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Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm with a rising incidence and is a leading public health challenge. Pancreatic ductal adenocarcinoma has been well characterized genomically, with findings of therapeutic actionability that have substantive implications for clinical practice based on recent high-level evidence.
Pathogenic germline alterations (PGAs) are relatively common in individuals with PDAC, as evidenced in multiple recent data sets, with a frequency of approximately 10%. The most common PGAs are in BRCA1, BRCA2, and ATM and more rarely in PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53, among others, with an aggregate frequency of 3.8% to 9.7%. These PGAs are of key interest owing to therapeutic actionability and the downstream identification of at-risk family members and possible hereditary cancer syndromes. Approximately 3% to 7% of individuals with PDAC harbor a BRCA1 or BRCA2 mutation, which are among the most frequently mutated genes in PDAC. Recent updates to the American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines recommend risk assessment for all individuals with PDAC irrespective of personal or family history or ethnicity. Treatment implications include the use of checkpoint inhibitor therapy for mismatch repair–deficient PDAC and the validation of poly-ADP (adenosine diphosphate)-ribose polymerase inhibitor (PARPi) therapy as a maintenance strategy in platinum-sensitive PDAC.
Conclusions and Relevance
With increasing evidence and slow improvement of outcomes, PDAC has entered the era of precision medicine. Germline mutations have been identified in key genes with an aggregate frequency of 3.8% to 9.7%, several of which are therapeutically actionable with platinum, PARPi, and checkpoint inhibitor therapy. Potential therapeutic targets need to be actively sought and identified.
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Accepted for Publication: October 7, 2019.
Corresponding Author: Eileen M. O’Reilly, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E 66th St, Office 1021, New York, NY 10065 (email@example.com).
Published Online: February 13, 2020. doi:10.1001/jamaoncol.2019.5963
Author Contributions: Drs Rainone, Singh, and O’Reilly contributed equally to this work. Drs Stadler and O’Reilly had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Rainone, Singh, O’Reilly.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Rainone, Singh, Stadler, O’Reilly.
Critical revision of the manuscript for important intellectual content: All authors.
Obtained funding: O’Reilly.
Administrative, technical, or material support: Rainone, Salo-Mullen, O’Reilly.
Conflict of Interest Disclosures: Dr Stadler reported that immediate family members hold consulting/advisory roles within the field of ophthalmology with Allergan, Adverum Biotechnologies, Alimera Sciences, Inc, BioMarin Pharmaceuticals, Inc, Fortress Biotech, Inc, Genentech, Inc, Novartis International AG, Optos, Regeneron Pharmaceuticals, Inc, Regenxbio, Inc, and Spark Therapeutics. Dr O’Reilly reported receiving personal fees from Merck & Co and AstraZeneca and grants from AstraZeneca during the conduct of the study and grants from Genentech, Inc, Roche, Bristol-Myers Squibb, Celgene Corporation, MabVax Therapeutics Holdings, Inc, Acta Biologica, and Silenseed, Ltd, as well as personal fees from Polaris Pharmaceuticals, Sobi, Bayer, Targovax, and CytomX outside the submitted work. No other disclosures were reported.
Funding/Support: This study was supported by Cancer Center Support grant P30 CA-008748-48, David M. Rubenstein Center for Pancreatic Cancer Research (principal investigator, Craig Thompson, MD).
Role of the Funder/Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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