This transcript has been edited for clarity.
Lidia Schapira, MD: Hello. I'm Dr Lidia Shapira, and I want to welcome you to Medscape InDiscussion: Breast Cancer. Today we're talking about RxPONDER trial and about immunotherapy — two topics that have attracted much attention in the breast cancer community of researchers, clinicians, and patient advocates. My guest in this program is Dr Kevin Kalinsky. Dr Kalinsky is an associate professor in medicine at Emory University, where he serves as the director of breast medical oncology in the Glenn Family Breast Center and holds the Louisa and Rand Glenn Family Chair in Breast Cancer Research. Dr Kalinsky is a lead author in The New England Journal of Medicine publication of RxPONDER and an active breast cancer translational researcher. Before we start the conversation and I get to welcome Dr Kalinsky, let me just start by reminding everybody who's listening that it was not that long ago, in fact, at the beginning of the 21st century, we were still recommending adjuvant chemotherapy routinely to women who came in with lymph node–negative small breast cancers. We thought that anybody with a cancer > 1 cm should be considered for adjuvant therapy. We then recognized the extremely favorable outcome and the lack of benefit from chemotherapy for many of these smaller, especially low-grade and biologically favorable, tumors. So this issue of avoiding treatment-related toxicity is now and has become a key area of research, thanks in large measure to the availability of tests that predict chemotherapy benefit for patients with early-stage, hormonally sensitive breast cancer. So Kevin, welcome to this program.
Kevin Kalinsky, MD: Lidia, thank you for having me.
Schapira: Can you review the design and findings of RxPONDER for our listeners today?
Kalinsky: Absolutely. The RxPONDER study was a trial of a randomized trial for patients utilizing the recurrence score, the Oncotype DX recurrence score, which is an assay of 21 different genes, five of which are reference genes. This study was asking the question for patients with hormone receptor–positive (HR+)/human epithelial growth factor receptor 2–negative (HER2-) breast cancer, with one to three nodes involved: What is the role of the Oncotype DX recurrence score assay? Could we identify patients who did not need chemotherapy? Patients who had a recurrence score from 0 to 25 were randomized in a one-to-one fashion to receive modern chemotherapy, followed by endocrine therapy vs endocrine therapy alone. If your recurrence score was > 25, you were recommended to receive chemotherapy, followed by endocrine therapy.
Schapira: What did you find?
Kalinsky: Ultimately, we saw that there was a difference between the postmenopausal and premenopausal population, and I will say that we reported this study out early because we saw this difference based on menopausal status, and menopausal status was a prespecified variable that we were looking at. Then we saw that in the postmenopausal population, if your recurrence score was < 26, we did not identify a population. We looked at 5-year invasive disease–free survival of patients who seemed to benefit from the addition of chemotherapy, and that was two thirds of the population of RxPONDER. Premenopausal women, however, we saw that if you had a recurrence score from 0 to 25, it appeared that there was an improvement in invasive disease–free survival.
Schapira: This brings up the debate that has raged in the community of breast cancer trialists and practitioners about the benefit observed here in the younger women and the question of mechanism. Right? Are you using chemotherapy as a way of inducing endocrine changes, amenorrhea, and early menopause? Or is it strictly a drug benefit that is observed? I know you can't quite answer the question, but tell me how you even think about it and discuss it with your patients.
Kalinsky: We did go back and look at the population for the premenopausal women who received endocrine therapy alone, as well as those who received chemotherapy, followed by endocrine therapy. We looked at both of those populations. If you stopped having regular periods, which we defined as having at least two consecutive 6-month times of which you were not having regular periods, did you do better? We saw in both of those arms that it appeared that if you stopped having regular periods, you did better. The other caveat to RxPONDER is that only about 16% of patients underwent ovarian function suppression. We retrospectively went back to try to answer this question. The truth is, despite all of these analyses, we can't conclusively say that the benefit was due to the ovarian function suppression effect of chemotherapy and whether there's a direct effect as well. So when I talk about this with patients, I think it's important just to think about what's the absolute benefit of chemotherapy or not. Right? So for instance, if you have a recurrence score of 3, your absolute risk is lower than if your recurrence score is, say, 22. We see even in these exploratory analyses that as we start to go to the larger increments, meaning 15-20 or recurrence score 20-25, that the risk is higher and the numeric benefit is higher. That is informative when having this conversation with the patient: "Okay, well, we know your risk is a little bit lower if your recurrence score is 3. Maybe we could think about ovarian function suppression plus hormone therapy." But the truth is that we really don't know if the effect is purely due to the ovarian function suppression or not.
Schapira: What sort of study would you design or what studies are already designed and in progress that will help us actually answer that very important question, perhaps even using newer genomic profiling techniques or a better understanding of the actual biology of the cancer, which is something that you're hinting at as well?
