Dr. Sara Tolaney:
Welcome to High-Risk HR-Positive, HER2-Negative Early-Stage Breast Cancer: Bridging Evidence, Risk Identification, and Real-World Practice, a JADPRO Virtual Roundtable. My name is Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute, and very lucky to be joined by my two esteemed colleagues, Dr. Erica Mayer, who leads clinical research in breast oncology at Dana-Farber, and Dr. Elahe Salehi, a very experienced nurse practitioner in breast oncology. Thank you to both of you for joining us today.
So, we're going to dive into our second case, where we're going to discuss the management of high-risk early-stage breast cancer in a patient who has a germline BRCA mutation. This is a case of B.K., who is a 42-year-old premenopausal woman who had a routine screening mammogram and was found to have a mass within her left breast. This was about 4 cm, and she did also have ipsilateral enlarged suspicious axillary lymph nodes. A biopsy of the breast mass was done and came back as an intermediate-grade invasive ductal carcinoma that was ER 90%, PR 25%, and HER2-negative.
The lymph node was biopsied and did come back having malignant cells within it. She had staging scans that were done and did not have any metastatic disease. Germline testing was done and she did have a BRCA mutation. She ended up going to upfront surgery with a mastectomy and sentinel node biopsy and was found to have a 5.2-cm grade 2 invasive ductal carcinoma with two out of three lymph nodes that were involved. An Oncotype Recurrent Score was sent off the breast tumor, which came back with a score of 21. She did have, again, no evidence of metastatic disease.
The summary is that this is a little over a 5-cm cancer with two positive nodes with an Oncotype of 21 in a patient who does have an underlying BRCA mutation. This is, again, a premenopausal patient, which I think does increase a bit of the complexity. Erica, I think the challenging question in premenopausal patients these days is this consideration about whether or not we need to be giving chemotherapy here, particularly now with this Oncotype that falls under 25. How would you think about this in this case?
Dr. Erica Mayer:
Yes, so this is a somewhat complex situation, but first I'd start by saying I feel concerned about this patient. I do think there's a number of high-risk features here. She has T3N1 disease, so she has a pretty large burden of disease, grade 2. But with the ER 90, PR 25, it's a little bit of a luminal B profile, and I think the Oncotype score of 21 reflects that. Technically less than 25, but edging in on 25, and again, reflecting that there may be a bit more of a proliferative state associated with this cancer.
This is a patient for whom I really want to be very comprehensive with my systemic therapy. Thinking about, first of all, what I would offer is hormone receptor–positive. So, we want to offer adjuvant endocrine therapy. We want to offer extended duration adjuvant endocrine therapy for higher stage disease. Because she has a BRCA mutation and she's older than 40, she probably needs to have her ovaries out and I'd be giving her ovarian function suppression regardless. I would offer this patient a CDK4/6 inhibitor, I think we're going to talk about that in more detail, but this is a patient who is likely a candidate for either abemaciclib or ribociclib. Personally, I would be offering abemaciclib here with a greater than 5-cm node-positive cancer given the overall survival benefit seen in the monarchE study with the use of abemaciclib.
Now, getting to chemotherapy, the RxPONDER study has shown us or suggested to us that premenopausal patients with an Oncotype score less than 25 are deriving some level of benefit from chemotherapy. But that's been a little hard to understand because many of those patients experience chemotherapy-induced amenorrhea, which is a very powerful tool in treating hormone receptor–positive breast cancer. The ongoing OFSET study, which is open around the United States, is attempting to prospectively answer the question of how much benefit in the patients with an Oncotype 25 or less is related to chemotherapy specifically or chemotherapy-induced amenorrhea when ovarian function suppression is used in both arms. That question remains still unanswered.
But in this situation, for me personally, given the burden of disease, the Oncotype that is approaching 25, and on some level, I think, the BRCA mutation, which may predict a little more of a chemosensitive cancer, I would be inclined to offer the patient adjuvant chemotherapy as well. Now, given the very recent OPTIMA data looking at Prosigna, perhaps one could send another test and try to clarify or confirm whether the disease is chemosensitive or not, or whether she's going to derive benefit from chemotherapy. Personally, I think given the information we have here, this is enough for us to make our systemic therapy decision. I don't think we need to do any additional testing beyond what we know already.
Dr. Sara Tolaney:
I certainly agree. This is a big cancer with nodal involvement. I also agree that I think with the BRCA mutation, they generally are very chemosensitive, so it seems like probably AC-T chemotherapy in this case would probably be quite reasonable, followed by oophorectomy or ovarian suppression and AI and CDK4/6 and bisphosphonate. I guess the question, though, that now comes up is, while we've just talked about CDK4/6 inhibitors and how important they are, we also in someone with a germline BRCA mutation have an approval for olaparib in a high-risk population. How do you then differentiate between giving a year of olaparib, as was done in the OlympiA study, or giving let's say 2 years of abemaciclib, as was given in monarchE? How do you make a determination about which one you're giving? I guess on top of that, would you ever sequence them and actually give both? Erica, what do you think about that?
