Endocrine Abstracts

JOINT2307

Introduction: Alpelisib is an emerging treatment for advanced breast cancer. It promotes α-selective phosphatidylinositol 3-kinase (PI3K) inhibition, which impairs insulin action and promotes hepatic glycogenolysis, leading to hyperglycemia and compensatory insulin release. Hyperglycemia has an early onset (median 2 weeks) and has been reported in 60% of the patients, with 28% facing moderate (fasting plasma glucose >250-500 mg/dL) and severe (>500 mg/dL) hyperglycemia. Alpelisib’s short half-life (8–9 hours) facilitates glucose normalization within 24–72 hours after interruption. We present two cases of severe hyperglycemia associated with alpelisib in metastatic breast cancer patients.

Clinical Cases: Patient 1, a 71-year-old woman with ER-positive, HER2-negative breast cancer submitted to bilateral mastectomy and hormone therapy. Bone metastasis appeared 28 years after the diagnosis and did not respond to multiple therapeutic regimens. Patient 2, a 44-year-old woman with the same breast cancer subtype, underwent neoadjuvant chemotherapy, left mastectomy and hormone therapy. Widespread metastasis developed 4 years later, unresponsive to 6 lines of chemotherapy. Both patients had PIK3CA mutations and started alpelisib (300 mg/day). Neither had previous diabetes (HbA1c 5, 4% and 5, 1%) and the BMIs were 35. 2 kg/m² and 23. 1 kg/m², respectively. Asymptomatic severe hyperglycemia (glucose 525 mg/dL and 552 mg/dL) occurred within 2 weeks (Patient 1) and 1 month (Patient 2) after initiating treatment. In both cases, metformin (850 mg twice daily) was initiated and alpelisib was stopped. Fasting glucose normalized within 72 hours, allowing alpelisib (200 mg/day) resumption 1 week after. Both patients experienced recurrent hyperglycemia, requiring basal insulin (10 IU/day). Patient 1 needed no further treatment, while Patient 2 had to increase basal insulin up to 18 IU/day and start prandial insulin for glycemic control. Despite initial control, alpelisib was discontinued within 4 months in patient 1 and 1 month in patient 2 due to disease progression. After stopping alpelisib blood glucose levels normalized in the next 24 hours and both patients could halt anti-diabetic drugs.

Conclusions: The anticipated expansion of alpelisib use will probably result in a significant rise of secondary hyperglycemia cases. Delayed diagnosis can affect metabolic control, potentially leading to alpelisib dose reduction or discontinuation and compromising efficacy and patient survival. The rapid onset of severe asymptomatic hyperglycemia may warrant regular glucose monitoring in patients initiating this treatment.