Abstract 339P
Background
The mTORC1 inhibitor everolimus (EVE) in combination with the aromatase inhibitor exemestane (EXE) is effective in patients (pts) with hormone receptor-positive (HR+) human epidermal growth factor receptor-negative (HER2-) advanced breast cancer (aBC). However, EVE-induced hyperglycemia and hyperinsulinemia could reactivate the PI3K/AKT/mTORC1 pathway, thus reducing EVE-EXE efficacy.
Methods
EVERMET is a retrospective, multicenter, Italian study that investigated the impact of baseline and on-treatment glycemia, as evaluated during the first 3 months (mos) of therapy, on progression-free survival (PFS) of HR+ HER2- aBC pts treated with EVE-EXE. We first used a machine-learning approach through a Random Forest method to exclude prognostically irrelevant variables. Then, we fitted a Cox proportional hazard model to assess the independent impact of baseline and on-treatment glycemia on PFS.
Results
Out of 848 pts evaluated, 809 pts fulfilled the inclusion criteria. All pts had previously received letrozole/anastrozole. With a median follow-up of 37.4 mos, median PFS and overall survival (OS) were 7.13 and 32.1 mos, respectively. Blood glucose levels significantly increased during the first three months of treatment (p<0.0001). At multivariable analysis, baseline and on-treatment glycemia were independently associated with PFS, and their impact on clinical outcomes was characterized by a significant interaction (p<0.0001). In particular, pts with low baseline glycemia (<95 mg/dl, 10th quantile) who experienced on-treatment diabetes (≥126 mg/dl, 90th quantile) had significantly lower PFS (mPFS: 4.14 mos) when compared to pts who were hyperglycemic (≥95 mg/dl) at baseline but did not develop diabetes (mPFS: 8.15 mos), or to pts with stably low or high glycemia (mPFS: 7.13 mos) (p=0.0002).
Conclusions
EVE-induced diabetes is associated with lower antitumor efficacy of EVE-EXE in HR+ HER2- aBC pts with normal baseline glycemia. While these data need prospective validation, dietary/pharmacological interventions to prevent or reverse EVE-induced hyperglycemia or diabetes should be investigated with the aim of improving EVE-EXE efficacy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Fondazione IRCCS Istituto Nazionale dei Tumori.
Funding
Has not received any funding.
Disclosure
L. Del Mastro: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Advisory/Consultancy: Pfeizer; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Ipsen. N.M. La Verde: Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Gentili; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Eli Lilly; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Eisai. F. Puglisi: Honoraria (self): Amgen; Honoraria (self): MSD; Honoraria (self): Takeda; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Novartis; Research grant/Funding (self): EISAI; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Pfizer; Travel/Accommodation/Expenses: Celgene; Research grant/Funding (self): AstraZeneca. F. de Braud: Advisory/Consultancy: Tiziana Life Sciences; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy: Novartis; Advisory/Consultancy: Servier; Advisory/Consultancy: Pharm Research Associated; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony: Ignyta; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Pfizer; Advisory/Consultancy: Octimet Oncology; Advisory/Consultancy, Research grant/Funding (self): Incyte; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Gentili; Advisory/Consultancy, Speaker Bureau/Expert testimony: Dephaforum; Advisory/Consultancy: MSD; Advisory/Consultancy: Bayer; Advisory/Consultancy: Fondazione Menarini; Speaker Bureau/Expert testimony: Biotechespert Ltd; Speaker Bureau/Expert testimony: Prime Oncology; Research grant/Funding (self): Kymab; Research grant/Funding (self): Tesaro. All other authors have declared no conflicts of interest.