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.

Impact of baseline and on-treatment glycemia on everolimus-exemestane efficacy in patients with hormone receptor-positive advanced breast cancer (EVERMET) / C. Vernieri, F. Nichetti, L. Lalli, L. Moscetti, C.A. Giorgi, G. Griguolo, A. Marra, G. Randon, C.G. Rea, F. Ligorio, S. Scagnoli, C. De Angelis, C. Molinelli, A. Fabbri, E. Ferraro, D. Trapani, A. Milani, E. Agostinetto, O. Bernocchi, G. Catania, A. Vantaggiato, M. Palleschi, A. Moretti, D. Basile, M. Cinausero, A. Ajazi, L. Castagnoli, S. Lo Vullo, L. Gerratana, F. Puglisi, N. La Verde, G. Arpino, A. Rocca, M. Ciccarese, R. Pedersini, A. Fabi, D. Generali, A. Losurdo, F. Montemurro, G. Curigliano, L. Del Mastro, A. Michelotti, E. Cortesi, V. Guarneri, G. Pruneri, L. Mariani, F. de Braud. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - (2021). [Epub ahead of print]

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

C. Vernieri
Primo
;
F. Nichetti
Secondo
;
A. Marra;G. Randon;F. Ligorio;E. Ferraro;D. Trapani;A. Milani;O. Bernocchi;A. Ajazi;D. Generali;A. Losurdo;G. Curigliano
Conceptualization
;
G. Pruneri;L. Mariani;F. de Braud
2021

Abstract

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.
Settore MED/06 - Oncologia Medica
30-mar-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/830163
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