Indications for Total Gastrectomy in CDH1 Mutation Carriers and Outcomes of Risk-Reducing Minimally Invasive and Open Gastrectomies

Abstract

Importance: CDH1 variants are increasingly identified on commercially available multigene panel tests, calling for data to inform counseling of individuals without a family history of gastric cancer.

Objectives: To assess association between CDH1 variant pathogenicity or family history of gastric or lobular breast cancer and identification of signet ring cell cancer and to describe outcomes of risk-reducing minimally invasive and open total gastrectomy.

Design, setting, and participants: This cohort study was performed from January 1, 2006, to January 1, 2020, in 181 patients with CDH1 germline variants from a single institution.

Interventions: Genetic counseling, esophagogastroduodenoscopy, and possible total gastrectomy.

Main outcomes and measures: CDH1 variant classification, family cancer history, findings of signet ring cell carcinoma at esophagogastroduodenoscopy and surgery, postoperative events and weight changes, and follow-up.

Results: Of 181 individuals with CDH1 germline variants (mean [SD] age at time of testing, 44 [15] years; 126 [70%] female), 165 harbored a pathogenic or likely pathogenic variant. Of these patients, 101 underwent open (n = 58) or minimally invasive (n = 43) total gastrectomy. Anastomotic leaks that required drainage were infrequent (n = 3), and median long-term weight loss was 20% (interquartile range [IQR], 10%-23%). In those undergoing minimally invasive operations, more lymph nodes were retrieved (median, 28 [IQR, 20-34] vs 15 [IQR, 9-19]; P < .001) and the hospital stay was 1 day shorter (median, 6 [IQR, 5-7] vs 7 [IQR, 6-7] days; P = .04). Signet ring cell cancer was identified in the surgical specimens of 85 of 95 patients (89%) with a family history of gastric cancer and 4 of 6 patients (67%) who lacked a family history. Among the latter 6 patients, 4 had a personal or family history of lobular breast cancer, including 2 with signet ring cell cancer. Of the 16 patients with pathogenic or likely pathogenic CDH1 variants who presented with locally advanced or metastatic gastric cancer, 3 (19%) had no family history of gastric cancer or personal or family history of lobular breast cancer.

Conclusions and relevance: Total gastrectomy may be warranted for patients with pathogenic or likely pathogenic CDH1 variants and a family history of gastric or lobular breast cancer and may be appropriate for those without a family history. A minimally invasive approach is feasible and may be preferred for selected patients.

Figure 1.. Patient Flowchart

Family history includes first-, second-, and third-degree relatives. EGD indicates esophagogastroduodenoscopy; GC, gastric cancer; MSKCC, Memorial Sloan Kettering Cancer Center; P/LP, pathogenic or likely pathogenic; SRCC, signet ring cell carcinoma.

Figure 2.. Signet Ring Cell Carcinoma (SRCC) Findings Based on Family History of Gastric Cancer (GC) and Invasive Lobular Breast Cancer (ILBC) Among 101 Asymptomatic Patients With CDH1 Variants Who Underwent Total Gastrectomy at Memorial Sloan Kettering Cancer Center (MSKCC)

EGD indicates esophagogastroduodenoscopy.

Figure 3.. Weight Change After Total Gastrectomy

A, Postoperative weight loss as a percentage of preoperative weight, according to preoperative body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). B, Postoperative change in BMI. Weight at postoperative months 3, 6, 12, and 24 or later represents the mean from 2 to 4, 5 to 8, 6 to 17, and 18 months onward, respectively.