Evolving Concepts in Treatment for Advanced Breast Cancer - Episode 5
Joyce A. O’Shaughnessy, MD: What about the implications with alpelisib for our need to find patients who have PIK3CA mutations?
Debu Tripathy, MD: We’re going to need to know their status now. In fact, I think it’s important to know it when they’re on first-line therapy. There’s a lot of interest now in doing this less invasively with liquid biopsies. The data from earlier trials—the BELLE-2 and BELLE-3 trials, also with PI3-kinase inhibition—have shown that both tissue-based and blood-based biopsies are reasonably close, with 80% concordance. I think that we will be needing to investigate this. Right now, Medicare is debating and has an open discussion period as to whether this should be covered. This is going to be necessary information to have for our patients to make decisions going forward.
Erika P. Hamilton, MD: I’ll pipe in here. I think everyone knows that I’m quite a proponent of molecular profiling for tumors. As a phase I investigator, it kind of comes with the territory. I echo that, and it’s not important just for PI3. We know about ESR1 [estrogen receptor 1], and we know if you have an ESR1 mutation, that predicts lack of response to exemestane/everolimus, and you would be much more interested in fulvestrant or some of the novel SERDs [selective estrogen receptor degraders] that are coming. I think it’s really going to be a paradigm shift. We’re either going to have to be biopsying these patients or at least doing blood testing. That helps us determine which pathway to go down after the first-line setting. I think it definitely has implications for practice.
Debu Tripathy, MD: I should clarify, since we didn’t say it earlier, but the SOLAR-1 trial was specifically for patients with PI3-kinase mutations. In fact, they had a separate cohort that was PI3-kinase wild type and they did not benefit.
Joyce A. O’Shaughnessy, MD: It really has to be PIK3CA-mutated. Do you think that will be our algorithm when patients are progressing on CDK4/6 [cyclin-dependent kinases 4 and 6]? I think in the PALOMA-3, upon progression, there were 10% of patients who had PIK3CA in both arms that had not been there in ctDNA [circulating tumor DNA] at baseline. Maybe right when patients are progressing on CDK4/6, we could send a liquid biopsy. I suppose if we don’t find it there, we would go back to the primary breast cancer, because mostly, this is a truncal mutation. Although it can be acquired, it’s mostly truncal. It’s there from the beginning in most patients, right? Do you think it’s going to be our natural algorithm to go on to alpelisib for patients who are progressing on CDK?
Sara A. Hurvitz, MD: I think so. I’m compelled by the data. It’s a very strong signal, and I agree wholeheartedly with you that we should try to get a biopsy, preferably liquid, at the time of progression, because there is some tumor evolution that occurs, and then reflex to tissue. I think the concordance they saw on the SOLAR-1 trial between liquid and tissue biopsies is very encouraging and reassuring. You can reasonably rely on it. The toxicity is going to be a learning curve for clinicians again in learning how to follow FPG [fasting plasma glucose] and HbA1c [hemoglobin A1c] every 3 months, and then utilizing drugs like metformin…and reading. I know you have been reading about the interaction between the insulin and PI3-kinase pathways, and that really impacts our choice of hypoglycemic agents that we’re going to be utilizing a lot more, given that one-third of patients will have grade 3/4 hyperglycemia on these medications.
Joyce A. O’Shaughnessy, MD: SOLAR-1 restricted eligibility to those who had less than 6.5 hemoglobin A1c, and that’s very important. I can attest to that from my own experience. We’ve got to be very careful. We will end up relaxing that a little bit in practice, but we have to make sure that our patients with pre-diabetes are well-controlled before we start. Interestingly, the package insert actually contains the metformin data because of the experience in SOLAR-1. It also contains the use of a non-drowsy antihistamine to prevent the rash. I use it BID [twice a day], but I think there’s enough anecdotal evidence about that. There was some study of that in patients on the SOLAR-1. For diarrhea, I’ve been using some of the dexamethasone steroid mouth rinse as short-term prophylaxis, just like everolimus.
Not exactly a ketogenic diet, but a low-carb diet, is actually very effective, preclinically, in terms of increasing the effectiveness of the PI3-kinase inhibitor, which indicates 100 g or fewer per day of carbohydrates. The average American diet includes 150 g to 200 g, so lower-carb is about 100 g or less. I think that will be really important for our women. I think it’s going to be fun. It’s good, and I can’t wait to use it and see some liver metastasis improve.
Transcript Edited for Clarity