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Early Triple-Negative Breast Cancer

Posted: 10/28/2023

This is Part 3 of Updates in Early-Stage Breast Cancer,, a three-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

 

In this video, Drs. Erika Hamilton, Michael Danso, and Komal Jhaveri discuss the management of early triple-negative breast cancer. The patient is a 54-year-old Black female who notices nipple retraction in the left breast. Ultrasound reveals a 3.8-cm mass, and biopsy confirms estrogen receptor 0, progesterone receptor 0, HER2 1+ by IHC, FISH nonamplified, grade 3 disease, with a high Ki-67 of 60%. She undergoes lymph node sampling, which is also positive for invasive ductal carcinoma.

 

The faculty review neoadjuvant chemotherapy options for patients with node-positive, triple-negative breast cancer, whether PD-L1 status has any impact in the early-stage setting, the importance of genetic testing, and the clinical implications of the KEYNOTE-522 and OlympiA trials.



Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.

Dr. Erika Hamilton: Welcome to The ASCO Post Roundtable Series on Updates in Early-Stage Breast Cancer. I'm Dr. Erika Hamilton. I'm the Director of the Breast Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee. And joining me today are two of my fantastic colleagues. Dr. Jhaveri, would you introduce yourself please? Dr. Komal Jhavari: I'm Komal Jhaveri. I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center, and it's a pleasure to join you and Dr. Danso today. I'm the Section Head for our Endocrine Therapy Research Portfolio at Memorial Sloan Kettering Cancer Center, and Clinical Director for Early Drug Development Service. Dr. Hamilton: Thanks so much for being here. And Dr. Danso? Dr. Michael Danso: Thank you very much for the invitation to join both of you. I'm Michael Danso. I'm Medical Director and Research Director at Virginia Oncology Associates, and also part of the Sarah Cannon Research Institute. Dr. Hamilton: Thank you so much. So today we're going to be discussing the treatment of early breast cancer with three patient cases. In this final installment, we'll focus on the treatment of early triple-negative breast cancer. Let's dive into this third case. This is a 54-year-old Black female who noticed nipple retraction in her left breast. Ultimately during workup, this revealed a 3.8-cm mass on ultrasound and mammogram. She ended up having a biopsy that revealed ER 0, PR 0, HER2-negative and 1+ by IHC, FISH nonamplified disease. This was high grade, grade 3, with a high Ki-67 of 60%. She ultimately had lymph node sampling and it was also positive for invasive ductal carcinoma. So we have a lady here with an almost 4-cm mass by imaging that's also lymph node positive with triple-negative disease. Dr. Danso, what neoadjuvant chemotherapy would you be thinking of, and anything else that you're thinking about this case? Dr. Danso: Yeah, so for this relatively young lady with node-positive disease that's 3 cm, I would routinely offer preoperative paclitaxel plus carboplatin with pembrolizumab, followed by AC plus pembrolizumab per the published KEYNOTE-522 trial. This combination improves pathological complete response rate by about 15% and offers an event-free survival benefit of about 7%. So clearly this lady would benefit from taking the KEYNOTE approach. I would say when I do give the KEYNOTE regimen, my preference is to give the carboplatin weekly, as I find it to be better tolerated and at least less dose interruption of the paclitaxel. Dr. Hamilton: Thanks, that's really helpful. Dr. Jhaveri, would you also agree with chemotherapy, with immunotherapy, and any other workup or test you're wanting to order for this patient? Dr. Jhaveri: Right. So I think I would completely agree with Dr. Danso that I would also offer the KEYNOTE-522 regimen given the benefit that he described, with event-free survival and pathological complete response rates. I do exactly the same thing as he does, but I do start with weekly carboplatin and paclitaxel with pembrolizumab followed by AC. I do think that that seems to be a little better tolerated. And then for triple-negative breast cancers, I think what we really have to remember when we get this started, is that germline testing is also very relevant because we want to understand if there is a BRCA germline carrier mutation that would be detected because we have implications and data for utilizing PARP inhibitors in such settings for these patients. So that would be something that I would be doing. And unlike the metastatic