PI3K Therapy for HR+/HER2- MBC: Metabolic Syndrome

Joyce O’Shaughnessy, MD: It sounds to me that as a community, we’re doing with alpelisib what we’ve done in many other agents that have toxicity. We’re figuring it out. When you’ve got the efficacy, we’re good at this. We try this, we try that, we work with the patients better education, etc. We’re getting there. I know I am. I’ve come a long way in my management with this agent. We all start at ground zero.

I want to emphasize a couple of things in my own practice. Prevention makes a big difference. I made the mistake of trying to fudge on the hemoglobin A1C. I allowed somebody 6.5% or above. It doesn’t work. They’ve got to have hemoglobin A1C 6.4% or lower. That was my first learning lesson. That has to be. I told them to get the glucose monitors. They’re very cheap. Just take them. Do fasting at home, write it down, then do it before breakfast, do it for a few days. Do it before lunch or before dinner, and write it down. If you get above 160 mg/dl , you call. And we get you on some metformin. We start low and work our way up.”

Rarely, I’ve had to go to a second agent. I use the SGLT2 inhibitors because they also lower insulin. Anything that lowers insulin is a good thing so we don’t drive that pathway. It’s all in the first 2 to 3 weeks. If they don’t have hyperglycemia, it’s all in the first 3 weeks. After that, it’s a steady state. But I tell the patients, “Make sure you’re eating a low carb diet. Don’t eat a lot of sugar and carbs. Don’t do it.” That makes a huge difference.

Then the rash. If you wait for the rash, it’s too late. You have to prevent the rash. I use the twice-a-day non-drowsy antihistamine. The package insert says once a day because they have data that you reduce the rash with even a once-a-day non-drowsy antihistamine. I use it twice a day because I want to be sure I get on top of that. That helps because once they’ve got a bad rash, the non-drowsy antihistamines don’t work that well.

The other thing is, women tend to lose weight on full-dose alpelisib, the 300 mg. I’ve got a number of women on this for a long time. They tend to be ladies who have been serially sensitive to things, like prior endocrine therapy. Some of these women got alpelisib later line because it came available to them. They already had some chemotherapy, but they benefit too. It’s the patients who have been serially sensitive to things getting a long-term benefit. For the women, it’s helpful for some of them to lose weight. It helps manage their hyperglycemia, but then I usually have to reduce the dose. If they’re continuing to lose a lot of weight, they’ve got to get down to 250 pounds. I don’t lose the efficacy and they stop losing weight.

Those are some of the things. I’ve had the greatest success, in terms of patient selection, with patients who’ve been doing well with other therapies. It’s not the galloping liver disease, for example. I haven’t seen the benefit there, but I’m getting it. I’m getting the hang of how to choose the patients for it and how to manage and prevent some of the toxicities.

Neil M. Iyengar, MD: Joyce, the points you make about managing hyperglycemia and insulin are really important because we know that this is important overall for patients with metastatic ER [estrogen receptor]–positive breast cancer, and that metabolic dysfunction can contribute to worse prognosis. This is critical. The point you made about managing patients early and optimizing their A1C is important because we have to remember that SOLAR-1 was amended to tighten the hemoglobin A1C inclusion criteria to 6.5%.

I’ll go back to the comment that I made at the beginning, that I like to know this information up front. If we’re going to use alpelisib in the second-line setting, then we have ample time to start following that A1C, to start optimizing their lifestyle, to get a nutritionist involved, and so forth. It’s worth it because ultimately when you drive down that insulin, you may be enhancing efficacy of the drug.

Joyce O’Shaughnessy, MD: Thanks, Neil. I’m glad to hear from all you guys and about all the trials you’re involved with because this is going to be important. We’re going to get more clear algorithms we can use about how to manage these toxicities, prevent them, etc. There’s lot of good research going on.

Transcript edited for clarity.