Sara Hurvitz, MD: Hello, and welcome to this OncLive® Peer Exchange®, “Expert Perspectives on Advanced Hormone Receptor–Positive Breast Cancer.”
I am Dr Sara Hurvitz, from the David Geffen School of Medicine at UCLA in Los Angeles, California. Joining me today in this virtual discussion are my colleagues Dr Massimo Cristofanilli from Northwestern University Feinberg School of Medicine in Chicago, Illinois; Dr Andy Seidman from Memorial Sloan Kettering Cancer Center in New York, New York; and Dr Sara Tolaney from the Dana-Farber Cancer Institute at Harvard University in Boston, Massachusetts.
Today we are going to highlight a number of topics pertaining to systemic treatment for HR+ [hormone receptor–positive] breast cancers and the impact of recent clinical trial data on clinical decision-making, including data from the 2020 San Antonio Breast Cancer Symposium. Let’s get started on our first topic.
What we’re going to do right now is focus primarily on CDK4/6 inhibitors in hormone receptor–positive metastatic breast cancer. To lead us in this discussion, I’d like to ask Massimo: What is your approach to molecular testing for patients with hormone receptor–positive metastatic breast cancer at the time of initial diagnosis? Are you doing molecular testing in the frontline setting?
Massimo Cristofanilli, MD: Thank you, Sara. This is an important question now that we have so many targeted therapies and so much information about the recent genomic data with regard to specific therapies, specifically resistance to therapies.
I would differentiate the 2 drugs that we deal with mostly. One was a de novo disease, because de novo and metastatic disease are usually what we have seen in 30% to 40% of the patients. In this case, we really don’t need genomic therapy because we already know the standard of care. There is no mechanism of resistance that we’re going to target up front, and we’ll talk more about the role of CDK4/6 information in these patients.
The patient has a recurrence, and that’s interesting because they may have a recurrence while they’re receiving adjuvant therapy. This primary resistant setting, and it’s very important to find out the genomic drivers of resistance. Obviously when we treat a biopsy in the metastatic setting, if there is tissue available from additional sites, we send for genomic testing and NGS [next-generation sequencing] to find out if there are, for example, ESR1 mutations or actionable mutations.
If there is bone disease, we can repeat NGS [next-generation sequencing], so we probably look at liquid biopsies and wait to understand the molecular driver for these patients. That would be very important to decide, for example, the endocrine therapy backbone, which can be more effective in these patients.
Sara Hurvitz, MD: So you are doing molecular testing in a patient whose disease has recurred on an aromatase inhibitor. Do you want to see whether there’s ESR1 mutation in order to determine which endocrine partner you’re going to use in the frontline setting? Is that the reason you would do that?
Massimo Cristofanilli, MD: Correct. In some cases we have seen, even more for cancer, we may even find F2 mutations that are actionable at this point. There are data suggesting this patient responds to tyrosine kinase inhibitors. But it’s very important to rule out immediately if the ESR1 mutation is the driver of the resistance. As you know, there are agents being developed in this space, especially after Faslodex or maybe in parallel as randomized studies, to find the best agent.
Endocrine resistance is becoming more of a complex issue that needs to be investigated; not 1 single mutation can be responsible. What we have is a mutation and the ESR1 mutation at the same time.
Sara Hurvitz, MD: Andrew, do you agree? Do you do molecular testing in the frontline setting, or are you waiting until the patients have progressed on frontline therapy to evaluate their tumor biology?
Andrew Seidman, MD: Besides considering patients for clinical trials in the first-line setting of novel agents like PI3 kinase inhibitors, all I really need to know to treat patients are ER [estrogen receptor], PR [progesterone receptor], and HER2 [human epidermal growth factor receptor 2] status. Generally, and certainly for the de novo patient, I don’t do additional molecular testing at that time. There are reasons to think about germline BRCA testing for subsequent use of PARP inhibitors, but even in the first-line setting that’s not top on the menu.
Sara Hurvitz, MD: Most patients are getting it done at some point. There may be some differences in the timing. Some people wait until second- or third-line setting. Certainly for clinical trials, many of us are interested in querying what the tumor biology is for clinical trial eligibility.
Sara, let’s turn to prognostic factors that you look at when you’re evaluating a patient in the frontline setting with hormone receptor–positive metastatic breast cancer. How do you weigh different prognostic features? What features do you look at when you’re determining a therapy?
Sara Tolaney, MD: In early stage disease we have discreet prognostic indictors—whereas, in metastatic disease, it has been generally a little more diffuse. When I’m trying to assess prognosis in someone with either recurrent disease in the first-line setting or de novo disease, 1 important feature is disease-free interval. If someone has recurred from prior adjuvant therapy, how long ago was that adjuvant treatment? Did they recur on their endocrine therapy? Did they recur off it? How long off their therapy had there been recurrence? These are really important features because we know that people who are recurrent on their endocrine therapy—particularly early on in their endocrine treatment, usually within the first 2 years of adjuvant therapy—are patients with endocrine-refractory disease. Those are patients who we know are not going to be as sensitive to future endocrine therapy and generally do have poor prognosis. Someone who recurs 10, 15 years later or who has de novo disease—those are patients with very different biology in their tumor and generally have better prognostic features.
We also try to look at sites of disease, so we know that patients who have significant amounts of visceral involvement generally have poorer prognosis than someone with, for example, bone-only metastases. So lots of liver metastases are certainly a worse prognostic feature. There are also some data to suggest that PR negativity can be a poor prognosis, and patients who have higher-grade tumors as well. Those are things we generally have kept in mind when trying to think about prognostic features.
There are also other molecular tests that could be prognostic. Massimo has done a lot of work in this area looking at CTCs [circulating tumor cells] that has been shown to be prognostic. It is an area that is a little more diffused than in the early sage setting, where we’re trying to factor in lots of pieces of the puzzle to best understand how those patients are going to do.
Transcript Edited for Clarity