Dr. Erica Mayer:
Yes, this is a question that we often talk about in our tumor boards or in our cases at conferences as we are left in a situation of having multiple tools available for a patient and figuring out how to prioritize and sequence what's most important in specific settings. We've known now for a few years from the OlympiA trial that providing the year of olaparib to high-risk hormone receptor–positive disease provides an overall survival benefit. So, for the past few years, if we are faced with the choice between a PARP inhibitor and CDK4/6 inhibitor or thinking how to sequence, we've always thought about prioritizing the PARP inhibitor given the overall survival advantage. Now we have seen from monarchE that there's an overall survival advantage as well to using adjuvant CDK4/6 inhibitor, the 2 years of abemaciclib. So, now we have two agents, both with overall survival advantage. I think we want to give both. We want the patient to get both of those benefits.
For me, and I think perhaps in our group, I would say that we tend to stay with our pattern of prioritizing olaparib first and then planning to offer the abemaciclib second. Technically, in monarchE there was a window during which patients could be on adjuvant endocrine therapy before they initiated the abemaciclib, and so one could think about tucking the olaparib into that window before moving to it. I also think the experience of getting olaparib is perhaps a little bit more like chemotherapy vs the abemaciclib, and so I would be shifting it closer to the chemotherapy experience. But I do think both agents are very important for a high-risk patient such as this, so I would want to offer both of them for this particular person and in the order of olaparib first, abemaciclib second.
Dr. Sara Tolaney:
It's a challenging situation. Obviously we don't really have even safety data for sequencing these drugs, or efficacy data. But I think as you point out, given this is a young patient with a very high-risk tumor, we in essence want to give every effective therapy that we have up our sleeve to help this patient and try to reduce risk. We've touched a bit upon some of the side effects that we can see with abemaciclib and monitoring. Elahe, if you're starting someone off on olaparib in this particular setting, so à la OlympiA, giving a year of olaparib therapy, how are you thinking about that? What do you need to counsel the patient on? How often do they need to be monitored? What do you recommend?
Dr. Elahe Salehi:
It's interesting because a lot of patients actually tolerate olaparib quite well. I mean, two things that we do mention is, one, fatigue, and the second one is their blood count. So, we do bring them back every month to follow up on their side effects and have a complete CBC with differential and complete chemistry. They do tolerate it. I probably have one patient in all of my years of experience that did complain about nausea component, which I usually don't see in this, but definitely people tolerate this drug so well.
Dr. Sara Tolaney:
I think that's really an important point. I will say upfront, sometimes I get those people who feel queasy, that low-grade nausea. I do give them a prescription when I prescribe the olaparib of ondansetron just to have on hand because particularly those first several weeks, I think if they're going to get nauseous, it typically happens early and tends to dissipate with time. Then as you very nicely pointed out, I think anemia is one of the things we look out for in people with olaparib. In fact, there are patients who can sometimes even require blood transfusion, and so it is really important to be monitoring counts, as you noted. I think those are the two big things. It is a year of therapy, and so sometimes people do need dose modifications as well, and so just to look out for that as we treat these patients.
I think the other thing I would just bring up is that there's been a little bit of concern, and we're not really sure how to think about this in the adjuvant setting, but how effective are CDK4/6 inhibitors in someone who has an underlying germline BRCA mutation? There's been some really interesting data in the metastatic setting among patients with BRCA2 mutations that they seem to derive less benefit in terms of PFS than someone who's BRCA wild type. It's hard because numbers are so small in the adjuvant setting from the monarchE study, but the relative benefits seemed similar in monarchE for BRCA2 mutant vs wild type. But again, the numbers are just too tiny to really know anything definitively. I think there's always been this biologic question about whether efficacy is going to be quite as good in these patients, and so just as Erica pointed out, I think for those reasons we tend to err on the side of giving the olaparib upfront, using something we think that biologically is very rational, and then sequencing that with a drug that also should have efficacy with a CDK4/6.
I think in this, the takeaways from this discussion are that decisions in using adjuvant CDK4/6 inhibition, one, don't need to be linked to a decision regarding chemotherapy. In the case that we presented, there could be a patient, for example, with a low recurrence score where you may not give chemotherapy. In this case, we felt like the patient had high enough risk to warrant it. But you don't have to give a CDK4/6 inhibitor just in a patient who's had chemotherapy exposure. Things have changed a lot since the time of monarchE being conducted where now we do have data for using genomic assays in node-positive patients to really try to use chemotherapy in patients who really need it. For patients who have very high-risk hormone receptor–positive disease and have a germline BRCA mutation, many would consider, just as was discussed, using upfront olaparib and then potentially sequencing that with abemaciclib. This I would just note, though, is not based on any real data, and both agents do have survival benefit in themselves and it is important to monitor these patients carefully when treating them in this regard.
Thank you so much Erica and Elahe for this really great discussion. This does bring us to the end of this case. Please see our other two videos for further discussion about the latest research in breast cancer at JADPRO.com.