setting where we need to really know about PD-L1 status, that's not something that we necessarily chase in the early-stage setting because there were really no differences in say, pathological complete response rates, if you will, when we were to look at PD-L1 status in the early-stage setting. So I think in terms of workup, I'm mostly thinking about the germline BRCA mutation status. Dr. Hamilton: Yeah, absolutely. Definitely want to know what the BRCA status is. It's linked to therapeutic now as well as maybe having implications for surgery choice in this patient. Agree PD-L1 does not matter in the neoadjuvant setting like it does in the metastatic setting. And then also with this patient's lymph node positivity, we'd also want to just get some scans and staging to make sure that we're not dealing with metastatic disease before we got started. So let's dive into KEYNOTE-522 just a little bit. Again, Dr. Danso went through some of this, but it's carboplatin paclitaxel followed by AC with pembrolizumab. The control arm was that same chemotherapy but without the pembrolizumab. Patients went to surgery and then they went on to finish a year of pembrolizumab in total or placebo at that point. In terms of efficacy data, again, pathologic complete response really increasing from about 51% up to about 65% with the addition of pembrolizumab and event-free survival analysis at interim analysis 4. Really looking at the 3-year mark showed a 7.7% improvement with the addition of pembrolizumab. To get to Dr. Jhaveri's point, in terms of PD-L1 expression, you can see that regardless of CPS score, less than 1, greater than 1, or greater than 10, all patients that received pembrolizumab benefited. You do see this trend that patients that had higher CPS scores had higher pathologic response rates, but again, this was in both arms. And so even for those patients that had a CPS less than 1, you can see that the magnitude of benefit in terms of improvement in PCR was 18%. So certainly we’re not waiting for PD-L1 testing to think about whether a patient is eligible for pembrolizumab in the neoadjuvant setting. Also, just to note, we did have IMpassion data as well. This drug is no longer approved here in the United States, but it is approved elsewhere, and I think that's important to call out. And PCR by PD-L1 status, about 13% difference in those patients that had PD-L1–negative disease, and about 19% difference in those patients that did have PD-L1–positive disease. So let's assume that we all agree and our patient does receive the KEYNOTE regimen of neoadjuvant carboplatin/paclitaxel/pembro, followed by AC/pembro. This patient does relatively well, but does have to have a dose reduction in cycle 2 of AC due to fatigue, as well as low counts. I see that this happens quite frequently in patients that are getting a lot of chemotherapy. BRCA testing reveals a deleterious BRCA-1 mutation. She ultimately finishes out her neoadjuvant chemotherapy, goes to surgery, and she has 1.2 cm of residual disease, and 4 mm of residual cancer in 1 of 7 removed lymph nodes. Dr. Danso, what are you thinking about in terms of adjuvant therapy for this patient that completed the KEYNOTE regimen but did have residual disease at the time of surgery? Dr. Danso: Yeah, so just going back to the issue about genetic testing, it is actually critical to perform genetic testing on this woman as she will clearly benefit from adjuvant olaparib as she harbors a BRCA mutation. A number of retrospective studies, including one from the US Oncology Network, suggests that African-American women are much less likely to undergo genetic testing than other patients. So it is critically important that this woman was offered genetic testing. Patients that have residual disease after receiving preoperative chemoimmunotherapy have a significantly higher risk of recurrence in patients that have a PCR. And amongst patients without a PCR, event-free survival is significantly improved by about 10% in patients receiving neoadjuvant and adjuvant pembrolizumab on the KEYNOTE trial. So I would definitely continue adjuvant pembrolizumab in her. Now, the CREATE-X trial showed that 6 months of adjuvant capecitabine improves disease-free survival and overall survival in patients with residual disease after neoadjuvant chemotherapy. And disease-free survival benefit is particularly improved in patients with triple-negative breast cancer. So the addition of 6 months of adjuvant capecitabine is an option for this woman, but she does harbor the BRCA mutation, so we'll derive benefit from a year of