Abstract P2-08-20: Risk of everolimus- and alpelisib-induced hyperglycemia in obese and non-obese breast cancer patients with or without pre-existing hyperglycemia
Authors: Xu Bing , Messiner Tobias , Williams Casey 
Published: March 2022

Abstract
Purpose:. Breast cancer is a common malignancy among women. About one in eight women in the US will be diagnosed with breast cancer during their lifetime. One of the most commonly altered genetic pathways in breast cancer patients is the PI3K/AKT/mTOR pathway. Among patients treated with everolimus and alpelisib, hyperglycemia is a frequently encountered adverse event. The cause of hyperglycemia is believed to be the inhibition of PI3K/mTOR, which not only plays a role in oncogenesis but also regulates glucose transportation and glycogen synthesis. Inhibition of PI3K/mTOR activity from treatment results in decreased insulin secretion and hyperglycemia. Obesity is a risk factor for both breast cancer and hyperglycemia. Over 70% of breast cancer patients seen in our center are overweight or obese. Being obese alone increases a patient’s risk of developing insulin resistance and hyperglycemia. Little research has been done on whether obese breast cancer patients are at higher risk of treatment induced hyperglycemia. The purpose of this study was to test whether obesity and pre-existing hyperglycemia are risk factors that increase the patients’ chance to develop hyperglycemia while being treated with anti-PI3K/mTOR drugs. Methods:. A retrospective study was performed on 119 breast cancer patients at Avera Cancer Institute. Female patients who had been treated with everolimus and/or alpelisib were included. According to the CDC standard, patients with body mass index (BMI) greater than 25 kg/m2 were considered as obese. Grade 2 and above hyperglycemia was defined as fasting blood glucose level greater than 160 mg/dl per CTCAE. Baseline blood glucose levels prior anti-PI3K/mTOR treatment were considered high if greater than 140 mg/dl per the American Diabetes Association. Results:. Of the 119 patients, 78 were ER+/HER2-; 22 were triple negative; 12 were ER-/HER2+ and 7 were ER+/HER2+. The BMI ranged from 17.79 to 52.87 (94 obese patients). Patients were kept on everolimus/alpelisib from 14 days to 5 years (median = 6 month). After starting everolimus/alpelisib, 17 patients developed hyperglycemia Grade 2 or greater, 16 of whom were obese. Being obese increased the odds of developing hyperglycemia under anti-PI3K/mTOR treatment by 4.58, However, this increase was not significant (p=0.16). Hyperglycemia in most patients was controlled by diet and lifestyle changes. Four patients (all obese) needed either insulin, metformin, DPP-4 and/or SGLT2 inhibitors to control blood glucose levels. Three patients had type 2 diabetes prior to therapy. The fourth patient developed Grade 3 hyperglycemia (&gt;250 mg/dl) nine month after starting everolimus and was put on insulin for two months, with blood glucose returning back to normal. Everolimus was continued for another three month without causing hyperglycemia in this patient. Our data suggests that baseline blood glucose levels play a significant role in developing high grade hyperglycemia under anti-PI3K/mTOR treatment. The odds of developing hyperglycemia increase by a factor of 5.38 in patients with high blood glucose prior treatment (p= 0.007). Conclusion:. Being obese does not alone present a significantly higher risk of developing high grade hyperglycemia while being treated with anti-PI3K/mTOR drugs compared to non-obese patients if their blood glucose is well controlled. Most patients can manage their blood glucose level by diet and lifestyle changes. Patients starting anti-PI3K/mTOR treatment with high blood glucose level at baseline are at a much higher risk of developing drug-induced hyperglycemia and should be closely monitored.
Citation Format: Bing Xu, Tobias Messiner, Casey Williams. Risk of everolimus- and alpelisib-induced hyperglycemia in obese and non-obese breast cancer patients with or without pre-existing hyperglycemia [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-20.