Data from Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor–Positive Advanced Breast Cancer (EVERMET)
Authors: Vernieri Claudio , Nichetti Federico , Lalli Luca , Moscetti Luca , Giorgi Carlo Alberto , Griguolo Gaia , Marra Antonio , Randon Giovanni , Rea Carmen G. , Ligorio Francesca , Scagnoli Simone , De Angelis Claudia , Molinelli Chiara , Fabbri Agnese , Ferraro Emanuela , Trapani Dario , Milani Andrea , Agostinetto Elisa , Bernocchi Ottavia , Catania Giovanna , Vantaggiato Amelia , Palleschi Michela , Moretti Anna , Basile Debora , Cinausero Marika , Ajazi Arta , Castagnoli Lorenzo , Lo Vullo Salvatore , Gerratana Lorenzo , Puglisi Fabio , La Verde Nicla , Arpino Grazia , Rocca Andrea , Ciccarese Mariangela , Pedersini Rebecca , Fabi Alessandra , Generali Daniele , Losurdo Agnese , Montemurro Filippo , Curigliano Giuseppe , Del Mastro Lucia , Michelotti Andrea , Cortesi Enrico , Guarneri Valentina , Pruneri Giancarlo , Mariani Luigi , de Braud Filippo 
Published: April 2023

<div>AbstractPurpose:<p>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<sup>+</sup>), HER2-negative (HER2<sup>−</sup>), advanced breast cancer (HR<sup>+</sup>/HER2<sup>−</sup> 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.</p>Experimental Design:<p>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<sup>+</sup>/HER2<sup>−</sup> aBC treated with everolimus-exemestane.</p>Results:<p>We evaluated 809 patients with HR<sup>+</sup>/HER2<sup>−</sup> 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; <i>P</i> = 0.008).</p>Conclusions:<p>The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR<sup>+</sup>/HER2<sup>−</sup> 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<sup>+</sup>/HER2<sup>−</sup> aBC.</p></div>