Impact of baseline and on-treatment glycemia on everolimus-exemestane efficacy in patients with hormone receptor-positive advanced breast cancer (EVERMET)

Purpose: The mTORC1 inhibitor everolimus (EVE) in combination with the aromatase inhibitor exemestane (EXE) is an effective treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer (HR+/HER2- aBC). However, EVE can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/AKT/mTORC1 pathway and induce tumor resistance to EVE. Experimental design: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first three months of therapy) blood glucose levels on progression-free survival (PFS) in HR+/HER2- aBC patients treated with EVE-EXE. Results: We evaluated 809 HR+/HER2- aBC patients treated with EVE-EXE as any-line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared to patients who are already hyperglycemic at baseline and experience diabetes during EVE-EXE therapy (mPFS 6.34 vs. 10.32 months; HR 1.76; 95% CI 1.15-2.69; p=0.008). Conclusions: The impact of on-treatment glycemia on the efficacy of EVE-EXE therapy in HR+/HER2 aBC patients depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in HR+/HER2 aBC patients.