Purpose: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor - positive (HR+), HER2-negative (HER2-), advanced breast cancer (HR+/ HER2- aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. Experimental Design: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and ontreatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2- aBC treated with everolimus-exemestane. Results: We evaluated 809 patients with HR+/HER2- aBC treated with everolimus-exemestane 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 with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15- 2.69; P = 0.008). Conclusions: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/ HER2- aBC 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 patients with HR+/HER2- aBC.
Impact of baseline and on-treatment glycemia on everolimus-exemestane efficacy in patients with hormone receptor-positive advanced breast cancer (EVERMET) / Vernieri C.; Nichetti F.; Lalli L.; Moscetti L.; Giorgi C.A.; Griguolo G.; Marra A.; Randon G.; Rea C.G.; Ligorio F.; Scagnoli S.; De Angelis C.; Molinelli C.; Fabbri A.; Ferraro E.; Trapani D.; Milani A.; Agostinetto E.; Bernocchi O.; Catania G.; Vantaggiato A.; Palleschi M.; Moretti A.; Basile D.; Cinausero M.; Ajazi A.; Castagnoli L.; Vullo S.L.; Gerratana L.; Puglisi F.; La Verde N.; Arpino G.; Rocca A.; Ciccarese M.; Pedersini R.; Fabi A.; Generali D.; Losurdo A.; Montemurro F.; Curigliano G.; Del Mastro L.; Michelotti A.; Cortesi E.; Guarneri V.; Pruneri G.; Mariani L.; De Braud F.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - ELETTRONICO. - 27:12(2021), pp. 3443-3455. [10.1158/1078-0432.CCR-20-4928]
Impact of baseline and on-treatment glycemia on everolimus-exemestane efficacy in patients with hormone receptor-positive advanced breast cancer (EVERMET)
Palleschi M.;
2021
Abstract
Purpose: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor - positive (HR+), HER2-negative (HER2-), advanced breast cancer (HR+/ HER2- aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. Experimental Design: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and ontreatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2- aBC treated with everolimus-exemestane. Results: We evaluated 809 patients with HR+/HER2- aBC treated with everolimus-exemestane 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 with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15- 2.69; P = 0.008). Conclusions: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/ HER2- aBC 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 patients with HR+/HER2- aBC.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
