are living long term with the consequences of their cancer treatment just highlights the importance of it. Lymphedema, quantifying the impact on patients, when you ask patients about their symptoms, I think it certainly can be life altering or really affect quality of life and ability to function. Those rates of lymphedema, which we have a bit better handle on from Dr Taghian’s work from Massachusetts General Hospital, as you know, and axillary dissection was really contributing a lot to this, potentially up to 25% risk of getting it with the dissection. So radiation contributes a little bit. That’s one of the reasons why this conversation we were talking about, whether or not to treat the nodes, that’s an element. It’s certainly a smaller contribution, which is good. But I do think, because of the potential long-term quality-of-life issues, that it’s very important to try to reduce the risk.
Schapira: And another question about the axilla, if we can stay on that topic. With more and more patients now receiving neoadjuvant therapy, what is your group’s approach to staging and then later deciding to treat the axilla?
Gillespie: We clinically stage upfront, certainly primarily by exam, and an increasing number of patients are getting neoadjuvant chemo. We were just reviewing KEYNOTE-522 this morning in our breast conference. As you know, there are increasing benefits in the neoadjuvant setting. In terms of the axilla, if you can downstage the nodes with neoadjuvant therapy, you can reduce the amount of surgery. There’s an ongoing trial, from NSABP, about whether you can reduce the amount of radiation you give to the lymph nodes. But I think there’s also an ongoing question: Even if you have residual disease in the nodes, can you then safely permit dissection? And that’s, again, an ongoing question. But certainly, neoadjuvant has helped us identify those patients with good response to do less surgery and potentially less radiation.
Schapira: So for the patient who has a pathologic complete response, how do you approach the radiation, the adjuvant radiation?
Gillespie: If they’ve had a pathologic complete response, the current algorithms really do not yet integrate that information because, again, our standard became that when the study suggested that node-positive patients benefited from comprehensive nodal radiation, that was applied to the neoadjuvant setting based on the clinical stage. We don’t yet know well whether, if their nodes respond, you can omit the nodal radiation without compromising the outcome. So again, that’s the question on that NSABP trial. It’s interesting that the radiation data are really in progress, and I think we’ll have a lot more answers for you in a couple of years.
Schapira: I’m sure that is exciting for our listeners and for all of these survivors who probably appreciate the work that is being done to further customize the treatment as we have discussed. Let me have you come back to the case. And let’s assume that you’re seeing this woman that we presented: 72 [years old]; fit; presents with a screen-detected, 2-cm or less, intermediate-grade, strongly ER-positive, node-negative cancer. Can we even think of omitting radiation here?
Gillespie: Yes, certainly in an over 70-year-old, we could consider that. The intermediate grade is a good sign. I think for someone with good performance status at the age of 72, it would be a shared discussion. We have decided that our preferred treatment in the over-70 group, if you go down that path, is partial-breast irradiation because it’s a smaller area and shorter treatment. But at this point in, that is very much a gray area.
Schapira: This was such an informative conversation. Let me just wrap up some of the lessons for our listeners, both the practicing oncologists, the cancer survivors, and those interested in learning more about the field. One is that there’s an enormous amount of progress, and the standards for options for radiation therapy are evolving. It’s very important to keep up with the literature.
The other is that having a good and frank conversation between the physician or the member of the cancer team and the patient and family is really important as well to lay out options. It doesn’t mean that we’re putting the burden of decision-making onto the patient, but we are helping her to come up with a treatment plan that is concordant with her expectations, her values, and what she prefers to do. And that can be affected by many factors: her comorbidities, the distance to the treatment side, her interest in longer vs shorter duration of treatments.
What I’m also taking away from this is that the standard for duration of treatment is shrinking, which is, I think, a very good thing for all of us to think about as we are all committed to improving access to treatments; it will be easier to live with the treatment if it can be done in a shorter period of time without compromising either the efficacy of the treatment or the cosmetic outcome, which is something that has been important to patients.
And while we’re on that topic, it’s really comforting to know that there are more and more very precise ways of identifying those who can be at risk for complications of radiation, such as lymphedema. We can try to minimize the risk by identifying those patients early on and also customizing their treatment or adjusting the program so that we leave them with a very good outcome and with few long-term symptoms. Is that a fair summary, Erin?
Gillespie: Yes, definitely. I think I’ll just highlight your point. The other thing that patients should feel open to ask is: “Can my treatment be shorter?” I think that that is something where there is an emerging amount of evidence to support and advocate for [a patient’s] personal needs and what might be better for their family-life situation. It’s something that should be part of every conversation.
Schapira: I thank you for participating in today’s discussion. It’s been a great opportunity for me, and I hope it’s been inspiring and instructive for our listeners as well. Thank you, Erin.
Gillespie: Great. Thank you.
Radiation Therapy for the Whole Breast: Executive Summary of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline
Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer
Hypofractionated Breast Radiotherapy for 1 Week Versus 3 Weeks (FAST-Forward): 5-Year Efficacy and Late Normal Tissue Effects Results From a Multicentre, Non-inferiority, Randomised, Phase 3 Trial
Partial-Breast Radiotherapy After Breast Conservation Surgery for Patients With Early Breast Cancer (UK IMPORT LOW Trial): 5-Year Results From a Multicentre, Randomised, Controlled, Phase 3, Non-inferiority Trial
External Beam Accelerated Partial Breast Irradiation Versus Whole Breast Irradiation After Breast Conserving Surgery in Women With Ductal Carcinoma In Situ and Node-Negative Breast Cancer (RAPID): A Randomised Controlled Trial
Once Daily Versus Twice Daily External Beam Accelerated Partial Breast Irradiation: A Randomized Prospective Study
Accelerated Partial-Breast Irradiation Compared With Whole-Breast Irradiation for Early Breast Cancer: Long-Term Results of the Randomized Phase III APBI-IMRT-Florence Trial
Acute and Short-term Toxic Effects of Conventionally Fractionated vs Hypofractionated Whole-Breast Irradiation: A Randomized Clinical Trial
De-escalation of Breast Radiation Trial for Hormone Sensitive, HER-2 Negative, Oncotype Recurrence Score Less Than or Equal to 18 Breast Cancer (DEBRA)
Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-term Follow-up of CALGB 9343
PRIME II Investigators. Breast-Conserving Surgery With or Without Irradiation in Women Aged 65 Years or Older With Early Breast Cancer (PRIME II): A Randomised Controlled Trial
Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011
Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer (EORTC 10981-22023 AMAROS): A Randomised, Multicentre, Open-Label, Phase 3 Non-inferiority Trial
Regional Lymph Nodes Radiation and Breast Cancer Related Lymphedema: Where We Stand
Event-Free Survival With Pembrolizumab in Early Triple-Negative Breast Cancer
Standard or Comprehensive Radiation Therapy in Treating Patients With Early-Stage Breast Cancer Previously Treated With Chemotherapy and Surgery
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