ANALYSIS OF PI3 K/MTOR PATHWAY, CELL CYCLE, AND APOPTOSIS IN PATIENTS WITH EVEROLIMUS-ASSOCIATED STOMATITIS

Objectives: Describe the epidemiologic profile of patients who used everolimus and identify possible alterations, through the analysis of PI3 K/mTOR proteins, cell cycle, and apoptosis, which may be associated with the development of everolimus-associated stomatitis. Study Design: Medical records from patients who used everolimus were analyzed. In the prospective study, patients with breast, kidney, and neuroendocrine cancer were evaluated. Patients with everolimus-associated stomatitis underwent biopsy for histologic, immunohistochemical, and immunofluorescence analysis. In parallel, dysplastic oral keratinocytes (DOK) were cultured and assays were conducted. Results: A total of 129 medical records were analyzed. Ninety-seven patients were female. The mean age was 57.02 years. The prevalence of stomatitis was 33.3%. Patients with breast cancer (everolimus plus exemestane) had a 2.34-fold increased risk of developing stomatitis. In the prospective study, 11 patients were female. The mean age was 59.09 years. Nine patients developed stomatitis. Three biopsies were performed. All sections revealed epithelial tissue with ulcerated areas and intense inflammatory infiltrates. In vitro experiments showed that DOK treated with everolimus plus exemestane reduced cell viability and inhibited cell migration. Conclusion: Everolimus plus exemestane increases the chances to develop stomatitis and the in vitro experiments suggest a greater damage to the oral epithelium when there is an association of these drugs.