Case 2

Dr. Matthew Goetz:

We're going to transition to the second case, which is also in the adjuvant setting. This is a 51-year-old female. This is perhaps a more clinically aggressive presentation. She is premenopausal and presented with a 4.9 cm left breast cancer, grade 2, ER 80% with strong nuclear staining, PR 10% HER2 1+, and a Ki67 of 60%. She, on physical examination, did not have palpable axillary nodes, but axillary ultrasound identified three abnormal lymph nodes with cortical thickening, an ultrasound-guided biopsy or percutaneous FNA was performed and was positive, and clips were placed in the lymph node. And so this patient, Sara, presents to your patient or to your clinic with a clinical T2. Again, N1 disease that's biopsy-proven with more aggressive features, a very high Ki67. Your thoughts on initial treatment for her?

Dr. Sara Chumsri:

Yes. So this case is similar to I think what Kevin was mentioning about the first case, but this one has documented lymph node positive disease with high Ki67. So I think the goal for the neoadjuvant therapy would be to try to downstage the axilla perhaps so that she can have less surgical intervention for her axilla. So I think considering neoadjuvant chemotherapy in this case would be a good thing to at least discuss with the patient about neoadjuvant chemotherapy.

Dr. Matthew Goetz:

Great. So she additionally underwent, during the process of workup, germline genetic testing, and she was found to have a deleterious BRCA2 mutation. So question for you, Kevin. We're getting this information more and more quickly than we did in the past. I know at our place, we would beg to have this and sometimes, it would take 2, 3, 4 months until we would get it. Now, we're starting to get these rapid stat tests and we might have results sometimes within time to make a treatment decision. Would BRCA mutation testing affect your decision here for initial therapy in either the neoadjuvant versus going to the adjuvant setting?

Dr. Kevin Kalinsky:

Yeah, I do think that doing the testing will have implications, right? I think the implications, being including the type of surgery and then if she were to not have a response to neoadjuvant therapy, that she would may be in the criteria for receiving something like olaparib, and so I think for this particular patient, compared to that first patient, the patient has a larger tumor, nodes involved, the surgeons may also have the preference to potentially give neoadjuvant systemic therapy to decrease, to debulk the axilla, for instance, and have less morbidity with their surgery. So giving neoadjuvant chemotherapy seems entirely appropriate. I'm not sure that the knowledge of the BRCA mutation would influence the type of neoadjuvant therapy the patient may receive, but it would definitely, outside of a clinical trial, impact adjuvant systemic therapy if she has residual disease.

Dr. Matthew Goetz:

Great, thank you very much. So this patient was indeed treated with neoadjuvant-based chemotherapy. In this case, she received four cycles of anthracycline-based chemotherapy. This was AC treated in a dose-dense fashion. And then she received 12 weeks of paclitaxel and tolerated chemotherapy very well. When she presented and during her treatment, she was found to have a partial clinical as well as imaging response. Her tumor mass decreased by perhaps a little less than half. And interestingly, she had a follow-up ultrasound of the axilla, and it was noted that the axillary nodes normalized. That is some of the findings such as cortical thickening went away.

So interestingly in this case, this patient, with this BRCA2 mutation, was recommended mastectomy as well as both a contralateral prophylactic mastectomy. She actually declined that and wanted a lumpectomy. Now, I thought this was really interesting, but I've actually encountered this several times in my clinic over the past few years, patients with a known BRCA mutation, diagnosis of cancer, and we would normally think about doing bilateral mastectomy, reconstruction, obviously eventually addressing the ovaries. Sara, have you seen this in the clinic where patients might elect breast conservation even in the setting of a BRCA1 or BRCA2 mutation?

Dr. Sara Chumsri:

I do see, but it's rare. I think most of the BRCA patients I encounter usually elected to have bilateral mastectomy. On the other hand, some of the other germline mutation that are rare, that we don't quite know about the incidence of breast cancer later on, I think I do have some of those patients that we don't have quite a recommendation whether they should get prophylactic mastectomy, those kind of things. Some of those patients still elected to have lumpectomy done, but I think with the BRCA patients, most of the time after genetic counseling and discussion, most of my patients actually underwent bilateral mastectomy.

Dr. Matthew Goetz:

Yeah, I agree completely. That certainly is usually what we see. Kevin, this is a patient who elected to undergo breast conservation. Is there any tools that you use to try to identify, inform the patient what the risk of a contralateral breast cancer is? Let's say in the setting of a known BRCA2 mutation perhaps over the next 10 or 15 years? Anything that you would recommend or use in this situation?

