HR+/HER2- Metastatic Breast Cancer: Impact of ESR1 Mutation on Treatment
Komal Jhaveri, MD, FACP: Pedram, do you think given that there are so many different kinds of alterations, that as you said, every ESR1 alteration can have its own implication of how activating or what is the confirmation change that actually makes it very relevant in terms of its activation? Not all of them are alike. We have one oral SERD [selective estrogen receptor degrader] that’s already approved, but there are many that might hit the finish line and might be available for our patients to use. And maybe other novel class of agents such as PROTACs [proteolysis-targeting chimeras] and CREMs [cyclic AMP element modulators] and SERCAs [sarcoplasmic reticulum calcium ATP-ases] that might also potentially get approved. Do you envision a future or a world where we might be able to offer a novel endocrine agent for a given ESR1 mutation, or do we think about one mutation for a different drug specifically?
Pedram Razavi, MD, PhD: I think that’s a great point, Komal. And we are in a very good time in breast oncology. I think all of us are excited. We’re going back to 15, 20 years ago when all of these targeted therapies were coming for non–small cell lung cancer and we had just a few targeted therapies in breast cancer, mainly anti-estrogens and anti-HER2 therapies. But this is an exciting time. And it is possible, Komal…[that] at some point we accumulate evidence to know, for example, this particular ESR1 mutation is more sensitive to a certain subtype of endocrine therapy, and then we can offer it to the patients. And…part of it is going to come from clinical trials, part of it is going to come from real-world data, and also the preclinical data looking at different SERDs and different mutations. I think this is a possibility. So we now have the first oral SERD approved [and] hopefully we have more and more of the new classes of endocrine therapy also come to clinic, and that’s a good problem to have.... I would like to highlight one thing. Going back to some of the data that’s already been published…[the] ctDNA [circulating tumor DNA] analyses of [the phase 3] BOLERO-2 [trial; NCT00863655] were associated with worse overall survival in patients in that setting. We didn’t have all these novel therapies at this point.... Also, the patients who had multiple ESR1 mutations generally did worse than the patients that had single ESR1 mutations. Another phenomenon that we are seeing in clinic now that we are doing more analyses of the ctDNA and also tumor is the polyclonal resistance. So ESR1 is one of the mechanisms of endocrine therapy resistance. We have the alterations involving the MAPK pathway, some of the transcription factors, some of the other factors that result in resistance.… So that adds again to the complexity of endocrine therapy sensitivity and resistance with a polyclonal resistance, something that we will be facing in-clinic now that we are doing these types of analyses.
Joyce A. O’Shaughnessy, MD: We’ll have to have sophisticated databases and [artificial intelligence] to help us with the very specific mutations on what’s going to be the best targeted therapy, et cetera, but also the polyclonality is certainly challenging. Makes me think we’ve got to get the endocrine therapy really right for the patients in the curative setting…so we can have less metastatic disease…to take care of.
Transcript is AI-generated and edited for clarity and readability.
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