BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts

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.... Clinical data in ovarian cancer show that patients with BRCA1 and BRCA2 mutations show higher response rates to treatment with cisplatin and other DNA-damaging agents resulting in improved outcome (Dann et al, 2012; Muggia and Safra, 2014). Similar observations have been made in case reports of patients with pancreatic cancer, suggesting that BRCA1 and BRCA2 mutations may sensitise to treatment with platinum drugs (Lowery et al, 2011; Sonnenblick et al, 2011). This is supported by preclinical studies using established pancreatic cancer cell lines (van der Heijden et al, 2005), and also by a large retrospective analysis of 71 pancreatic cancer patients with germline BRCA1 and BRCA2 mutations, where it was reported that patients with stage 3/4 disease who were treated with a platinum-containing regimen had a median survival of 22 months, compared with 9 months for those who did not receive platinum (Golan et al, 2014).

There are important unanswered questions concerning the optimum design of platinum-containing treatment protocols for this group of patients, as well as the role of newer agents such as inhibitors of poly-ADP-ribose polymerase (PARP) that have shown early promise in other cancer patients carrying germline BRCA mutations......

 Discussion

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• Materials and methods
• Results
• Discussion
• Conflict of interest
• References
• Acknowledgements
• Figures and Tables

....Germline mutations in BRCA1 and BRCA2 result in defects in BRCA-mediated HR, which is important for the maintenance of genome stability (Venkitaraman, 2001; Gudmundsdottir and Ashworth, 2006). These mutations predispose to breast and ovarian cancers (Foulkes and Shuen, 2013; Kobayashi et al, 2013), and are associated with increased risk of pancreatic cancer (Fernandes et al, 1994; Klein et al, 2001; Bartsch et al, 2004; Grant et al, 2014). In addition to a role in tumour development, BRCA1 and BRCA2 mutations are associated with sensitivity to platinum drugs and other DNA-damaging agents in ovarian cancers (Dann et al, 2012; Muggia and Safra, 2014), and there are anecdotal reports that this is also the case in pancreatic cancers (Lowery et al, 2011; Sonnenblick et al, 2011).....