Future Directions in HR+ Breast Cancer Management

Mark Pegram, MD: Can you summarize this discussion? Is there anything that we left out in this short format? For example, what future directions should we highlight?

Lee Schwartzberg, MD, FACP: First, to summarize very quickly, genomic classifiers are extremely useful in making decisions about adjuvant therapy for patients with HR [hormone receptor]-positive breast cancer—the majority of patients with breast cancer. We integrate the clinical features with the genomic features to make initial decisions about chemotherapy, and we have the BCI [Breast Cancer Index], which is, to my knowledge, the only test to date that has been shown in multiple data sets to be predictive of extended adjuvant therapy. It's very useful when you’re coming up to that 5-year mark. We’d like to treat every patient optimally, which means getting the tools that can help us do that, and the BCI is a very valuable tool to do it in the extended setting. I’ll turn the question over to you about future directions because you’re so involved with the research.

Mark Pegram, MD: One potentially exciting technology, if we can figure out how to use it, is the circulating tumor DNA [ctDNA] liquid biopsy testing that has become so sensitive now that you can detect early relapse well before a clinical relapse is evident. The best example of this is the ctDNA assay from Natera. The reason it’s so sensitive is they find the 16 most frequently mutated genes that are private to each individual patient’s tumor. Breast cancer [cells] are like snowflakes: no 2 are the same, so that list of 16 mutations will be unique to every single breast cancer [case]. Natera has developed custom primers constructed for all of these 16 private mutations in each patient sample, so they’re making a lot of different primers. When you do that, it allows for extreme sequencing depth, perhaps 100,000-fold coverage of those 16 particular mutants, which makes the assay very sensitive.

But I don’t know what to do with somebody who has a positive result at the end of their adjuvant therapy and still has detectable circulating tumor DNA, or if you’re following them serially over time and 5 years later they go from negative to positive on this assay. I have no idea what to do. It still isn’t ready for prime time. It’s a very powerful prognostic tool if you have detectable ctDNA for the patient’s tumor at the end of adjuvant therapy, and if their prognosis is poor. That would certainly be a patient population for future generations of clinical trials because the event rate would be particularly high. But aside from that, I’m not sure where this is going. It’s exciting technology, but it’s an example of the technology possibly outpacing progress in the clinic, at least at the moment.

Lee Schwartzberg, MD, FACP: Circulating tumor DNA is one of the most exciting technologies and can be used in so many different ways. The tumor-informed assays, such as Signatera, which you mentioned, are the most developed assays. We saw at ASCO [American Society of Clinical Oncology Annual Meeting] 2022 the single-institution data looking at HR-positive patients showing that you could detect patients with a positive signal in this different tumor-informed assay, and it predicted for eventual clinical relapse.

The most important thing that you’re asking is whether there’s any benefit to intervening early before you can detect these patients by symptoms or by imaging. If the tumor burden is less, can you change their outcome long term? We don’t know the answer to that. That will require pretty large clinical trials to understand, and there will be long studies, especially in the HR-positive metastatic space.

Mark Pegram, MD: Great points. Thank you very much, Lee. It has been a delight discussing this with you. I’d like to thank our listeners. We very much hope that our comments in this discussion will be helpful to you and your patients in your clinical practice. Special thanks to OncLive Insights® for providing the format for this discussion in this series titled “Tools to Guide Treatment Decisions in Breast Cancer.” Thank you all for taking time out of your busy schedules to participate in this session, and we bid you a farewell. Thank you.

Lee Schwartzberg, MD, FACP: Thank you, Mark. Thank you, OncLive® and our listeners. This was a wonderful discussion as always.

Transcript edited for clarity.