Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor–Positive Advanced Breast Cancer (EVERMET)

Abstract

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.

Everolimus plus aromatase inhibitors as maintenance therapy after first-line chemotherapy: Final results of the phase III randomised MAIN-A (MAINtenance Afinitor) trial

“…Anyway, in an exploratory analysis, we found no PFS differences in patients presenting with stage IV versus relapsing disease, overall and per treatment arm (data not shown). Recent data from Vernieri et al [24] have demonstrated an impact of on-treatment glycaemia on everolimus efficacy In our study, very few patients experienced hyperglycaemia, not allowing for statistical analysis.…”

Effect of Concomitant Drug Use on the Onset and Exacerbation of Diabetes Mellitus in Everolimus-Treated Cancer

“…Thus, it is possible that the effects of inter-individual variability and concomitant drug treatment on hyperglycemia are more pronounced in patients who are not taking DM drugs than in patients who are taking them. In fact, Vernieri et al (21) recently reported that patients who are normoglycemic at baseline and experience treatment-induced DM have lower progression-free survival than patients who are already hyperglycemic at baseline and experience breast cancer treatment-induced DM. Therefore, in the absence of concomitant DM drug treatment, these patterns suggest that patients who develop DM early in treatment may have poor DM outcomes and require prompt treatment, especially considering that everolimus-induced hyperglycemia can also induce drug resistance in cancer cells (14).…”

Nutritional Metabolomics in Diet–Breast Cancer Relations: Current Research, Challenges, and Future Directions—A Review

“…Metabolites of fat (e.g., Palmitic acid) CD36 [199,203] Metabolites of protein (e.g., Insulin-like growth factor 1) IGF-1 Receptor [204] Metabolites of carbohydrate (e.g., Glucose) Hexokinase 2 (HK2) [205] Hormone receptor-negative (HR-) Piperine HER2 [13,135,184] Metabolite of alcohol (e.g., Acetaldehyde) Estrogen Receptor (ER) [206] 2-amino-4-cyano butanoic Aromatase [107] Alpha-Tocopherol HER2 [190] Metabolites of fat (e.g., Palmitic acid) CD36 [207] Metabolites of protein (e.g., Insulin-like growth factor 1) IGF-1 Receptor [201] Metabolites of carbohydrate (e.g., Glucose) Hexokinase 2 (HK2) [208]…”