Wiesner, Georgia L.

Abstract Objective To describe the development and implementation of an automated platform for genomic risk prediction that integrates multiple data types. Materials and methods Using the REDCap infrastructure, we constructed the R4 (Recruitment, Results, and Risk Reduction) platform to intake data from clinical sites, partner laboratories, participant surveys, and electronic health record (EHR) data across 13 institutions. Results The R4 Portal successfully integrated data to generate genome-informed risk assessments (GIRAs) across 11 conditions for a 23 840 person cohort. Testing phases and quality control led to network-wide protocols ensuring consistency and accuracy. Discussion As the science of estimating disease risk evolves, standardized and high-throughput methods of collecting and manipulating complex data are required. Platforms should be open-source, modular, and reusable, ensuring flexibility, security, and integration across healthcare environments. Conclusion The electronic MEdical Records and GEnomics (eMERGE) network successfully generated and returned comprehensive risk profiles using logic and data specific to 11 conditions in a secure and semi-automated fashion employing a customized REDCap database.

PURPOSE BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian ). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2 , a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer–related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.

Background: Susceptibility to cardiometabolic diseases (CDs) is shaped by genetic, socio-environmental, and lifestyle factors. We evaluated the associations of disease-specific polysocial risk scores (PSSs)— derived from social determinants of health (SDOH) and lifestyle factors—and genetic risk factors with six CDs, across self-identified race/ethnicity (SIRE) groups in the eMERGE IV cohort. Methods: The six CDs included: atrial fibrillation, coronary heart disease, chronic kidney disease, hyperlipidemia, obesity, and type 2 diabetes. Disease-specific PSSs were developed using machine-learning models based on 65 SDOH and lifestyle factors. Participants were grouped based on their SIRE as Asian, Black, Hispanic/Latino, and White. We evaluated PSS distributions across SIRE groups. Genetic risk was assessed through disease-specific polygenic risk scores (PRSs), monogenic etiologies, and family history (FamHx). High PSS and high PRS were defined as the top 5th percentile. Associations were tested using multivariable logistic regression; model performance was assessed using the C-statistic. Results: Among 20178 participants (50±15 years, 68% female, 40% non-White), the most frequently associated PSS components were physical activity, sleep, self-perceived health, and income. PSS distributions varied across SIRE groups, with Whites having the lowest and Black and Hispanic/Latinos the highest scores for most CDs (Figure 1). All PSSs were significantly associated with their respective CDs, independent of confounders (OR per 1 SD increase: 1.19–2.68; Figure 2-A). No significant interactions were observed between PSSs and PRSs or monogenic etiologies. However, significant interactions were noted between PSSs and FamHx for CKD and obesity. PSS and PRS effects on the odds of CDs were independent (Figure 2-B) and additive (Figure 2-C). Incorporating PSSs into models that included clinical and genetic risk factors improved predictive performance of risk prediction models (Figure 3). Conclusion: PSSs, reflecting socio-environmental and lifestyle disadvantage, varied significantly across SIRE groups and were associated with risk of six CDs, independent of and additive to PRS. Given the substantial variation in socio-environmental and lifestyle risks across SIRE groups, integrating these factors into risk prediction models for CDs may help address health disparities and enhance preventive efforts, especially in marginalized populations.

