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Published on: August 12, 2015
BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer
Michael J Pishvaian1, Andrew V Biankin2,3,4, Peter Bailey2
1Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
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.
Insights
Pancreatic cancer patients with BRCA2 mutations initially respond well to PARP inhibitors. However, resistance can develop through secondary BRCA2 mutations, leading to treatment failure.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Pancreatic cancer remains a leading cause of cancer death with limited treatment advancements.
- Poly (ADP-ribose) polymerase (PARP) inhibitors show promise for DNA repair-deficient cancers.
- Mechanisms of resistance to PARP inhibitors, including secondary mutations, are critical to understand.
Observation:
- A patient with pancreatic cancer and a germline BRCA2 mutation experienced an exceptional response to platinum and PARP inhibitor therapy.
- Tumor analysis revealed a secondary BRCA2 mutation upon recurrence during PARP inhibitor treatment.
Findings:
- The initial response was likely due to the germline BRCA2 mutation, enabling sensitivity to PARP inhibition.
- A secondary BRCA2 mutation in the tumor restored gene function, conferring resistance to PARP inhibitor therapy.
Implications:
- This case highlights a novel BRCA2 reversion mutation mechanism conferring PARP inhibitor resistance in pancreatic cancer.
- Understanding this resistance pathway is crucial for optimizing future therapeutic strategies in pancreatic ductal adenocarcinoma.
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