Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer

Purpose: The combination of fulvestrant with alpelisib, a PI3K inhibitor, improves progression-free survival in metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. This study describes the incidence, risk factors, and treatment of alpelisib-associated hyperglycemia.

Methods: Patients with metastatic breast cancer who received alpelisib from 2013 to 2021 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Alpelisib prescription dates and patient/tumor characteristics were abstracted from medical records. Risk factors associated with hyperglycemia and alpelisib dose reduction/discontinuation were evaluated using Pearson's χ² tests.

Results: Among 247 patients, baseline median body mass index was 25.4 kg/m² and median hemoglobin A1c (HbA1c) was 5.5%. A total of 152 patients (61.5%) developed any-grade hyperglycemia and 72 patients (29.2%) developed grade 3-4 hyperglycemia; median time to onset was 16 days. A total of 100 patients (40.5%) received alpelisib on a clinical trial; rates of hyperglycemia were significantly higher in patients treated as standard care versus on a clinical trial (any-grade hyperglycemia 80.3% vs. 34.0%, grade 3-4 hyperglycemia 40.2% vs. 13.0%, p < .001). Baseline HbA1c was significantly associated with development of hyperglycemia (p < .001) and alpelisib dose reduction/discontinuation (p = .015). Among those who developed hyperglycemia, 101 (40.9%) received treatment, most commonly with metformin. A total of 49 patients (19.8%) were referred to an endocrinologist, which was associated with SGLT2 inhibitor prescription (p = .007).

Conclusions: Rates of hyperglycemia among patients treated with alpelisib as standard care were significantly higher than patients treated on clinical trials. Elevated baseline HbA1c is associated with alpelisib-induced hyperglycemia and requiring dose modification. Optimization of glycemic status before alpelisib initiation should become routine practice.