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 on-treatment (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 PI'S. 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 1557-3265. - 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)
Scagnoli S.;Palleschi M.;Cortesi E.;
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 on-treatment (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 PI'S. 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.| File | Dimensione | Formato | |
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