Wassim McHayleh, MD, MBA, FACP: The first-line treatment of metastatic hormone-positive, HER2-negative breast cancer depends on whether the patient is endocrine resistant or endocrine sensitive. If a patient presents with de novo metastatic disease or recurs years after stopping endocrine therapy, this is an endocrine-sensitive patient. For those particular patients, the first-line treatment consists of an AI [aromatase inhibitor] in combination with a CDK4/6 inhibitor. With the CDK4/6 inhibitors, there are 3 options: abemaciclib, ribociclib, and palbociclib. The choice between those drugs depends on the available data, the patient comorbidities, and the disease itself. If the patient presents with endocrine-resistant disease—meaning progression shortly after starting an AI in the metastatic setting or recurrence on adjuvant endocrine therapy—you suspect an ESR mutation and you consider treatment with CDK4/6 in combination with fulvestrant instead.

In the second line, if you had sent your molecular profile and identify particular mutations, such as a PIK3CA mutation, which is positive in about 40% of those patients, then alpelisib in combination with fulvestrant would be an option. Other endocrine combinations, such as exemestane plus Afinitor [everolimus], an mTOR inhibitor, would be another option. I tend to use all my endocrine options until I run out of options and move to the next line, which consists of chemotherapy. The only oral chemotherapy would be capecitabine, which is another valuable option for those patients. The SERDs [selective estrogen receptor degraders] are a new option in development. They’re being studied in multiple clinical trials across multiple companies, and we expect it to be commercially available very soon. In our practice, we have a clinical trial for using a SERD in advanced lines of therapies. It plays a very important role in the treatment of those particular patients.

The resistance to endocrine therapy depends on the ESR mutation and the other pathways that the cancer cells use to escape, as well as the CDK4/6 inhibitor. In practice, the only place where we have a way to go around the mechanism of resistance is the ESR mutation, which actually predicts some resistance to AIs. How has it changed the testing considerations? It hasn’t affected the testing considerations. It’s telling us more and more to perform molecular testing through next-generation sequencing to try to understand the biology of the disease as more mechanisms of resistance are uncovered and more treatment options and targets become available for those patients.

Are there any unmet needs in the data published and the trials that we’d like to see develop? Definitely. We’d like more targeted treatments, more targeted pathways, and to adjust our treatment by finding the mechanism of resistance. Because those particular patients respond to those treatments for a very long time and then they reach a point where they start progressing. You want similar treatment options staying effective, long lasting, and well tolerated. It’s very important to uncover the mechanism of resistance for us specifically to be able to find new treatment options to go around the resistance and assure good responses as previously.

Transcript edited for clarity.