The Effect of FAS and FAS Ligand Genetic Polymorphisms on the Clinical Outcome of Patients with Malignant Pleural Mesothelioma Treated with Platinum-Based Regimens

Abstract

Malignant mesothelioma is considered one of asbestos-related diseases which affects the mesothelium of the pleura in the majority of cases.(Robinson, 2012) In Egypt, mesothelioma is considered a dreadful problem due to its increasing incidence and the dismal prognosis where one and two year survival rates are estimated to be 60% and 27%, respectively.(Gaafar et al., 2005) Features of mesothelioma associated with poor prognosis include: non-epithelioid subtype, advanced age, performance status (PS) ≥ 2 and advanced tumor stage.(Ceresoli et al., 2014) Multimodality therapy comprising surgery, radiotherapy and chemotherapy offers modest improvement in survival in malignant pleural mesothelioma (MPM) but only a limited subset of patients is eligible for it because the majority of patients are diagnosed at advanced stage when the surgical resection of the tumor is impossible.(Takuwa et al., 2015) So, Platinum-based chemotherapy is considered the main therapeutic strategy for MPM patients.(Baas et al., 2015) Cisplatin combined with pemetrexed is the current standard first-line chemotherapy regimen in MPM setting.(Vogelzang et al., 2003) An alternative option is the combination of cisplatin and gemcitabine which showed comparable results in phase II trials.(Nowak et al., 2002) Carboplatin shows similar survival benefits and could replace cisplatin especially for elderly patients who cannot tolerate cisplatin.(Ceresoli et al., 2008) FAS ligand (FASL) is a transmembrane protein which binds to its cell receptor, FAS, to initiate apoptosis cascade in cells.(Itoh et al., 1991) It is proposed that cisplatin exerts its anticancer activity in MPM partly by induction of the FAS pathway.(Stewart et al., 2002) In addition, studies demonstrate that both gemcitabine and pemetrexed depend on FAS pathway to initiate apoptosis in cancer cells.(Yang et al., 2013; Siena et al., 2014) So, we hypothesize that expression levels of FAS and FASL may affect anticancer activity of these agents. FAS-670 A>G and FASL-844 C>T are two polymorphisms located in the promoter region of FAS and FASL genes, respectively and affect their expression levels.(Huang et al., 1997; Wu et al., 2003) Several studies have investigated the association of these polymorphisms with predicti