Dr. Kevin Kalinsky:

Yeah, no, that's a really good question. Oftentimes, these patients are seeing a genetic counselor as well. There are different computational models that can help determine the risk. I honestly don't know off the top of my head of things like BRCA PRO, things like that can incorporate in somebody who's been diagnosed with breast cancer, that risk. But this would certainly be something that would be imperative that a patient who's opting for a lumpectomy meets with a genetic counselor, not just also to discuss risk of breast cancer, but also other potential inherited diseases like gynecologic malignancy, right? So it's important that this patient also follow with a gynecologist as well.

Dr. Matthew Goetz:

Yeah, it's really interesting. I think again, as we begin to do more of this testing, it will give us the opportunity, I think to be discussing these things, which in the past, we may not have had information, for example, the age-adjusted risk of a contralateral breast cancer in a PALB2 mutation. And as Sara just said, and again, most of our patients in this situation will be undergoing bilateral mastectomy.

Okay, so this patient did go on to have surgery. Pathology from surgery demonstrated a nearly 3 cm invasive ductal carcinoma. The final grade was grade 3, and again, she had a positive sentinel lymph node and a total of one of three positive lymph nodes were seen and one of the clipped nodes was positive.

So in this particular situation, and what I don't have here is the RCB status, which I think would be very helpful, but I'm going to assume that in this situation that she had a substantial cellularity with regard to that residual disease. And I think what we could know is for sure she would be at least RCB-2 given the presence of the lymph node status. So in this situation, Kevin, this patient you're seeing after her surgery, what are the additional therapeutic options that you would think about here and how might you sequence in? What's the best way to approach this case?

Dr. Kevin Kalinsky:

Yeah. I mean, I think that based upon the OlympiA study, if patients receive neoadjuvant therapy and then high enough risk at the time of surgery per the CPS and EG score, which I think she would meet those criteria just based upon grade. And then her clinical and pathologic staging, I would favor the patient undergoing a year of olaparib-based therapy along with endocrine therapy. I think the question is whether you would give CDK4/6 inhibitor after, we definitely would not give it concurrently. I think that would raise some real safety concerns. We don't really have any data about that sequencing.

So that would be part of a discussion with the patient. I mean, I will say that I think that we may end up after that completion of a year of olaparib just doing an aromatase inhibitor. This is an absence-free zone. She would meet the criteria for something like monarchE and that her tumor was almost at 5 cm at diagnosis, lymph node positive, grade 3, all of those things, but I do think that she would probably have greater benefit with olaparib, understanding that this is cross draw comparisons and there's no direct comparison.

Dr. Matthew Goetz:

Thanks very much. Sara, how about you?

Dr. Sara Chumsri:

Yeah, I do agree with Kevin. I think if you look at the OlympiA trial, the separation of the curve started early. So I would totally offer her with the olaparib first. I think with the abemaciclib and the monarchE trial, the trial actually allowed patients up to 18 months after the surgery to be randomized and get the abemaciclib. So I think maybe after 1 year of olaparib, then maybe consider abemaciclib afterward, but definitely not concurrently because of the safety concern.

Dr. Matthew Goetz:

Yeah, I completely agree with both of you. And I think one of the things that's of course so striking now from the recent virtual presentation that Andrew Tutt had was of course that now we're seeing a survival advantage fairly early on with this class of drugs. And of course, we don't see that or have it, of course, the data are too immature in the monarchE. So I think just using survival data alone, I would be very much, and of course, knowing that BRCA2 is being directly targeted via synthetic lethality in the very robust data, the separation, the immediate separation of the curves. I think for all that reasons, adjuvant olaparib to start out with makes sense. Certainly, I think I would speak to the patient about adjuvant abemaciclib. I think, like Kevin, sometimes, patients can get a little fatigued after a period of time and so you'd have to see where the patient is both physically, emotionally, mentally, are they ready to embark upon additional therapy? But I certainly would have that discussion.

Dr. Kevin Kalinsky:

Yeah. I mean, I think it's similar when we think about neratinib in the extended HER2-positive setting. I think we see that fatigue for patients who've been on HER2 targeted therapy for at least a year and they want to take another medicine which may cause GI upset and things like that. So I think it is a bit patient-specific but worth a discussion.