BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer

Pishvaian, M. J., Biankin, A. V. , Bailey, P. , Chang, D. K. , Laheru, D., Wolfgang, C. L. and Brody, J. R. (2017) BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer. British Journal of Cancer, 116, pp. 1021-1026. (doi: 10.1038/bjc.2017.40) (PMID:28291774)

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Background: Pancreatic cancer has become the third leading cause of cancer death with minimal improvements in outcome for over 40 years. Recent trials of therapies that target-defective DNA maintenance using poly (ADP-ribose) polymerase (PARP) inhibitors are showing promising results, yet invariably patients recur and succumb to disease. Mechanisms of resistance to platinum-based and PARP inhibitor therapy in other cancer types include secondary mutations, which restore the integrity of DNA repair through an increasing number of different mechanisms. Methods: Here we present a case of a 63-year-old female patient with a germ line pathogenic BRCA2 mutation (6714 deletion) who developed pancreatic cancer and had an exceptional response to platinum and PARP inhibitor therapy. Through nextgeneration sequencing and clinical follow-up, we correlated tumour response and resistance to the BRCA2 mutational status in the tumour. Results: Initially, the patient had an exceptional response to platinum and PARP inhibitor therapy, most likely due to the BRCA2 mutation. However, the primary lesion recurred while on PARP inhibitor therapy and contained a secondary mutation in BRCA2, which mostly likely restored BRCA2 function in PARP inhibitor-resistant tumour cells. Conclusions: To our knowledge, this is the first report of a BRCA2 reversion mutation that conferred resistance to PARP inhibitorbased therapy in a pancreatic ductal adenocarcinoma patient. Future studies are needed to understand this important mechanism of resistance and how it may impact the choice of therapy for patients with pancreatic cancer.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Bailey, Dr Peter and Biankin, Professor Andrew and Chang, Professor David
Authors: Pishvaian, M. J., Biankin, A. V., Bailey, P., Chang, D. K., Laheru, D., Wolfgang, C. L., and Brody, J. R.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:British Journal of Cancer
Publisher:Cancer Research UK
ISSN (Online):1532-1827
Published Online:14 March 2017
Copyright Holders:Copyright © 2017 Cancer Research UK
First Published:First published in British Journal of Cancer 116:1021-1026
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS