Molecular Signatures Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy

Abstract

Background. Radical Hemithoracic Radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of genetic markers able to predict the relative susceptibility for newly diagnosed MPM patients to develop lung adverse effects if they were to be treated with RHR. Methods. The study included individuals with MPM, treated with lung-sparing surgery and neoadjuvant chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the impact of grade 3 pulmonary toxicities on the quality of life, for further genetic analyses patients were divided into a none or tolerable pulmonary toxicity group (Grade ≤2) and a severe pulmonary toxicity group (Grade=3). Whole exome sequencing (WES) was performed to identify genetic variants in biological pathways associated to pulmonary toxicity after radiotherapy.Results. We identified crucial pathways driving the lung response to ionizing radiations in patients affected by mesothelioma: by affecting both the fibrinolytic activity and RNA editing pathways, irradiation could be responsible of the severe toxicity events reported by some patients, who present specific mutations in genes involved in these pathways. Conclusions. Our preliminary results could pave the way for the definition of a panel of predictive genomic variants, capable of supporting the management of MPM patients. By allowing for early identification of patients at high risk for treatment-dependent pulmonary toxicity, this predictive tool could play a major role in the design of new therapeutic combinations.