Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma

Abstract

Introduction: BRCA1 associated protein-1 (BAP1) is a key tumor driver in mesothelioma and a potential biomarker predicting response to several targeted therapies in clinical testing. Whether it also modulates response to cytotoxic chemotherapy is undetermined. This study used retrospective response analysis of BAP1 expression in archival tumor biopsies taken from patients in the MS01 trial (NCT00075699). We aimed to determine if BAP1 expression correlated with overall survival within the three treatment arms in this trial, namely active symptom control (ASC); ASC plus mitomycin, vinblastine and cisplatin (MVP); and ASC plus vinorelbine. Materials and Methods: We used immunohistochemical analysis of tumor samples from the MS01 trial to identify subgroups with and without nuclear BAP1 expression. We performed correlative analysis of clinical characteristics (age at diagnosis, sex and histological subtype) and overall survival within treatment arms with nuclear BAP1 expression. Results: 89 tumor samples from the 409 patients originally in the trial were available for analysis. Of these, 60 samples harbored a positive internal control, in the form of positive staining of inflammatory cells for BAP1, and were carried forward for analysis. Correlative analysis suggested no significant association between loss of nuclear BAP1 expression and age at diagnosis, sex and histological subtype. Kaplan Meier survival analysis revealed a small, though non-significant, overall survival disadvantage associated with BAP1 expression in tumors from patients treated with vinorelbine. Discussion: This exploratory analysis suggests BAP1 expression may modify response to vinorelbine in MPM, possibly due to prevention of mitotic microtubule formation. We suggest ongoing and planned clinical studies of vinorelbine in MPM assess BAP1 expression as a predictive biomarker of response.

BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma

“…This correlation was further supported by immunohistochemistry in primary mesothelioma tissue samples collected as part of the MSO1 clinical trial (NCT00075699) (37). MPM tissue samples that lacked nuclear BAP1 did show elevated levels of DR4 and DR5 ( Supplementary Fig.…”

“…were stored as formalin fixed paraffin embedded (FFPE) blocks or as unstained mounted sections as previously described (37) ; medium staining=2; strong staining=3).…”

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

“…RT is used as an adjuvant or neoadjuvant treatment in MPM, mainly in a palliative setting (8)(9)(10). As standard practice, patients undergoing an EPP receive adjuvant conventionally fractionated RT (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) in the ipsilateral hemithorax area (18,19). In node-negative MPM patients, neoadjuvant therapy, based on intensity-modulated RT (IMRT) consisting of a fractionated irradiation of 5-6 Gy, is delivered before EPP (20)(21)(22).…”

“…Genomic studies on MPM cells reported a reduced or absent expression of an enzyme involved in DNA repair and Ca 2+ -dependent apoptosis BAP1 in ∼50% of sporadic MPMs. In vitro studies demonstrated that BAP1-mutated cells are less sensitive to ionizing radiation causing DNA doublestrand breaks (50,51) or to the DNA synthesis inhibitor gemcitabine (52), highlighting the contribution of BAP1 in DNA damage signaling and repair and a possible role as a predictive biomarker (53). Inherited loss-of-function mutations in BAP1 predispose to multiple carcinomas, including mesothelioma (54)(55)(56).…”

Genetic Alterations of Malignant Pleural Mesothelima

“…Recently, BAP1 status has been associated with drug response [28,29]. In vitro studies showed MPM cell lines carrying BAP1 mutations were significantly less sensitive to gemcitabine compared to wild-type cells.…”