Low adenoma burden in unselected patients with a pathogenic APC variant.

PURPOSE: Genomic screening can improve clinical outcomes, but presentation of individuals with risk for polyposis identified via genomic screening is unknown. To inform assessment of clinical utility of genomic screening for polyposis risk, clinical presentation of individuals in an unselected health care system cohort with an APC pathogenic or likely pathogenic (P/LP) variant causative of familial adenomatous polyposis are described. METHODS: Electronic health records of individuals with an APC P/LP variant identified via the MyCode program (MyCode APC+) were reviewed to assess adenoma burden and compare it among individuals with a clinical diagnosis of familial adenomatous polyposis and matched variant-negative controls. RESULTS: The prevalence of APC P/LP variants in this health care cohort is estimated to be 1 in 2800. Twenty-four MyCode APC+ individuals were identified during the study period. Median age at result disclosure was 53 years. Rate of clinical polyposis was 8%. Two of six participants with a classic region variant and none of those with an attenuated region variant had polyposis. MyCode APC+ participants did not differ from controls in cumulative adenoma count. CONCLUSION: APC P/LP variant prevalence estimate in the MyCode cohort is higher than prior published prevalence rates. Individuals with APC P/LP variants identified via genomic screening had a low adenoma burden.

Human-Centered Design Study to Inform Traceback Cascade Genetic Testing Programs at Three Integrated Health Systems.

INTRODUCTION: A traceback genetic testing program for ovarian cancer has the potential to identify individuals with hereditary breast and ovarian cancer and their relatives. Successful implementation depends on understanding and addressing the experiences, barriers, and preferences of the people served. METHODS: We conducted a remote, human-centered design research study of people with ovarian, fallopian tube, or peritoneal cancer (probands) and people with a family history of ovarian cancer (relatives) at three integrated health systems between May and September 2021. Participants completed activities to elicit their preferences about ovarian cancer genetic testing messaging and to design their ideal experience receiving an invitation to participate in genetic testing. Interview data were analyzed using a rapid thematic analysis approach. RESULTS: We interviewed 70 participants and identified five preferred experiences for a traceback program. Participants strongly prefer discussing genetic testing with their doctor but are comfortable discussing with other clinicians. The most highly preferred experience for both probands and relatives was to discuss with a knowledgeable clinician who could answer questions, followed by directed (sent directly to specific people) or passive (shared in a public area) communication. Repeated contact was acceptable for reminders. CONCLUSION: Participants were open to receiving information about traceback genetic testing and recognized its value. Participants preferred discussing genetic testing with a trusted clinician. Directed communication was preferable to passive communication. Other valued information included how genetic tests help their family and the cost of genetic testing. These findings are informing traceback cascade genetic testing programs at all three sites.

Feasibility and Assessment of a Cascade Traceback Screening Program (FACTS): Protocol for a Multisite Study to Implement and Assess an Ovarian Cancer Traceback Cascade Testing Program.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. "Traceback" cascade testing -outreach to potential probands and relatives-is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program's feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program's feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs.

Clinical outcomes of a genomic screening program for actionable genetic conditions.

PURPOSE: Three genetic conditions-hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia-have tier 1 evidence for interventions that reduce morbidity and mortality, prompting proposals to screen unselected populations for these conditions. We examined the impact of genomic screening on risk management and early detection in an unselected population. METHODS: Observational study of electronic health records (EHR) among individuals in whom a pathogenic/likely pathogenic variant in a tier 1 gene was discovered through Geisinger's MyCode project. EHR of all eligible participants was evaluated for a prior genetic diagnosis and, among participants without such a diagnosis, relevant personal/family history, postdisclosure clinical diagnoses, and postdisclosure risk management. RESULTS: Eighty-seven percent of participants (305/351) did not have a prior genetic diagnosis of their tier 1 result. Of these, 65% had EHR evidence of relevant personal and/or family history of disease. Of 255 individuals eligible to have risk management, 70% (n = 179) had a recommended risk management procedure after results disclosure. Thirteen percent of participants (41/305) received a relevant clinical diagnosis after results disclosure. CONCLUSION: Genomic screening programs can identify previously unrecognized individuals at increased risk of cancer and heart disease and facilitate risk management and early cancer detection.

Perspectives from individuals with familial hypercholesterolemia on direct contact in cascade screening.

Familial hypercholesterolemia (FH) is the most common inherited form of high cholesterol that significantly increases the risk for coronary artery disease. Early detection and treatment can decrease morbidity and mortality and provide important risk information to family members. However, FH remains vastly underdiagnosed and undertreated. Cascade screening is the process of iteratively testing first-degree relatives for a genetic disease. It has been shown to effectively identify individuals with undiagnosed FH. The majority of research on methods for cascade screening has been conducted outside of the United States (U.S.). For indirect contact, index cases encourage relatives to undergo testing, and for direct contact, healthcare providers (HCP) obtain the index case's consent to contact relatives and offer information. Currently, there is not an accepted strategy for cascade screening programs in the U.S. This study investigated perspectives on direct and indirect contact for cascade screening from individuals with FH. An online survey was designed in collaboration with the Familial Hypercholesterolemia Foundation (FHF). Fifty-eight percent of U.S. index cases (11/19, 57.9%) and all international index cases (8/8, 100%) indicated willingness to provide contact information for certain at-risk relatives to a HCP for the purpose of directly informing relatives of their risk for FH in a hypothetical scenario. These findings provide an example of U.S. data and additional international data suggesting that some individuals with FH may consider direct contact a reasonable approach to improve screening uptake among family members. These initial findings need further confirmation in a larger group.