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

Claudio Vernieri, Federico Nichetti, Luca Lalli, Luca Moscetti, Carlo Alberto Giorgi, Gaia Griguolo, Antonio Marra, Giovanni Randon, Carmen G. Rea, Francesca Ligorio, Simone Scagnoli, Claudia De Angelis, Chiara Molinelli, Agnese Fabbri, Emanuela Ferraro, Dario Trapani, Andrea Milani, Elisa Agostinetto, Ottavia Bernocchi, Giovanna CataniaAmelia Vantaggiato, Michela Palleschi, Anna Moretti, Debora Basile, Marika Cinausero, Arta Ajazi, Lorenzo Castagnoli, Salvatore Lo Vullo, Lorenzo Gerratana, Fabio Puglisi, Nicla La Verde, Grazia Arpino, Andrea Rocca, Mariangela Ciccarese, Rebecca Pedersini, Alessandra Fabi, Daniele Generali, Agnese Losurdo, Filippo Montemurro, Giuseppe Curigliano, Lucia Del Mastro, Andrea Michelotti, Enrico Cortesi, Valentina Guarneri, Giancarlo Pruneri, Luigi Mariani, Filippo De Braud

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3443-3455
Number of pages13
JournalClinical Cancer Research
Issue number12
Publication statusPublished - Jun 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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