Case 1: Using Adjuvant Abemaciclib for High-Risk HR+ Early Breast Cancer
Joyce O’ Shaughnessy, MD; Sunil Badve, MD, FRCPath; and Massimo Cristofanilli, MD, FACP, consider the role of adjuvant abemaciclib plus endocrine therapy for the treatment of patients with high-risk, node-positive, HR+ early breast cancer.
Joyce O’ Shaughnessy, MD: The FDA [Food and Drug Administration] approved abemaciclib [Verzenio] with endocrine therapy for HR [hormone receptor]–positive HER2-negative node positive breast cancer with high risk of recurrence, not otherwise, specifically defined in the label with a Ki67 score of 20% or greater as determined by an FDA approved test. Sunil will guide us on exactly what that means. They approved a companion diagnostic at the same time, and we’ll get Sunil’s feeling about that companion diagnostic vs what people already have going in their lab. ASCO [American Society of Clinical Oncology] said the intent-to-treat population was reasonable—that’s the second panel here—and the NCCN [National Comprehensive Cancer Network] said the same, that it’s reasonable to utilize the intent-to-treat population as we think about recommending abemaciclib for patients.
We know that monarchE [trial] on the left column is different from PENELOPE-B and PALLAS, where adjuvant palbociclib [Ibrance] was tested in PENELOPE-B and PALLAS. Those trials were negative trials that didn’t improve IDFS [invasive disease-free survival]. Is it because there’s no break with abemaciclib? It’s continuous. Is it because it’s got a broader spectrum of activity against various CDKs? Or is it because the population was the highest risk in monarchE or some combination therein? I don’t think we know, but that’s the fact right now. Unfortunately, we don’t have palbociclib. That’s where we are with the data to help us in practice here.
I wanted to look at some questions together. What do you think about the monarchE data? Is it a new standard of care? We got the FDA, ASCO, and NCCN. What do you guys think in terms of your own practices? Do we need the Ki67? Let’s ask Sunil first. Sunil, this is the first time we’ve ever had Ki67 in a label to my knowledge, and it’s not even done by some pathology departments because it’s never been part of the ASCO/CAP [College of American Pathologists] recommendations to be done. What do you think of these data? Basically, how are we supposed to get it analyzed?
Sunil Badve, MD, FRCPath: That’s a great question. Everybody is struggling with it. In the clinical trial, they used a specific clone of the antibody which is a variant from the MIB1 [mindbomb homolog 1] antibody. It’s still the Dako MIB1, but supposedly a slight variant of hyper purified or something. Then, they used it on a relatively new machine which is the Omnis platform for adjuvant. There are number of questions that come up. Is this pharmDx antibody the same or similar to the regular antibody that we have been using from the same company for a long time? How does it perform on the more commonly used machines, such as the Link 48 machines? We have some preliminary data that suggest that the performance is very similar. That manuscript is undergoing review. The question that then comes up is, what about the 10 other companies and vendors that have Ki67 antibodies? How will they differ? Will it have the same 20% cutoff? Those are additional questions that we don’t know much about.
Furthermore, over the last 10 years, the International Ki67 in Breast Cancer Working Group has done a lot of work, because they found 10 years ago that there’s a lot of heterogeneity in the way Ki67 is scored. There’s a manuscript that was published late last year in JNCI [Journal of the National Cancer Institute]. Torsten Nielsen, MD, PhD, FRCPC, is the first author of the paper which describes the 10 years’ worth of work and what has been done in terms of standardization. But very briefly, the main thing is you don’t look for hot spots. You look at the entire tumor and try to score it. The second major point in the pharmDx assay is that you look at the entire nucleus to be positive, even if it’s weakly positive. Focal spots of brown don’t qualify for a case or a nucleus to be called positive.
This is somewhat different from the International Ki67 Breast Cancer Working group recommendation which said that any brown spot is good enough. There are some minor differences, but overall, both methods recommend a global analysis and use of a biopsy tissue because it’s the best fix. There’s a lot of synergy in those kinds of things. The rollout is going to be difficult because different people have different platforms and we need to figure out what the equivalency and cutoffs are going to be. The cutoff used for Ki67 is 20%, and you can see that there are a lot of data around things like a 10% and a 14% cutoff. There are a lot of variables that we need to make sure are standardized before we start using Ki67 routinely in the way that it was used in the clinical trial.
Joyce O’ Shaughnessy, MD: A pathology department can certainly use an outside reference laboratory, but not all of them have been. You can maybe speak to that. But if they’ve been doing it in-house, is it like the old HER2 days where they have to go through quality assurance and make sure their assay is standardized and basically is performed similarly to the pharmDx antibody?
Sunil Badve, MD, FRCPath: That may be required. We don’t know because the MIB1 antibody has been out and around for the last decade or more. Most people have the antibody. The major changes are going to be the minimum level of positivity that we need within a nucleus and the use of the global method for count. Most cases are either very low or very high. There are very few cases that are close to the borderline. In most cases, we may have to worry a little. But by and large, if you have a score of 80 or 70 or 46, using any antibody shouldn’t be a major problem. This is a personal opinion. I don’t have any data to support that.
Joyce O’ Shaughnessy, MD: Just so I’m clear and because this is new to all of us here, there are 2 things. When we all go to our tumor boards, we want to see a uniform brown on the nucleus. But also in terms of the counting, you don’t just count the hot spots, you look across the entire slide and include everything, and your numerator is the brown nuclei and your denominator is how many tumor cells are on the side. Is that right?
Sunil Badve, MD, FRCPath: Absolutely correct.
Joyce O’ Shaughnessy, MD: Awesome. Thank you. Massimo, what do you think of these data? Are they standard of care? In your practice, who would you consider abemaciclib for?
Massimo Cristofanilli, MD, FACP: I remember the first presentation where everybody was a little surprised and not convinced, so we were discussing the short-term follow-up and the need to wait because CDK4/6 didn’t seem to have the same efficacy. Over the last year, these data became more mature. There’s an effect of the combination on minimal residual disease. The only way I can explain it is that there’s an immediate impact on early recurrence. I don’t think the molecular endocrine resistance that we mentioned many times has developed, so it seems like these tumors are very high risk. They aren’t being completely relegated by the neoadjuvant or adjuvant therapy. Single-agent endocrine therapy by itself won’t be enough, and the combination is extremely effective.
These are the patients in whom I start to use abemaciclib in combination with endocrine therapy. Most of the patients are the ones who have completed neoadjuvant therapy with minimal response and have residual disease. Some of my patients also have inflammatory, locally advanced breast cancer. Some patients went straight to surgery and were found to have a large number of lymph nodes, which wasn’t immediately known upfront. At Northwestern, but also another institution, we have been using the Ki67 mostly to understand which patients will get more benefit from chemotherapy, but we’re also learning a new way to use Ki67 in the context of combination endocrine therapy. The discussion about the amount of the antibody is very useful and we need to have a collaboration with our pathologists to be able to effectively report these data.
Joyce O’ Shaughnessy, MD: Thanks, Massimo.
Transcript Edited for Clarity
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