Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study

Asif, Bilal; Sarvestani, Amber Leila; Gamble, Lauren A.; Samaranayake, Sarah G.; Famiglietti, Amber; Fasaye, Grace‐Ann; Quezado, Martha; Miettinen, Markku; Korman, Louis Y.; Koh, Christopher; Heller, Theo; Davis, Jeremy L.

doi:10.1016/s1470-2045(23)00057-8

Cited by 29 publications

(16 citation statements)

References 27 publications

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“…Random endoscopic gastric biopsies revealed occult, microscopic foci of signet ring cell carcinomas in approximately half (47.2%, 59/125) of the patients, which is consistent with the disease phenotype. 22 , 23 Total gastrectomy was conducted with an open surgical approach in all but two cases. Median operative duration was 168 minutes (range, 111-373 minutes) with a median estimated blood loss of 50 mL.…”

Section: Resultsmentioning

confidence: 99%

“… 20 , 21 Although recent studies have demonstrated that endoscopic surveillance with random and targeted biopsies can be a reasonable alternative to surgery in some patients, the long-term safety of surveillance is not yet known. 22 , 23 Attempts to risk-stratify individuals on the basis of genotype or family cancer history to help guide clinical management have not been successful. 24 , 25 …”

Section: Introductionmentioning

confidence: 99%

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Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy

Gallanis,

Gamble,

Samaranayake

et al. 2024

JCO

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PURPOSE Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy

Gallanis,

Gamble,

Samaranayake

et al. 2024

JCO

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“…For these reasons, a shift in the paradigm of endoscopic surveillance is discussed: the aim is not to detect all precursor lesions but to detect abnormal lesions that tend to infiltrate deeper toward the submucosa Recognising the lesion limited to the mucosa which tends to progress is probably the biggest challenge of endoscopic surveillance for these patients. A key feature proposed by Asif et al is the presence of ulceration, whereas Van der Post et al proposed a new categorisation for endoscopic findings, with pT1 with atypia defined by the presence of deeper infiltration towards or in the submucosa; mixture with smaller or pleomorphic and eosinophilic cells; atypical cells not restricted to the base of the lesion; some inflammatory or stromal reaction; or increased proliferation [ 30 , 31 ]. A prospective study found two cancers at an advanced stage (pT3) in 120 patients in the endoscopic surveillance arm but did not observe any invasive gastric cancer in prophylactic gastrectomy specimens from patients (98) who did not have any concerning findings in their endoscopy [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Case Series of 11 CDH1 Families (47 Carriers) Including Incidental Findings, Signet Ring Cell Colon Cancer and Review of the Literature

Lepage,

Uhrhammer,

Privat

et al. 2023

Genes

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Germline pathogenic variants in E-cadherin (CDH1) confer high risk of developing lobular breast cancer and diffuse gastric cancer (DGC). The cumulative risk of DGC in CDH1 carriers has been recently reassessed (from 40–83% by age 80 to 25–42%) and varies according to the presence and number of gastric cancers in the family. As there is no accurate estimate of the risk of gastric cancer in families without DGC, the International Gastric Cancer Linkage Consortium recommendation is not straightforward: prophylactic gastrectomy or endoscopic surveillance should be proposed for these families. The inclusion of CDH1 in constitutional gene panels for hereditary breast and ovarian cancer and for gastrointestinal cancers, recommended by the French Genetic and Cancer Consortium in 2018 and 2020, leads to the identification of families with lobular cancer without DGC but also to incidental findings of pathogenic variants. Management of CDH1 carriers in case of incidental findings is complex and causes dilemmas for both patients and providers. We report eleven families (47 CDH1 carriers) from our oncogenetic department specialized in breast and ovarian cancer, including four incidental findings. We confirmed that six families did not have diffuse gastric cancer in their medical records. We discuss the management of the risk of diffuse gastric cancer in Hereditary Lobular Breast Cancer (HLBC) through a family of 11 CDH1 carriers where foci were identified in endoscopic surveillance. We also report a new colon signet ring cancer case in a CDH1 carrier, a rare aggressive cancer included in CDH1-related malignancies.

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“…This is because stage IA gastric cancer is a frequent (88%-100%) diagnosis among asymptomatic CDH1 P/LP variant carriers who undergo risk-reducing total gastrectomy and, to our knowledge, no cancer recurrences have been reported in such cases. [20][21][22] A secondary analysis was performed that included all diagnoses of gastric cancer irrespective of pathologic stage or clinical presentation.…”

Section: Key Pointsmentioning

confidence: 99%

Germline CDH1 Variants and Lifetime Cancer Risk

Ryan,

Fasaye,

Gallanis

et al. 2024

JAMA

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ImportanceApproximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants.ObjectiveTo describe gastric and breast cancer risk estimates for individuals with CDH1 variants.Design, Setting, and ParticipantsMulticenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022.Main Outcomes and MeasuresHazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years.ResultsA total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%).Conclusions and RelevanceAmong families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

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Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study

Cited by 29 publications

References 27 publications

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy

Case Series of 11 CDH1 Families (47 Carriers) Including Incidental Findings, Signet Ring Cell Colon Cancer and Review of the Literature

Germline CDH1 Variants and Lifetime Cancer Risk

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