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Certain CDH1 variants tied to gastric cancer risk in hereditary lobular breast cancer

Journal
JAMA Surgery
Reuters Health - 22/10/2021 - Hereditary lobular breast cancer (HLBC) patients carrying CDH1 pathogenic or likely pathogenic (P/LP) variants are apt to be at increased risk of gastric cancer, even without a family history of the disease, researchers suggest.

"Our results indicated pretty clearly that the CDH1 gene mutation is the driving factor in determining an individual's risk of HLBC and gastric cancer, regardless of their family history," Dr. Jeremy Davis of the National Cancer Institute in Bethesda told Reuters Health by email. "Our results are critically important to share because our study presents a different view than some of the existing beliefs in the oncology and genetics communities."

"Some experts have suggested that HLBC could be a distinct cancer syndrome," he noted. "Our results suggest otherwise, and therefore should affect the counseling of patients. The next iteration of guidelines surely will take these data into consideration."

"We believe that more data will be forthcoming to help explain why some families exhibit lobular breast cancer more frequently than diffuse gastric cancer," he added. "Those data will very likely affect our management of future patients."

As reported in JAMA Surgery, Dr. Davis and colleagues analyzed data on 283 patients with CDH1 P/LP variants (median age, 48; 70% women; 92% White) enrolled in a prospective study of HDGC. The cohort consisted of 151 families.

Patients were categorized into groups: family history of breast cancer and no gastric cancer (HLBC group; 15.5%); family history of gastric cancer and no breast cancer in the hereditary diffuse gastric cancer group (HDGC; 16.2%); and family history of both breast and gastric cancers (mixed; 68.2%).

The HLBC group included 31 families with 19 CDH1 variants, 10 of which were also present in the HDGC and mixed groups (52.6%).

Nearly all patients with HLBC (93.8%) who elected to have risk-reducing total gastrectomy due to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology, at a median age of 50.

A similar prevalence of occult gastric cancer was seen among asymptomatic patients in the HDGC group (94.7%).

The authors state, "Carriers of CDH1 P/LP variants with no family history of gastric cancer exhibited high rates of occult signet ring cell gastric cancer. Germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history. These data may prove useful for counseling families with CDH1 variants presumed to have HLBC."

Katherine Clayback, a genetic counselor in the Clinical Genetics Service at Roswell Park Comprehensive Cancer Center in Buffalo, New York, commented in an email to Reuters Health, "The current Genetic/Familial High Risk Assessment: Breast, Ovarian, and Pancreatic NCCN guidelines (v1.2022) do acknowledge that there is controversy over how to manage the gastric cancer risk in individuals with a CDH1 mutation without a family history of gastric cancer; however, they note the high rate of identification of gastric cancer in such individuals at the time of risk-reducing gastrectomy, which was supported by this study."

"Therefore," she said, "we agree with the suggestion of considering prophylactic gastrectomy based on the presence of a germline CDH1 P/LP mutation, regardless of family history. We would like to see additional research on larger populations where there is no family history of gastric cancer to provide more robust data."

"Our overall message would be to recommend that any individuals identified to have a P/LP CDH1 mutation meet with a multidisciplinary team with experience/expertise with hereditary diffuse gastric cancer to have a thorough discussion of risks and benefits of each management option," Clayback concluded.

SOURCE: https://bit.ly/3puv7Y6 JAMA Surgery, online October 13, 2021.

By Marilynn Larkin



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