Sara Hurvitz, MD: Thirty-five percent to 40% are going to have this actionable mutation PIK3CA here. And if the liquid biopsy is negative, reflex to tumor tissue testing is important to pick up those false negatives, or where the mutation wasn’t selected.

Sara, what would you do for this patient? What treatment would you recommend for her, having progressed on an AI [aromatase inhibitor] and CDK4/6 inhibitor and having this mutation identified?

Sara M. Tolaney, MD, MPH: Given the SOLAR-1 data I would recommend fulvestrant with alpelisib. We know that it did have a significant improvement in progression-free survival [PFS] from 5.7 to about 11 months. We know that it improved response rates. And while there was not a significant improvement in overall survival, if you looked at the absolute improvement in patients with visceral involvement, such as this patient, it is quite striking—about a 14-month difference. So it seems like it is adding a lot of benefit. And while SOLAR-1 did not specifically look at patients with prior exposure to CDK4/6 inhibition, with only 20 patients in that trial, we now do have some data from the BYLieve trial to support that. Even though it was a single-arm study, compared to what we have historically seen for endocrine therapy alone, it does seem that adding PI3 kinase inhibition is likely adding a benefit in the CDK4/6 refractory population.

Sara Hurvitz, MD: Now Massimo, you had in our initial discussion talked about doing sequencing and genetic analysis of tumors at the first diagnosis of metastatic breast cancer, and some people are waiting for the time of progression. Let’s assume that you sequence this patient’s tumor right at the time she was diagnosed with metastatic breast cancer, and you know she has a PIK3CA mutation. Would this influence your selection of frontline therapy? Would you ever use alpelisib in the frontline setting, or would you still use a CDK4/ inhibitor in that particular patient?

Massimo Cristofanilli, MD: That’s a good question, and I think regardless the PALOMA data looked specifically at the upfront mutations that were present in patients enrolled with endocrine resistance, that was a particularly resistant population. And we see the baseline PIK3CA mutation in this population being common. It does not affect that because of the combination. We know that it’s absolutely appropriate to use the combination of a CDK4/6, in this case with an AI, otherwise fulvestrant, for patients in spite of the presence of a PIK3CA mutation up front. I think this is very important because it gives some sense of the type of sequence or treatment now that we have all these targeted agents. And as we talked about a patient who’s been exposed to CDK4/6, we certainly have the data that we could use a PI3 kinase inhibitor. We don’t have the data of the reverse, what if we used alpelisib first, and then we used a CKD4/6? I don’t think we can do the study because the data are overwhelming in regard to CDK4/6 with mutation. The data are available that show CD4/6 is effective for a PIK3CA-mutated tumor.

Sara Hurvitz, MD: Okay, great. Andrew, to round out this case now, let’s assume this woman had received instead fulvestrant plus a CDK4/6 inhibitor in the frontline setting. How would that influence the endocrine partner that you would use with alpelisib in this particular case? Do we have data to support the use of an AI with alpelisib?

Andrew Seidman, MD: Well, I guess I could say I believe that we do from the BYLieve trial data. So the endocrine partner can be an AI. I think the data that we have right now show better than expected results in terms of the proportion of patients who are free of progression at 6 months. As Hope Rugo, MD, had reported, roughly 50% median PFS of 7.3 months. There’s not yet randomized comparison to other approaches, for example, exemestane and everolimus. There was an interesting report, a real-world data study with Flatiron Health’s assistance, that compared outcomes of such patients to real-world choices, that did not involve alpelisib. The use of alpelisib with an endocrine partner following a CDK4/6 inhibitor yielded a PFS that was about double of whatever physicians were choosing to do in the real world. It’s nice to have options.

Sara Hurvitz, MD: Absolutely, I agree.

Transcript Edited for Clarity