Case 1

Dr. Matthew Goetz:

Hello, welcome to the JNCCN Video Roundtable series on Clinical Conversations in Breast Cancer. I'm your host, Dr. Matthew Goetz. I am Professor of Oncology and Pharmacology at the Mayo Clinic in Rochester, Minnesota, where I lead the Breast Cancer Research Program, the Breast Cancer SPORE, and co-lead the Women’s Cancer Program. I’m very excited today to have joining me two of my colleagues who are outstanding experts in this area, Dr. Sara Chumsri and Dr. Kevin Kalinsky. And I’m going to let each of them introduce themselves. Kevin?

Dr. Kevin Kalinsky:

Hi, I'm Kevin Kalinsky. I'm Director of the Glenn Family Breast Center and Director of Breast Medical Oncology at Winship Cancer Institute in Atlanta, Georgia. And nice to see everybody.

Dr. Sara Chumsri:

Hi, I'm Sara Chumsri. I'm one of the medical oncologists at Mayo Clinic in Jacksonville. I specialize in cancer vaccine and immunotherapy. Thank you for having me.

Dr. Matthew Goetz:

Great, thank you very much. Today, we'll be discussing the treatment of hormone receptor–positive, HER2-negative breast cancer using CDK4/6 inhibitors. And we have several case studies that we're going to go over today that really illustrate the potential importance of utilizing CDK4/6 inhibitors both in the adjuvant as well as the metastatic setting.

Our first case today is actually a case in the adjuvant setting. It's a 56-year-old woman who presented with a newly diagnosed breast cancer. This was a mass that she palpated within her right breast. It was an invasive ductal carcinoma grade 2, ER 90%, PR 40%, and HER2 1+. The Ki67 was measured at 25%. By ultrasound and MRI, this mass was nearly 3 cm, 2.9 cm, and there was no palpable adenopathy seen on clinical examination.

She had a radiographic examination of the axilla by ultrasound that demonstrated no abnormal lymph nodes, and so a decision was made to proceed with surgery first. And maybe before we start, I'm going to just ask Kevin, just based on this initial presentation, this is a 56-year-old woman and we're not given information about her menopausal status, but I'm going to assume that she's perimenopausal. What are your thoughts about this initial presentation and what would your thoughts be about treating this patient with either neoadjuvant chemotherapy, neoadjuvant endocrine therapy versus taking her to the operating room first?

Dr. Kevin Kalinsky:

Yeah. I mean, I think that this is representative of the kind of case that we tend to discuss at our weekly multidisciplinary tumor board where this case comes up and we ask the question, "Okay, well what is the intent of giving neoadjuvant therapy? Right?" And this is a patient who has a T2 lesion, nothing on exam or by imaging is suggestive of lymph node involvement. I do think that this is the circumstance where we would think about the patient potentially going to surgery mostly so that we know pathologically what her stage is as well as what her lymph node status is. And if this was a patient who had a triple-negative breast cancer is HER2-positive, that would be a different circumstance. But for this patient, I do think we would lean toward in the absence of a patient going onto a trial, patient going to surgery and giving adjuvant systemic therapy.

Dr. Matthew Goetz:

Great, thank you very much. So this patient did proceed indeed with surgical resection first. She was interested in breast conservation, so she underwent a lumpectomy and a sentinel lymph node assessment. Findings from the surgery demonstrated a 3.2 cm grade 2 invasive ductal carcinoma, margins were negative. And interestingly, two of the three sentinel lymph nodes that were examined were positive. There was a 4 mm and 1 mm metastases, one was macrometastatic and the other micrometastatic. The surgeon and the patient discussed, and because she met the Z11 criteria, she did not have actually a lymph node dissection. So Sara, and this is something of course that we see in this situation and as we've thought about this over many years, we would sometimes ask surgeons to get more tissue so that we could be making a treatment decision. Is this a situation where you'd be asking for more information about lymph nodes, or do you have enough information here with regard to making a treatment decision?

Dr. Sara Chumsri:

I think because she already has N1 disease and based on the Z11 criteria, and we know that based on the ACOSOG Z11 doing axillary lymph node dissection in this group of patient probably will increase morbidities like with the lymph node dissection and the increased risk of lymphedema. So I think in her case, we already have enough information and putting her through axillary lymph node dissection probably will increase the morbidity but might not give us more information. So in her case, I feel comfortable with proceeding with the adjuvant therapy.

Dr. Matthew Goetz:

Great. And I think that's a real important part of, certainly with the emerging data with regard to the drug abemaciclib, which already is FDA-approved in the adjuvant space and that is, do we need to obtain more tissue to meet the criteria for eligibility for the drug, in this case doing more lymph node surgery. And I agree completely that in that doing more surgery in this situation would simply just lead most likely to more morbidity and not necessarily would give us additional information that would necessarily change our management. So Kevin, what are your thoughts? So this patient presents with essentially a clinical T2 N1 disease. What are your thoughts about next steps?

