Germline CDH1 Variants and Lifetime Cancer Risk.

Importance: Approximately 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. Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Design, Setting, and Participants: Multicenter, 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 Measures: Hazard 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. Results: A 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 Relevance: Among 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.

The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.

Risk perception and surveillance uptake in individuals at increased risk for pancreatic ductal adenocarcinoma.

BACKGROUND: Surveillance for pancreatic ductal adenocarcinoma (PDAC) is recommended for high-risk individuals with genetic variants in PDAC-associated genes and/or family history. Surveillance uptake and adherence may depend on the perception of PDAC risk and cancer worry. We aimed to determine PDAC risk perception in at-risk individuals and assess factors associated with PDAC surveillance uptake. METHODS: At-risk individuals identified from a prospective academic registry were sent a survey electronically. PDAC risk perception, cancer worry and surveillance uptake were surveyed. Factors associated with increased risk perception and surveillance were assessed. Five-year PDAC risk was calculated using the PancPRO risk assessment model, and correlation with subjective risk assessment was assessed. RESULTS: The overall survey response rate was 34% (279/816). The median perceived PDAC risk was twofold (IQR 1-4) above respondents' estimates of general population risk. Factors significantly associated with higher perceived PDAC risk included non-Hispanic white race, post-graduate education level, PDAC-affected first-degree relative, genetic variants and lack of personal cancer history. Cancer worry had a very weak correlation across PDAC risk estimates (r=0.16). No correlation between perceived PDAC risk and 5-year calculated PDAC risk was found. Older age, having a first-degree relative with PDAC, meeting with a medical provider about PDAC cancer risk and awareness of surveillance modalities were significant predictors of undergoing PDAC surveillance. CONCLUSIONS: Individuals at risk for PDAC do not report risk perception that correlates with calculated risk. This presents an opportunity for counselling of at-risk patients to individualise management and improve surveillance uptake for eligible individuals.

Outcomes of Universal Point-of-Care Genetic Testing in Diverse Patients With Pancreatic Ductal Adenocarcinoma.

PURPOSE: Guidelines recommend all patients with pancreatic ductal adenocarcinoma (PDAC) undergo germline genetic testing (GT). Rates of recommendation and completion of GT among diverse patients with PDAC are not known. The aim was to determine rates of recommendation and completion of point-of-care GT in diverse patients with PDAC. METHODS: A retrospective review of patients with PDAC seen at an academic center between April 2019 and December 2020 was performed. Recommendation, completion and results of point-of-care GT, and demographic and clinical factors were recorded. Univariate and multivariate analyses of GT were performed using the chi-square test and logistic regression. RESULTS: In total, 579 patients with PDAC were included. The median age at diagnosis was 67 years; 52% were male; 63% were non-Hispanic White (NHW) patients, and 20% were African American (AA) patients. GT was performed in 216 (37%) patients. Of those tested, 47 (22%) had a pathogenic/likely pathogenic variant identified of which 25 (12%) were in PDAC-associated genes. On multivariate analysis, age, NHW race, personal and family cancer history, medical oncology visit, and number of visits were independent predictors of GT completion. AA patients had significantly lower rates of recommendation and completion of GT compared with NHW patients. CONCLUSION: Point-of-care GT in patients with PDAC is unacceptably low, especially among AA patients. Testing disparity might be due to lack of provider recommendation more than patient uptake. Lack of testing leads to missed opportunities for potential targeted therapies, improved outcomes, and identification of at-risk family members who could potentially benefit from surveillance.

How many is too many? Polyposis syndromes and what to do next.

PURPOSE OF REVIEW: The goal of this review is to help providers recognize, diagnose and manage gastrointestinal (GI) polyposis syndromes. RECENT FINDINGS: Intestinal polyps include a number of histological sub-types such as adenomas, serrated, hamartomas among others. Over a quarter of individuals undergoing screening colonoscopy are expected to have colonic adenomas. Although it is not uncommon for adults to have a few GI polyps in their lifetime, some individuals are found to have multiple polyps of varying histology throughout the GI tract. In these individuals, depending on polyp histology, number, location and size as well as extra-intestinal features and/or family history, a polyposis syndrome should be considered with appropriate testing and management. SUMMARY: Diagnosis and management of polyposis syndromes has evolved with advent of multigene panel testing and new data on optimal surveillance strategies. Evidence-based recommendations and current practice guidelines for polyposis syndromes are reviewed here. Areas of uncertainty and future research are also highlighted.

Colorectal Cancer Screening Recommendations and Outcomes in Lynch Syndrome.

Screening for colorectal cancer (CRC) in Lynch syndrome enables early detection and likely cancer prevention. CRC screening guidelines have evolved from universal to gene-specific recommendations based on lifetime neoplasia risks. Regular screening for Lynch syndrome reduces CRC-related mortality; however, high CRC incidence during regular colonoscopy screening suggests the possibility of nonpolypoid carcinogenesis. Colonoscopy is the primary modality for screening for Lynch syndrome with mixed and emerging data on quality metrics, chromoendoscopy, artificial intelligence, and nonendoscopic modalities. Screening adherence varies across studies. In this review, we present the current state of CRC screening recommendations, outcomes, and modalities in Lynch syndrome.

Prevalence of germline variants in inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. METHODS: Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel-based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. RESULTS: Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple-negative IBC, 13% (13 of 99) among women with estrogen receptor- and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 9.3% (10 of 108) among women with HER2-positive IBC. CONCLUSIONS: The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non-IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.