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Targeting DNA damage repair pathways in pancreas cancer

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Abstract

Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15–25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.

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Funding

Cancer Center Support Grant P30 CA0008748, David M. Rubinstein Center for Pancreas Research, Paul Calabresi Career Development Award K12 CA184746, Parker Institute for Immunotherapy Pilot Grant, and Society of Immunotherapy for Cancer (SITC)—TimIOs.

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  1. Fionnuala Crowley and Wungki Park contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA

    Fionnuala Crowley, Wungki Park & Eileen M. O’Reilly

  2. Internal Medicine, Mount Sinai Morningside West Hospital Center, New York, NY, USA

    Fionnuala Crowley

  3. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Fionnuala Crowley

  4. David M. Rubenstein Center for Pancreas Research, New York, NY, USA

    Wungki Park & Eileen M. O’Reilly

  5. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA

    Wungki Park

  6. Weill Cornell Medical College, New York, NY, USA

    Wungki Park & Eileen M. O’Reilly

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WP: Research funding to institution: Merck, Astellas, Gossamerbio.

EOR: Research funding to MSK: Genentech/Roche, Celgene/BMS, BioNTech, BioAtla, AstraZeneca, Arcus, Elicio. Consulting Role: Cytomx Therapeutics (DSMB), Rafael Therapeutics (DSMB), Sobi, Silenseed, Molecular Templates, Boehringer Ingelheim, BioNTech, Ipsen, Polaris, Tyme, Seagen, Merck, AstraZeneca, Noxxon, BioSapien, Bayer (spouse), Genentech-Roche (spouse), Celgene-BMS (spouse), Eisai (spouse).

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Crowley, F., Park, W. & O’Reilly, E.M. Targeting DNA damage repair pathways in pancreas cancer. Cancer Metastasis Rev 40, 891–908 (2021). https://doi.org/10.1007/s10555-021-09983-1

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