Dr. Kevin Kalinsky:

Yeah and I do think for this particular patient, it is appropriate to send an Oncotype. This is a patient who would fall into the RxPONDER trial. I'll also say, just in the context of the conversation we just had about sentinel lymph nodes, in RxPONDER, about a third of patients had sentinel lymph node biopsy only, right? So I would also feel comfortable with just having the information we have now with not additional axillary surgery. If this patient is perimenopausal, we would await the results of the Oncotype. She would have theoretically fallen into that premenopausal population.

It is worth mentioning that in the forest plot when we look at age and then the potential benefit of chemotherapy, because of course in RxPONDER, we saw for the premenopausal women, if their recurrence score was 0 to 25, they benefited from chemotherapy. And when we looked at age, the hazard ratio—if you were greater than 50 years of age—was a little bit different than if you were younger. The hazard ratio was about 0.8 as opposed to about 0.4 for younger women, but there was no significance to that interaction term. So, I think we would await the results of the Oncotype and then have a discussion about the risks and benefits of chemotherapy.

Dr. Matthew Goetz:

Great. So let's just say that this patient returns, we run an Oncotype DX and that Oncotype recurrent score comes back in that intermediate-risk category, clearly not high but perhaps in that range of 15 to 18, your recommendation then. Sara, what would you do next?

Dr. Sara Chumsri:

I think if she's, you said come back in 15 to 18 and she's perimenopausal, I think it might be a good idea to, because I think like Kevin was just mentioning that they probably fall into the premenopausal, perimenopausal category. So, in that case, I think maybe a conversation regarding chemotherapy like adjuvant chemotherapy might be a good idea, but on the other hand, let's say she's more postmenopausal based on the RxPONDER trial, then omit the chemotherapy and proceed with the adjuvant endocrine therapy. And because her Ki67 is more than 25%, it does meet one of the cohort with the N1 and Ki67 more than 25%, the cohort 2, in the monarchE trial. So, discussion about adjuvant abemaciclib for 2 years in combination with aromatase inhibitor would be important in this case.

Dr. Matthew Goetz:

Great, thank you very much. Kevin, at your institution, as you are seeing these patients and beginning to make decisions about not only chemotherapy, you mentioned obviously the use of the recurrence score, which would be a standard approach based on the study that you led with RxPONDER. What about Ki67 and how is your institution utilizing that in this scenario?

Dr. Kevin Kalinsky:

Yeah, I mean, we have been checking Ki67. It's been something that, for years, has been part of the immunohistochemical assessment for newly diagnosed patients with breast cancer. I will say we don't use the same assay as what was evaluated in monarchE. I'll also say we're lucky in that our pathologist, with whom we work with at Emory, has been involved in some of those studies and feels confident in terms of how we're reporting out Ki67 and thinking about that in the context of use of abemaciclib or not. But, of course, this is one of the main issues with us hanging our hat on Ki67 is that there are a number of analytic considerations. This has been something that has been a controversial and somewhat unreliable marker internationally. There have been international guidelines looking to standardize Ki67 and then now part of the FDA label has incorporated Ki67 with a marker with which there has been some controversy for years.

Dr. Matthew Goetz:

Yeah, it's really quite fascinating that, and quite interestingly, Sara and I here at Mayo, we're in a very similar situation. We've been using Ki67 for some years. I think some people will look at a marker like Ki67 in isolation and try to make treatment decisions, but I think it's one of these markers where truly, you use it along with a series of other markers. And it does as was shown of course in monarchE, Ki67 clearly does provide prognostic information. One of the things of course that was a question mark was whether Ki67 would be predictive of abemaciclib benefit. And clearly, that's not the case. But what we can do of course is utilize Ki67 to identify a group of patients that perhaps we might have previously referenced them as more intermediate risk and would perhaps classify them as higher or lower risk just from a prognostic standpoint. Kevin, in this situation with this patient, your thoughts on the use of adjuvant abemaciclib?

Dr. Kevin Kalinsky:

Yeah. I mean, I think it would come up in the conversation. If we look at the FDA label, she does not meet the criteria, right? She meets it per Ki67 and having one to three lymph nodes involved, but she's a grade 2 tumor, not a grade 3 tumor. It's not greater than 5 cm, but what we also had seen is that ASCO recommendations are a little bit broader than that. And so we would have the conversation that this doesn't really fit the label necessarily, but there's the potential that you may have some benefit and it's that conversation of the risk/benefit ratio.

Dr. Matthew Goetz:

Right, and I think if we look at that dichotomy or if you will, a little bit of that controversy with where the FDA came out in this situation, I think they were trying to be a little bit more conservative knowing that the drug is relatively new in the adjuvant space, perhaps reserving it for those higher-risk patients, if you will. And I think one of the things that will be very important to learn over time is this benefit of abemaciclib obviously maintained, so as we get more data. I think the other thing of course is as we get farther out and more events occur, it could be that we all look at this over time and say Ki67 truly is not something that is going to impact in terms of our decision making. I still think at the end of the day, it's one of those biomarkers that provides a bit of additional information and can take a patient perhaps in this category and move them a bit from that intermediate into that higher-risk category.

And for a given patient, that may be very important for treatment decision-making. Okay, thank you very much both of you. I think this is a case that really brings up several very important points.