Abstract 4908: Exemestane worsens everolimus-associated stomatitis in cancer patients

Everolimus is an antitumor drug usually indicated for the treatment of breast, kidney and neuroendocrine malignancies that inhibits the activation of the mammalian Target of Rapamycin (mTOR). Despite the efficacy and success of the treatment, side effects are not uncommon, and stomatitis is quite prevalent. mTOR inhibitor associated stomatitis (mIAS) is described as ulcerated aphthous-like lesions associated with mTOR inhibitors use. mIAS may cause severe pain, leading to nutritional deficiency and general health decline, besides drug dose reduction or suspension. Clinical observation suggested mIAS to be more common among breast cancer patients. Thus, we hypothesized that exemestane could contribute to increase everolimus toxicity in the oral mucosa. We prospectivelly collected clinical data from patients who used everolimus, associated or not with exemestane, from March 2016 to September 2017, and correlated them with information regarding mIAS (date of onset, number of lesions in the oral cavity, grading). We also performed in vitro experiments with Dysplastic Oral Keratinocytes (DOK). Cells were treated with vehicle, everolimus, exemestane or the combination of everolimus and exemestane. Drug induced citotoxicity was evaluated by MTT assay and migration inhibition by scratch wound healing assay. All assays were done in triplicate. Frequencies were compared by Fisher9s exact or McNemar test. Log-rank and Wilcoxon tests were employed to compare time to mIAS development. Multivariate ANOVA was used to compare results from in vitro experiments. SPSS and Image J were used to make all statistical analysis. One hundred and thirty patients were evaluated. Mostly were females, with mean age of 60 years, and had previously treated advanced stage (IV) breast cancer. 30.3% developed mIAS. Breast cancer patients (treated with exemestane plus everolimus) had 2.29 higher chance to develop mIAS when compared to neuroendocrine tumos patients (treated with everolimus alone). In vitro experiments showed that the association of everolimus and exemestane increased cell death and migration (wound healing) inhibition of DOK in comparison with cells treated with everolimus or exemestane alone. The clinical data suggests that exemestane increases the risk of developing mIAS, and the in vitro experiments reinforces the idea that exemestane may enhance oral mucosa toxicity mediated by everolimus. Citation Format: Vladmir C. de Lima, Matheus H. de Lima, Fabio A. Alves, Glaucia N. Hajj. Exemestane worsens everolimus-associated stomatitis in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4908.