Targeting the PI3K Pathway in HR+/HER2- MBC

Joyce O’Shaughnessy, MD: Let’s go on to another pathway that we often turn to upon progression on CDK4/6 inhibitors, of course, the PI3 kinase pathway. We have 2 inhibitors, we’ve got alpelisib, we have everolimus. First of all, let’s start with a little bit of an overview of the pathway and what’s going on in that pathway, what targets do we have? Maybe you could start us off with that, Sarah.

Sarah Sammons, MD: The PI3 kinase pathway is probably the most studied signaling pathway in hormone receptor-positive [HR+]/HER2- breast cancers. It’s implicated in cell survival, proliferation, cell differentiation, angiogenesis. It really plays a key role in metastatic progression. What we’ve learned over time is that it also plays a key role in endocrine therapy resistance. We have several studies that implicate this pathway in patients developing resistance to endocrine therapies over time. We also have studies that tell us that patients with PI3 kinase-mutated hormone receptor-positive breast cancer have worse overall survival. Those patients also respond less well to chemotherapies. Given the negative prognostic and predictive implications of this mutation, naturally, it was studied. In preclinical studies it looked like in endocrine-resistant populations that by suppressing this PI3 kinase pathway, you could essentially suppress tumor growth. That’s where the class of drugs called PI3 kinase inhibitors came about. About 40% of patients with hormone receptor-positive breast cancer will have these alterations. They seem to be an early event that’s present in most early stage disease. Not a lot of them seem to evolve over time. A small subset, like you mentioned, maybe about 10%, do evolve over time on endocrine therapy.

Joyce O’Shaughnessy, MD: That’s right. Which number did you use? What percentage of patients have the PIK3CA mutations would you estimate?

Sarah Sammons, MD: I would say about 40%, most of the studies show.

Joyce O’Shaughnessy, MD: Yes. Pretty high.

Sarah Sammons, MD: Yes.

Joyce O’Shaughnessy, MD: Very high. Mostly truncal, but I remember the PALOMA-3 data, that was the fulvestrant plus/minus palbociclib, looking at baseline ctDNA [circulating tumor DNA] before they started either fulvestrant alone or fulvestrant plus palbociclib. Then upon progression, about 10% of patients, regardless of the arm, fulvestrant with or without the palbociclib, had a new PIK3CA mutation. It may have been in the tissue, but it was new in the circulation basically, so you can find them. You can find them upon progression on CDK4/6 inhibitors. As we mentioned earlier, it’s important to look for them everywhere: in the blood, in the tissue, in the metastatic biopsy, in the progressing blood. Just keep looking for them, for the appropriate patients.

Sarah Sammons, MD: Right. As you mentioned, in SOLAR-1, the registration alpelisib trial, 50% of patients who did not have the PI3 kinase mutation in the circulation did have it in the tumor. It’s important to reflex back.

Joyce O’Shaughnessy, MD: Yes. Excellent. Thanks for putting the numbers to that.

Transcript edited for clarity.