Role of Molecular Profiling in HR+ Metastatic Breast Cancer


Andrew D. Seidman, MD; Aditya Bardia, MD, MPH; Dejan Juric, MD; Nicholas McAndrew, MD, MSCE; and Hope S. Rugo, MD, discuss when it is appropriate to order molecular testing and the impact of testing on the treatment of HR-positive metastatic breast cancer.

Andrew D. Seidman, MD: Hello, and welcome to this OncLive® Peer Exchange® titled “Clinical Advances in Hormone Receptor–Positive Breast Cancer.” I’m Dr Andrew Seidman from Memorial Sloan Kettering Cancer Center in New York. Joining me in this discussion are my colleagues Dr Aditya Bardia from Massachusetts General Hospital in Boston, Dr Dejan Juric from the Massachusetts General Hospital in Boston, Dr Nicholas McAndrew from UCLA [University of California, Los Angeles] in Los Angeles, and Dr Hope Rugo from UCSF [University of California San Francisco] in San Francisco.

Today we’re going to highlight a number of topics pertaining to the systemic therapy of hormone receptor–positive breast cancers and the impact of recent clinical trial data on clinical decision-making, including data from the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting. Without further ado, I’d like to get started on our first topic, which relates to the use of CDK4/6 inhibitors in metastatic breast cancer. Aditya, I’ll start with you. Can you talk a little about how and when you order molecular testing, or molecular profiling, for patients with hormone receptor–positive metastatic disease? Do you tend to do this at initial diagnosis of metastatic disease or at first progression?

Aditya Bardia, MD, MPH: That’s a good question about the role of molecular testing or genotyping in hormone receptor–positive metastatic breast cancer. In my opinion, everyone with hormone receptor–positive metastatic breast cancer should have molecular profiling. When a patient has a diagnosis of metastatic breast cancer, a tissue biopsy is usually done. Potentially that specimen—besides getting ER [estrogen receptor], PR [progesterone receptor], and HER2—could be sent for tissue-based genotyping. One could also consider plasma-based genotyping, but I tend to use plasma-based genotyping later on.

When a patient has disease progression on first-line regimens, like endocrine therapy plus a CDK4/6 inhibitor, that’s where the molecular genotyping could have an impact on therapy selection, particularly standard of care. In that setting, if a patient is not getting a biopsy, I routinely get plasma-based genotyping because it’s actionable. If we see a mutation in PIK3CA, the patient could potentially get alpelisib as standard of care. At our institution, we have a number of genotype-driven trials, so we tend to do genotyping serially. If an actionable alteration is seen, the patient could be triaged to that specific trial. For example, we have a trial with a PARP inhibitor for patients with somatic BRCA mutation. There’s a trial with H3B-5942 for ESR1 Y537S alterations. Based on the alteration, it could help select the appropriate clinical trial.

Andrew D. Seidman, MD: Thank you. Clearly, PIK3CA mutations are critical to know. Do you find ESR1 mutations actionable in your clinical decision-making?

Aditya Bardia, MD, MPH: At our institution, yes, because we have specific clinical trials that preferentially enroll patients with ESR1 mutations. Outside the trial setting, although we don’t have level 1 evidence, I do find it helpful to get the results of ESR1 mutations. Because if a patient has an ESR1 mutation, I would generally not use an aromatase inhibitor [AI]. Even if I’m considering exemestane and everolimus, if a patient has ESR1 mutation, I would do fulvestrant plus everolimus as standard of care.

Andrew D. Seidman, MD: Great.

Dejan Juric, MD: I couldn’t agree more with Aditya. PIK3CA is the first precision oncology biomarker we have. We have a clear link with the use of alpelisib. ESR1 is critically important because this very example—exemestane plus everolimus—comes from a really nice analysis by Sarat Chandarlapaty of the BOLERO-2 data. They show that if you have a mutation in Y537S, which presumably makes the patient resistant to the aromatase inhibitor backbone, then the entire combination fails. Exemestane plus everolimus has really limited activity, at least based on that post hoc analysis in Y537S mutants. This is just 1 example of how these mutations can be used as a positive predictive factor or biomarker, PIK3C alpelisib, negative ESR1 Y537S and AI, or AI plus everolimus.

Andrew D. Seidman, MD: Dejan, that’s a great point, particularly when we lack a comparison between the BOLERO-2 regimen and a selective estrogen receptor down-regulator as far as I’m aware.

Hope S. Rugo, MD: It’s also important to know that the ESR1 mutations are not all the same. Some of them predict much more resistance than others. There’s a relatively poor understanding of that in terms of which ones matter. Some of the trials focus on using novel agents like SERCA [selective estrogen receptor covalent antagonist] in ESR1 mutations, or SERM [selective estrogen receptor modulator] lasofoxifene, focusing on specific ESR1 mutations, which is fascinating.

Transcript Edited for Clarity

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