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Pancreatic Cancer:
Fergus Keane1,2, Catherine A O'Connor1,2, Wungki Park1,2,3
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.
Insights
Pancreatic cancer (PDAC) treatments are improving for patients with BRCA mutations. Research is expanding PARP inhibitor use to other DNA damage repair gene mutations, addressing resistance challenges.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with limited treatment options.
- Germline BRCA1/2 mutations define a subgroup of PDAC patients with better prognosis and targeted therapies.
- PARP inhibitors offer new hope for BRCA-mutated PDAC but resistance is a challenge.
Purpose of the Study:
- To review the current treatment landscape for PDAC with BRCA1/2 and other DNA damage repair (DDR) gene mutations.
- To discuss experimental therapeutic approaches and future directions for managing PDAC.
- To highlight the challenges of primary and acquired resistance to therapies.
Main Methods:
- Literature review of current and emerging treatments for PDAC.
- Analysis of clinical trials investigating PARP inhibitors and other DDR-targeting agents.
- Discussion of resistance mechanisms and strategies to overcome them.
Main Results:
- BRCA-mutated PDAC patients benefit from PARP inhibitors and platinum-based chemotherapy.
- Ongoing trials explore expanding PARP inhibitor indications to other DDR-deficient PDAC.
- Resistance to current therapies remains a significant hurdle for long-term patient outcomes.
Conclusions:
- Biomarker-driven therapy, including PARP inhibition, is transforming PDAC management for specific subgroups.
- Further research is crucial to overcome therapeutic resistance and improve survival in PDAC.
- Expanding treatment strategies to encompass a broader range of DDR mutations is a key future direction.
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