Adolescents and Young Adults with Germline CDH1 Variants and the Risk of Overtreatment

Amber F Gallanis; Cassidy Bowden; Rachael Lopez; Grace-Ann Fasaye; David Lang; Jill Rothschild; M Constanza Camargo; Jonathan M Hernandez; Anjali Rai; Theo Heller; Andrew M Blakely; Jeremy L Davis

doi:10.1093/jnci/djaf002

Adolescents and Young Adults with Germline CDH1 Variants and the Risk of Overtreatment

J Natl Cancer Inst. 2025 Jan 6:djaf002. doi: 10.1093/jnci/djaf002. Online ahead of print.

Authors

Affiliations

¹ Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD, USA.
³ Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD, USA.
⁵ Office of Patient Safety and Clinical Quality, National Institutes of Health Clinical Center, Bethesda, MD, USA.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

PMID: 39760880
DOI: 10.1093/jnci/djaf002

Abstract

Background: Adolescents and young adults (AYA) with germline CDH1 variants are at risk of overtreatment when precancer lesions are detected with endoscopic screening. We characterize diffuse-type gastric cancer prevalence and survival in AYA managed with prophylactic total gastrectomy (PTG) or endoscopic surveillance.

Methods: Prospective cohort study of 188 individuals aged 39 and younger enrolled from January 27, 2017, to May 1, 2023. Clinicopathologic data, prevalence of early gastric signet ring cell (SRC) lesions, advanced gastric cancer diagnoses, and cancer-specific survival were measured.

Results: Among 188 AYA patients, 104 chose surveillance and 67 pursued PTG for management of elevated gastric cancer risk. AYA who enrolled early in the study period and had SRC lesions detected on preoperative endoscopy were more likely to elect for PTG compared to surveillance. SRC were detected on preoperative endoscopy in 48% of patients who subsequently had PTG, yet nearly all (93%, 62/67) had multifocal SRC (pT1aN0) on final pathology. Median age at enrollment (30 vs. 31 years, p = .21), biologic sex (p = .17), and median number of family members with gastric cancer (3 vs. 4, p = .14) were not different between groups. No patients under surveillance developed advanced cancer or developed cancer recurrence after PTG with a median follow-up of 2.5 years (IQR 1.6-4.0) from initial endoscopy.

Conclusions: Cancer-specific outcomes were not different in AYA who harbored SRC and were managed with surveillance or PTG. Lack of cancer-specific deaths and low prevalence of advanced gastric cancer underscore the risk of overtreatment of SRC lesions and suggest that active surveillance is warranted.