Kalinsky: This is a critical question, and I will say that thankfully, there is now an approved study that is being conducted by NRG that should be coming to a clinic near us within the next year or so. That's going to be looking at patients, all premenopausal women who have a recurrence score with one to three nodes involved at the recurrence score 0-25, but also for those patients who are node-negative and high–clinical risk to ask the question. And the randomization will be about 4000 patients of ovarian function suppression plus hormonal therapy with or without chemotherapy. So hopefully this study will help answer that question. In the interim, until we get that answer of what do we do in a patient with a genomically defined population, I think that there really is an individual discussion. When I talk about this with the patient, I often reference Table 2 of the RxPONDER paper where it has those increments of risk. If you had chemotherapy, if you had just endocrine therapy — just talk about the numeric difference and then make an individualized decision.
Schapira: Thinking about how we talk about this in the clinic with our patients, one of the old arguments is always, "Well, what do I have to lose by taking more treatment?" Can you answer that in terms of the biological risks of receiving either chemotherapy or adding ovarian suppression for a very young woman?
Kalinsky: We've learned that more is not always better. For the chemotherapies that we can give, these can have associated toxicities that can last lifelong — peripheral neuropathy, other potential side effects. If one thinks about utilizing an anthracycline, there's the risk for cardiomyopathy and leukemia. Even though those risks are low, still, when you have a patient who has that adverse effect, you know it makes anybody think, Oh, I really need to utilize that agent when I need to utilize that agent. I will also say, if we look at the data from SOFT/TEXT, which were two different studies that looked at the role of a very functional depression where we saw at San Antonio 12 years of follow-up — what we also know from that dataset is that not all patients can tolerate ovarian function suppression. We can see issues just with cognition, with bone health, with mood, with menopausal symptoms. That's why this randomized study that I have mentioned is going to be a really important one because it will help us understand, for the patients who were just randomized to ovarian function suppression and hormone therapy, "Well, how do they do in the context of a genomically defined population?"
Schapira: The final question I want to ask you about, which comes up more and more in our clinics, is the duration of therapy and how we can customize, personalize, and give proper advice to women who are reaching that 5-year mark — that we know means very little to the women who are reaching it — and are coming to you and asking for advice: "Should I continue and if so, for how long and with what?"
Kalinsky: One of the issues that we see with this subtype of breast cancer is that it's not just the risk within the first 5 years but that there's a risk that can occur years out — that we can see late recurrences in patients who are node-negative, as well as those who are node-positive. What we also have seen with our studies that have looked at extended endocrine therapy, ie, particularly those with extended aromatase inhibitor, a lot of the decrease in risk has really been in terms of development of a new breast primary. This is where I think the field is going in a few different directions. One, there is a genomic assay, the Breast Cancer Index (BCI), that can be utilized that looks at HOXB13/IL17BR (H/I) and tells you a risk within years — 5-10 — and whether you may benefit from extending your endocrine therapy. So there is a commercially available test. I will also that where I think the field is going is further personalization, and the role of blood biomarkers may be helpful in this arena, whether it's circulating tumor cells or circulating tumor DNA. We know, for instance, with circulating tumor DNA, that there is risk associated. We know it's prognostic; what we don't quite know yet is if you switched the therapy, for instance switching with a selective estrogen receptor degrader (SERD) — or an oral SERD — whether you can change the biology and change the likelihood of developing a late recurrence. I do think that this is where the field is going. The other thing I will say is that there are other targeted therapies. Now we utilize cyclin-dependent kinase (CDK) 4 and 6 inhibitors in high-risk stage II or III disease on the basis of the MonarchE study. When we think about opting in or opting out of therapies, the field is changing and evolving so quickly. We're at an exciting time period, not just with new therapeutics, but also for us to further define the biology, whether it's with tumor-based approaches or whether it's with circulating-marker approaches, to help us define risk and what we should be doing.
Schapira: One of the issues I find very difficult and challenging and I wonder how you approach it is when you order the tests, a BCI, or when you think somebody is at risk but you also have some indication that perhaps just continuing what you're doing is not going to help, that puts you in a very difficult position. It's lovely when the test shows that the prognosis is good. The chance of recurrence is low. And you can say with reassurance that it's great to have a favorable result that allows a patient who is experiencing some discomfort from adjuvant therapy to stop at 5 years. But it's more difficult when the result shows that they are at risk for recurrence, and yet the treatment that they're on may not be effective. How do you handle those kinds of conversations?
Kalinsky: I think of a seesaw — of the risk associated with continuation vs the potential benefit. For some patients, where there's a suggestion that, say, theoretically, you had a patient with one to three nodes involved and you decide, that you're going to check a BCI, and there's a suggestion that there's risk and that the patient may benefit for continuing endocrine therapy, and the patient is really not tolerating it... If the patient says, "There's no way I'm going to continue beyond the 5 years," then there's little utility for checking the test. We have data from some series that 7 years may be better than 5. For that patient, where we're just worried about continuing for another 5 years, that's somewhere where I feel like maybe we can meet in the middle.
