Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane

Background: Treating breast cancer patients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. Objective: We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. Patients and Methods: We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [¹⁸F]fluorodeoxyglucose-positron emission tomography (¹⁸F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). Results: Among 44 evaluable patients, the geometric mean (GM) C_trough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 μg/L (p = 0.02)). The optimal cut-off value to predict toxicity was C_trough > 19.2 μg/L. GM C_trough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 μg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SUL_{peak high}) at day 14. Patients with <11% versus >11% decrease in SUL_{peak high} at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. Conclusions: Our results show that everolimus toxicity is related to everolimus C_trough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.