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BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer
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BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer
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Journal Article
BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer
2017
Overview
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 next-generation 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 inhibitor-based 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adenocarcinoma - drug therapy
/ Antineoplastic Combined Chemotherapy Protocols - therapeutic use
/ Benzimidazoles - administration & dosage
/ Biomedical and Life Sciences
/ Carcinoma, Pancreatic Ductal - drug therapy
/ Carcinoma, Pancreatic Ductal - genetics
/ Carcinoma, Pancreatic Ductal - pathology
/ Female
/ Fluorouracil - administration & dosage
/ Humans
/ Oncology
/ Organoplatinum Compounds - administration & dosage
/ Pancreatic Neoplasms - drug therapy
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - pathology
/ Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