adjuvant olaparib. In the OlympiA trial, patients with stage II or III disease, or a lack of path CR after neoadjuvant chemotherapy, had an improvement in invasive disease–free survival of about 7% with the use of adjuvant olaparib. In this trial adjuvant capecitabine was not permitted, but so the choices olaparib vs capecitabine along with pembrolizumab. For patients without a germline BRCA mutation with residual disease after preoperative chemotherapy, I routinely offer the combination of capecitabine combined with pembrolizumab. For patients with a germline BRCA mutation, I offer the combination of olaparib and pembrolizumab, really extrapolating from metastatic trial suggesting that olaparib in the metastatic setting is certainly superior to capecitabine. Dr. Hamilton: Yeah, that's a great summary. Dr. Jhaveri, this goes back to something we were discussing earlier, that a lot of times we have clinical data that kind of comes out at the same time and it's difficult to kind of integrate everything. How do you feel in terms of adjuvant treatment? Do you feel comfortable putting pembrolizumab with capecitabine? Do you feel comfortable putting pembrolizumab with olaparib? How would you be thinking about this patient? Dr. Jhaveri: Yeah, I think it's always very interesting that we're trying to address a question, and by the time we have the answer, the treatment landscape has evolved from other points, and then we are trying to figure out how do we incorporate that new treatment landscape data. So that's the situation here with the CREATE-X trial, which obviously did not have the pembrolizumab component and then did offer a DFS benefit, a disease-free survival benefit, at 6 months of capecitabine. And similarly, the OlympiA trial, the delta benefit was over 7% when it came to both invasive disease–free survival and distant disease–free survival, certainly changing our standard care practice of utilizing olaparib in this setting. I feel very comfortable despite not having the purest data from the KEYNOTE-522 itself, because that trial was only addressing the pembrolizumab question and not addressing the capecitabine or the olaparib question. But we have a lot of data in the metastatic setting for both combinations of capecitabine. And of course we have data for chemotherapy with pembrolizumab for multiple trials, including KEYNOTE-522. We have data for PARP inhibitors, and checkpoint inhibition including PARP inhibitors with pembrolizumab in the metastatic setting as well. So given those comfort of safety data that we already have in the metastatic setting, given the data that we've seen with the KEYNOTE-522 regimen with pembrolizumab, given the data we've seen with CREATE-X for capecitabine, given the data we've seen for germline carriers for olaparib, I feel very comfortable combining. Especially given the fact that we know that for an individual patient who does not achieve a pathologic complete response, despite a KEYNOTE-522 regimen in the neoadjuvant setting, we know that the prognosis for that patient is not necessarily very great, and we would want to offer them all the therapies that we have that can improve their outcomes further. So given that comfort from the safety data, I feel very comfortable utilizing that combination in that setting. Dr. Hamilton: Thanks. Very well said. So also just to note, that OlympiA included both patients with hormone receptor–positive as well as triple-negative disease, everyone had to have a germline BRCA1 or 2 alteration. It's a little bit complicated, to be quite honest, how you qualified in terms of neoadjuvant or if you received chemotherapy in the adjuvant setting. For this patient with triple-negative breast cancer, if you receive neoadjuvant therapy, you just have to not have a pathologic complete response. If we only receive adjuvant chemotherapy, it's based on initial characteristics and risk based on at least a T2 tumor or node positive disease. When we look at the overall survival at the first data cutoff at OlympiA, this is at 2.5 years, it looked to be about 3.7%. However, despite the fact that the P value is.02, this really was not statistically significant based on how they use their alpha as part of the trial. But the difference in 3-year overall survival data, again, looking to be around 3.7%. In terms of invasive disease–free survival and distant disease–free survival at the second interim analysis, we see a 7.3% benefit of using olaparib over not, in terms of invasive disease–free survival, and 7.4% improvement in distant disease–free survival. So I think based