Advancing the Evaluation and Management of CDH1-Associated Gastric Cancer

Authors:
Benjamin A. Lerner Division of Gastroenterology, Department of Medicine, Yale University, New Haven, CT

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Samir Gupta Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA

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Carol A. Burke Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Cleveland Clinic, Cleveland, OH

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Sonia Kupfer Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago, Chicago, IL

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Bryson W. Katona Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA

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William M. Grady Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, and Gastroenterology Division, University of Washington School of Medicine, Seattle, WA

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Jewel J. Samadder Division of Gastroenterology, Department of Medicine, Mayo Clinic, Phoenix, AZ

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Matthew B. Yurgelun Dana-Farber Cancer Institute, Boston, MA

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Kaitlyn J. Kelly Department of Surgery, University of Wisconsin, Madison, WI

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Mariana Moreno Prats Department of Pathology, University of Utah, Salt Lake City, UT

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Nora Joseph Department of Pathology, University of Michigan, Ann Arbor, MI

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Gregory E. Idos Division of Gastroenterology, Department of Medicine, City of Hope, Duarte, CA

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Benjamin J. Swanson Department of Pathology, Microbiology, and Immunology, University of Nebraska, Lincoln, NE

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AnnMarie Kieber-Emmons Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC

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Jennifer M. Weiss Division of Gastroenterology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI

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Xavier Llor Division of Gastroenterology, Department of Medicine, Yale University, New Haven, CT

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Volume/Issue:
Volume 23: Issue 4
Online Publication Date:
Apr 2025
DOI:
https://doi.org/10.6004/jnccn.2025.7006
Restricted access

Gastric cancer is a significant global health concern, with CDH1-associated gastric cancer representing a small but important subset of cases. Historically, individuals with CDH1 pathogenic germline variants were advised to undergo prophylactic total gastrectomy due to the high reported risk of gastric cancer and the limited sensitivity of upper endoscopy in detecting signet ring cell carcinoma (SRCC). However, emerging data suggest that the cumulative lifetime risk of advanced gastric cancer among CDH1 germline pathogenic variant carriers is lower than previously thought, and early-stage SRCC detected on endoscopy does not necessarily indicate imminent—or even eventual—progression to advanced cancer. The near-universal presence of T1a SRCC in gastrectomy specimens from asymptomatic CDH1 pathogenic variant carriers calls into question the reflexive recommendation for gastrectomy, including upon detection of SRCC during surveillance. Furthermore, the morbidity and quality-of-life impact associated with total gastrectomy require careful consideration. Active endoscopic surveillance has shown promise as an alternative management strategy for gastrectomy in patients lacking indicators of >T1a SRCC, though current data are limited by short follow-up periods and selection bias. This review synthesizes recent findings on the natural history of CDH1-associated gastric cancer and evaluates the risks and benefits of gastrectomy versus active endoscopic surveillance, with the goal of helping clinicians provide personalized and evidence-based recommendations for patients with CDH1 pathogenic variants.

Submitted September 15, 2024; final revision received November 18, 2024; accepted for publication January 13, 2025.

Disclosures: Dr. Grady has disclosed serving as a scientific advisor for Guardant Health, and serving as a consultant for Karius and DiaCarta. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Xavier Llor, MD, PhD, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street/LMP 1080, P.O. Box 208019, New Haven, CT 06520-8019. Email: Xavier.Llor@yale.edu
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Print ISSN:
1540-1405
Online ISSN:
1540-1413
Publisher:
National Comprehensive Cancer Network
Cover Journal of the National Comprehensive Cancer Network
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Copyright:
Copyright © 2025 by the National Comprehensive Cancer Network 2025
Article Category:
Review Article
Received:
15 Sep 2024
Accepted:
13 Jan 2025
Print Publication Date:
01 Apr 2025
Online Publication Date:
Apr 2025

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