Background: We investigated the impact of genetic risk factors for coronary heart disease (CHD) -polygenic risk score (PRS), familial hypercholesterolemia (FH), and family history (FamHx)- on CHD risk estimates, across the age spectrum, in two diverse cohorts of US adults -eMERGE IV (eIV) and All of Us (AoU). Methods: CHD was defined as myocardial infarction, unstable angina, and coronary revascularization. Self-identified race/ethnicity (SIRE) was used as a population descriptor. We calculated a PRS for CHD (PRS CHD , PGS004698), ascertained FH as the presence of pathogenic/likely pathogenic variants in FH genes, and defined FamHx as early-onset CHD in first-degree relatives. We employed Pooled Cohort Equations (PCE) to estimate the 10y risk of CHD for adults ≥40y and modeled the association of conventional risk factors with CHD in adults <40y. AoU served as the training set, and eIV as the testing set. We analyzed the impact of PRS CHD and FamHx on CHD risk estimates by a) using multivariable logistic regression and Cox proportional hazard models, assessing discrimination and the extent of risk reclassification; and b) net benefit analysis and decision curves to assess the performance of prediction models across actionable thresholds. Results: We analyzed data for 19348 participants from eIV (age 50±15, 68% female, 41% non-White) and 239645 participants from AoU (age 55±17, 61% female, 48% non-White). Genetic risk factors were significantly associated with CHD. PRS CHD performance varied by SIRE groups, while FamHx was consistent. The effects of PRS CHD and FamHx on CHD were independent and additive (Figure 1). In adults ≥40y, incorporating PRS CHD and FamHx into PCE improved discrimination (C-statistic increased from 0.719 to 0.753; P -diff=9.1×10 -3 , Figure 2) and reclassified risk in 19% and 20% of participants at the 7.5% and 10% 10y CHD risk thresholds, respectively. Between the 7.5% and 10% 10y CHD risk thresholds, incorporating PRS CHD and FamHx into the PCE improved the net benefit of the risk prediction models across White, Black, and Hispanic/Latino groups (Figure 3). Conclusion: PRS CHD and FamHx were independently and additively associated with CHD in two large diverse cohorts in the US. Incorporating PRS CHD and FamHx into PCE improved risk discrimination, reclassified risk in a significant portion of participants, and improved net benefit of the PCE across all three major SIRE groups, motivating the addition of these factors to clinical risk calculators.

Abstract Objectives To implementation an automated multi-institutional pipeline that delivers breast-cancer risk integrated with polygenic risk scores, monogenic variants, family history, and clinical factors, emphasizing operational challenges and their solutions. Materials and Methods A five-stage process was executed at ten sites. Data streams from REDCap surveys, PRS and monogenic reports, and MeTree pedigrees were normalized and forwarded through a REDCap plug-in to the CanRisk API. Results Integrated risk was returned to &gt;10 000 women; 3.6% were ≥25 % lifetime risk and 0.9% carried pathogenic variants. Pipeline generated score aligns well with manual generated ones. Major barriers such as heterogeneous pedigree formats, missing data, edge-case handling, and evolving model versions were identified and resolved through mapping rules, imputations, and iterative testing. Discussion Cross-platform data harmonization and stakeholder alignment were decisive for success. Borderline-risk communication and model-version drift remain open issues. Conclusion Large-scale PRS-integrated breast-cancer risk reporting is feasible but requires robust interoperability standards and iterative governance.

Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.

ImportancePreventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined.ObjectiveTo evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation.Design, Setting, and ParticipantsIn this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023.ExposuresSelf-reported bilateral oophorectomy (with or without salpingectomy).Main Outcomes and MeasuresAll-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.ResultsThere were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P &amp;lt; .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P &amp;lt; .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy.Conclusions and RelevanceIn this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Purpose: The electronic Medical Records and Genomics (eMERGE) Phase III study was undertaken to assess clinical utility of returning medically actionable genomic screening results. We assessed pediatric clinical outcomes following return of pathogenic/likely pathogenic (P/LP) variants in autosomal dominant conditions with available effective interventions. Methods: The two eMERGE III pediatric sites collected outcome data and assessed changes in medical management at 6 and 12 months. Results: We returned P/LP results to 29 participants with outcome data. For 23 of the 29 participants, the P/LP results were previously unknown. Five of the 23 participants were already followed for conditions related to the P/LP variant. Of those receiving novel results and not being followed for the condition related to the P/LP result (n = 18), 14 (77.8%) had a change in healthcare after return of results (RoR). Following RoR, cascade testing of family members occurred for 10 of 23 (43.5%). Conclusions: The most common outcomes post-RoR included imaging/laboratory testing and health behavior recommendations. A change in healthcare was documented in 77.8% of those receiving results by 6 months. Our findings demonstrate how return of genomic screening results impacts healthcare in pediatric populations.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.