on the wealth of this data, and really the fact that this therapeutic is linked to something specific and testing in a patient's tumor leads us really to put a lot of confidence in PARP inhibitors, perhaps over something like capecitabine alone. So Dr. Danso, I think this is a tough question that maybe doesn't have one right answer, but how do you think about the contribution of adjuvant pembrolizumab to the event-free survival? Is it possible for those patients that perhaps do have a pathologic complete response separate from our patient, could we omit the adjuvant pembrolizumab? This certainly would save a lot of infusions for patients, would save a lot of health-care dollars. What are your thoughts on that? Dr. Danso: So that’s a very interesting question. So we know that in the KEYNOTE-522 trial, if you had a pathological complete response, regardless of whether you got a pembrolizumab or not, the event-free survival was excellent and well over 90%, like 93%, 94% at 3 years, if you had a pathological complete response, regardless of whether you got pembrolizumab or not. So in this patient population that does have a complete pathological response, it's not unreasonable to omit adjuvant pembrolizumab if they're having any toxicities. If they've had any significant immune-mediated toxicities, I'm quite comfortable foregoing the adjuvant portion of the pembrolizumab. However, if they're tolerating the pembrolizumab well, I'm a bit of a purist and I prefer that I continue the regimen out as was done in the trial. Dr. Hamilton: Yeah. Dr. Jhaveri, do you agree there? I think I do as well. Dr. Jhaveri: Yeah, I do. I do. And I think right now, I mean, we learn from our experiences, even with HER2-positive breast cancer, where we started off with something and then we were trying to right size the right regimen for a patient. And maybe with more data and trial efforts, such as the OPTIMIZE, which is trying to address this question of whether everybody needs adjuvant pembrolizumab, especially if they achieve a pathologic complete response. Short of those data that we can get, I think currently we would offer based on the KEYNOTE-522 regimen, unless we are really struggling with toxicity issues that warrants us to hold that medication back. Because while we saw that the delta benefit was larger in those that did not achieve pathologic complete response, there was still benefits seen with continuing pembrolizumab in that setting. So right now, I would continue. Dr. Hamilton: Yeah, absolutely. Our patients with triple-negative breast cancer still have the poorest outcomes compared to other tumor types. So in the absence of really reassuring data that they don't need this, I too err on the side of continuing it, really wanting to give patients all benefit that they may be able to claim from this drug. So Dr. Danso, I think I heard both you and Dr. Jhaveri say that you feel comfortable with pembrolizumab with both capecitabine or olaparib. Is it fair to say for those patients with a BRCA alteration, you are favoring olaparib backbone instead of capecitabine? Dr. Danso: Yes. If my patients have a BRCA mutation, I favor olaparib. Now, very occasionally, I've done something even more than that, on a very rare occasion where patients have multiple positive lymph nodes after standard of care therapy with preoperative pembrolizumab, I have occasionally given 6 months of adjuvant capecitabine followed by a year of olaparib. But that's on a very rare occasion. My preference is to use the olaparib for patients with a BRCA mutation, and use capecitabine for patients without a BRCA mutation. Dr. Hamilton: Fantastic. Dr. Danso: There are ongoing clinical trials of ADCs, such as Dato-DXd and sacituzumab, for patients with residual disease after neoadjuvant chemotherapy. So I would encourage patients to enroll in those trials. Dr. Hamilton: That's a great point. So key clinical takeaways from this case. Pembrolizumab is approved for all patients with high-risk triple-negative breast cancer, regardless of PD-L1 scoring, and this includes node positivity or a tumor size of at least 2 cm. And then our two options really for escalating treatment for patients with residual disease, they may be eligible for adjuvant capecitabine, or patients with BRCA alterations who are high risk may be eligible for adjuvant olaparib. This brings us to the end of case. Please see the other segments for further discussion about the latest data in breast cancer or visit ascopost.com. Thank you so much for joining me.

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