Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer

Abstract

Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

Keywords: PIK3CA-mutated metastatic breast cancer; adverse effect; alpelisib; hyperglycemia.

Figure 1

PI3K inhibitors prevent the conversion of PIP2 to PIP3 and the activation of AKT through phosphorylation by PIP3. Blockade of the metabolic effects of AKT leads to (1) transient insulin resistance due to lack of translocation of the glucose transporter GLU4 from cytoplasmic vesicles to the cell membrane, and therefore lack of passage of glucose molecules into the liver, fat, and muscle cells, as well as (2) increased glycogenolysis in the liver. In turn, both (1) and (2) lead to hyperglycemia, as well as increased insulin release by the pancreas with ensuing hyperinsulinemia. AKT, protein kinase B; GLU4, glucose transporter 4; IRS1p, insulin receptor substrate 1, phosphorylated; PI3K, phosphatidylinositol 3-kinase PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate.

Figure 2

Changes in mean FPG over time according to glycemic status in patients with hormone receptor-positive breast cancer receiving alpelisib plus fulvestrant in the SOLAR-1 trial. Adapted with permission from Ref. [17], Copyright 2020 Elsevier. ^a FPG > 7.0 mmol/L (>126 mg/dL) and/or HbA1c > 6.5%; ^b FPG 5.6 to <7.0 mmol/L (100 to <126 mg/dL) and/or HbA1c 5.7 to <6.5%; ^c FPG < 5.6 mmol/L (<100 mg/dL) and HbA1c < 5.7%. FPG: fasting plasma glucose; HbA1c: glycated hemoglobin.

Figure 3

Algorithm for the monitoring and management of alpelisib-induced hyperglycemia. If positive for ketones, discontinue oral agents, and start insulin and intravenous hydration. BG: blood glucose; BMI: body mass index; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; hrs: hours; IV: intravenous; MTD: maximum tolerated dose; SGLT2: sodium–glucose co-transporter 2.