Schapira: And then you have the data from the intermittent use after 5 years. I like that. I call that the academic approach to therapy: 9 months on and 3 months off. And for some women who have difficulties tolerating it but are at high risk, that may be an option. Also, for years, say, 5-7 or 5-8 — however you choose to do this. Let me turn now to a different topic that is top of mind for many of the patients that we see. Can you talk a little bit about how we should think about using immunotherapy for patients who are newly diagnosed with high-risk triple-negative breast cancer?
Kalinsky: The KEYNOTE-522 trial led to the approval of pembrolizumab along with chemotherapy. In the way that that study was designed is that patients received carboplatin plus paclitaxel, followed by an anthracycline and cyclophosphamide. Patients received pembrolizumab along with that in the neoadjuvant setting. And then, regardless of the response that they had at the time of surgery, continued for a full year of pembrolizumab. This has led to the approval, as you'd mentioned, in high-risk stage II/III breast cancer. We see that there is an improvement in pathologic complete response and we also see that there's an improvement in event-free survival, and this is what led to the approval. As we talk about these agents with patients, it's important for us to always consider the risk benefits. One thing to note about that regimen is that we've really fully escalated the chemotherapy that we're utilizing. We're utilizing our active agents. And also, you're adding in immunotherapy, which can have some long-term, rare but significant side effects for patients. So it continues — this seesaw of your determination of risk and benefit in terms of the discussion with our patients.
Schapira: I always worry a little bit about permanent side effects from treatments when we use them with curative intent. In your experience, and I realize we haven't been doing this for very long, what sorts of problems have you seen with the use of immunotherapy again, given with curative intent?
Kalinsky: The main toxicity that we see is thyroid dysfunction. And when we talk about this with patients, it's important to mention that if one experiences thyroid dysfunction and requires thyroid replacement, this could be something that patients would be taking for the rest of their lives. There are other rare toxicities that we can see: adrenal dysfunction, colitis, pneumonitis, which require steroid utilization. And when presenting pembrolizumab to patients, I do think it's important to recognize that these are patients that we're hoping to cure. We don't necessarily want to be in a situation where they are remaining on some sort of replacement for the rest of their lives because of the therapy that we gave them. It's important that the patients are informed about these risks before we start the drugs.
Schapira: You talk a little bit more about ongoing translational research in this particular space using immunotherapy for early-stage breast cancer. Where do you see the field now and what do you think is coming our way in the next couple of years?
Kalinsky: For patients with HR+/HER2- disease, it would be curious to see where some of these targeted agents go. The oral SERDs are a particular class of interest. I really do think that this role of circulating markers to identify risk — I don't think we're there quite yet — I hope that there will be clinical utility based on some of the studies that are either ongoing now or about to start up. For patients with triple-negative breast cancer, there have been a lot of advances — there have been some advances that have been made with antibody drug conjugates. We'll see how those agents perform in the early-stage setting. There's also the possibility for circulating markers in those patients to identify risk, and for HER2+ disease, I also feel the same way; we have some exciting new agents that are in the metastatic setting. We'll see how this translates to the early-stage setting. Also, a few years ago, I distinctly remember hearing you say to a colleague of mine — you probably don't remember this, but we were talking about new agents in the early-stage setting and you had made the comment that even if we see one patient die in the early-stage setting from an agent, that's unacceptable. That is true, right? Even when we see some of these very active antibody drug conjugates in the metastatic setting when we don't want to be seeing any toxicities relating to this to any patients, especially in our patients with early-stage disease.
Schapira: Thank you for reminding me. Actually, I do remember that conversation a little bit. This whole idea of balancing risk and benefit does get quite complicated, and I love the idea of being as precise as possible. But sometimes when we're not as precise and when there is that uncertainty, our own biases may also influence the conversation. We're talking about more than just being uncomfortable for a few years. We're talking about real toxicities and often life altering or life-threatening toxicities. Well, Kevin, it's been such a pleasure to chat with you today. Do you have any final comments as we wrap up today?
Kalinsky: We have new agents and we are increasingly trying to give the right agent to the right patient at the right time. We want to be able to opt out appropriately and not give toxicity to an agent if it's not necessary. And I do think we've made advances with biology. But there's some additional room to grow in that maybe for some patients, we don't need to fully escalate the therapy that we're doing. Hopefully future studies will help inform that decision-making.
Schapira: Thanks so much for the work you're doing, for the clarity of your responses. I will have your voice in my head for the next consultation with the patients. Thank you so much.
Randomized Comparisons of Adjuvant Aromatase Inhibitor Exemestane Plus Ovarian Function Suppression vs Tamoxifen in Premenopausal Women With Hormone Receptor–Positive Early Breast Cancer: Update of the TEXT and SOFT trials
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Cite this: RxPONDER Trial and Immunotherapy - Medscape - Jun 14, 2022.