Predicting hyperglycemia among patients receiving alpelisib plus fulvestrant for metastatic breast cancer.

Abstract

1060 Background: Although hyperglycemia is recognized as a common adverse event (AE) on alpelisib (ALP), this AE has been little studied outside clinical trials. We report the frequency of ALP-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. Methods: We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with ALP+fulvestrant (FUL) between August 2019 and December 2021. Five primary characteristics (diabetes, prediabetes, body mass index (BMI), age, Asian ancestry) were evaluated as independent risk factors for ALP-associated hyperglycemia using ordinal logistic regression that considered 3 glycemic levels: normoglycemia, grade 2, and grade 3-4 hyperglycemia. Overall risk of error from multiple hypothesis testing was kept below 5% using the False Discovery Rate method. Results: The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years, 13.0% with Asian ancestry. One third (33.7%) of patients had pre-existing diabetes, another 9.8% had pre-diabetes only. One third (32.6%) were obese, another third (31.5%) were overweight. Hypertension and hyperlipidemia were present in 53.3% and 41.3%, respectively. On ALP+FUL, 59 (64.1%) current subjects developed hyperglycemia of grade 1-4, a rate no different than the 181/284 (63.7%) reported in the ALP+FUL arm of the SOLAR-1 trial. Among our subjects, risk of grade 2-4 hyperglycemia was independently increased by 4 of 5 hypothesized risk factors, specifically pre-existing diabetes (Odds Ratio 3.75, 95% Confidence Interval: 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), each unit of BMI above 20 (1.17, 1.07-1.28), but not by additional year of age (1.01, 0.97-1.05). Exploratory analysis detected no association with pre-existing hypertension or hyperlipidemia. Conclusions: These findings suggest that Asian ancestry merits further study as a predisposing factor for ALP-associated hyperglycemia. Our study of this AE also demonstrates that pre-existing hyperglycemia and greater BMI are independent risk factors; diabetes and pre-diabetes confer similar degrees of risk; risk from BMI begins after BMI 20 and rises incrementally; and age is not a contributing factor.

The Challenges of Treating Patients with Breast Cancer and Obesity

“…One retrospective study of 27 patients with metastatic PIK3CA-mutated breast cancer treated with alpelisib showed no difference in response to alpelisib according to BMI (p = 0.966), although the study was limited by the small sample size [112]. Other studies have shown that patients with increased BMI, pre-existing hyperglycemia, and prediabetes/diabetes are at increased risk of alpelisib-induced hyperglycemia [113,114]. Management strategies have been proposed to prevent and treat alpelisib-induced hyperglycemia, including counseling on healthy lifestyle behaviors, optimization of blood glucose prior to alpelisib treatment, and treatment with anti-hyperglycemia agents [111].…”

Amino acids and their roles in tumor immunotherapy of breast cancer

“…In addition, the function of macropinocytosis can provide amino acids to breast cancer cells by degrading proteins, which supports their survival and proliferation 105 . Two PI3K inhibitors in clinical trials, BKM120 106 and ZSTK474, and a US Food and Drug Administration‐approved drug, Alpelisib, 107,108 have been reported to suppress macropinocytosis. BKM120 completed a phase III clinical trial for breast cancer (NCT01610284).…”