Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer – A Real-Life Experience

Abstract

PIK3CA activating mutations are found in 40% of advanced breast cancer and are associated with worse prognosis. PI3K blockage is associated with insulin resistance, leading to hyperglycemia and hyperinsulinemia. Alpelisib is the first PI3K inhibitor used in cancer treatment. Laboratory evidence indicated that alpelisib-induced hyperinsulinemia offsets the drug’s efficacy, but insulin levels were not tested in the clinical trials that evaluated alpelisib for breast cancer. Hyperglycemia could also interfere with anti-tumor effects of PI3K inhibitors by inducing Immune tolerance and altered mitochondrial metabolism. We have monitored insulin levels in 4 breast cancer patients with concomitant metabolic syndrome treated with alpelisib, and pre-treated patients with baseline increased insulin levels with pioglitazone, a potent insulin sensitizer, to target both hyperinsulinemia and hyperglycemia, and we report the treatment course of these patients. All patients achieved glycemic control and were able to maintain alpelisib dose intensity. Duration of response to alpelisib was longer than anticipated in this treatment setting. Insulin dynamics confirmed the efficacy of pioglitazone as a specific on-target hypoglycemic and hypo-insulinemic agent in the unique setting of PI3K blockade. Our experience suggests that targeting hyperinsulinemia in patients with is safe and feasible and results in good metabolic and oncologic outcomes.

Keywords:

• alpelisib
• hyperglycemia
• insulin
• pioglitazone
• hyperinsulinemia
• diabetes mellitus

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from Dr. Ruth Percik on reasonable request.

Ethics Approval

The protocol was approved by the Sheba Medical Center Institutional Review Board (SMC-21-8549) and by the Galilee Medical Center Institutional Review Board (NHR-21-0135). Patients gave their informed consent to publication of the cases.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Dr Ayelet Shai reports personal fees from Novartis, during the conduct of the study; personal fees from Pfizer, outside the submitted work. The authors declare that they have no other competing interests.

Additional information

Funding

This study was carried out without funding.