BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Abstract Background: Tumor genomic testing (TGT) has become standard-of-care for all patients with metastatic breast cancer (MBC). American Society of Clinical Oncology (ASCO) and American College of Medical Genetics (ACMG) guidelines for patient education prior to TGT are not widely followed. We have previously demonstrated disparities in general genomic knowledge across race and income. The purpose of this study was to develop a concise (3-4 minute) video for patient education prior to TGT and evaluate the video’s impact in a prospective interventional trial. We report the results of the primary endpoint of the MBC cohort (ClinicalTrials.gov NCT05215769). Methods: We previously published our internal quality improvement cycle involving provider surveys, patient focus groups, and adult learning theory-based content development for TGT educational videos. An animated video incorporating culturally diverse images available in English and Spanish was created to be applicable to any cancer type, with MBC-specific content included for patients with breast cancer. A total of 150 participants were enrolled at a single tertiary academic institution, of whom 53 were diagnosed with MBC. Participants completed validated survey instruments immediately prior to video viewing (T1), immediately post-viewing (T2) and 60-90 days later, after TGT results were documented (T3). Instruments included: 1) 10-question objective genomic knowledge/understanding (GKU); 2) 10-question video message-specific knowledge/recall (VMSK); 3) 11-question Trust in Physician/Provider (TIPP); 4) attitudes regarding TGT. The primary objective was to assess change in VMSK between T1 and T2 and a cohort of 50 participants provided 90% power to detect an effect size of 0.47 from pre- to post-video using two-sided Wilcoxon signed-rank test with alpha of 0.05. Associations of VMSK, GKU, and TIPP with categorical demographic variables were explored with Kruskal-Wallis test. Results: From April 2022 to May2023, a total of 150 participants were enrolled (MBC n=53, lung cancer n=38, metastatic cancer of any type n=59). The MBC cohort analysis is presented. The MBC cohort had a median age of 59; all were female; majority Caucasian (48/53, 91%); most were married/in domestic partnership (35/53, 66%). For the primary endpoint, there was a significant increase in video message-specific knowledge (Wilcoxon signed rank p< 0.0001) but there was no significant change in general genomic knowledge (p=0.89) or trust in provider (p=0.59). Improvement of video message-specific knowledge was consistent across demographic groups, including age, income, and education. Of the 10-questions in the VMSK survey, results for four questions significantly improved after viewing the video, including questions informing the likelihood of TGT impact on treatment decision, incidental germline findings, and cost of testing (Table 1). Baseline genomic knowledge was significantly associated with income (nominal p=0.028), with higher income associated with higher baseline knowledge. Conclusions: A concise, 3-4 minute, broadly applicable video incorporating culturally diverse images administered prior to TGT significantly improved video message-specific knowledge across all demographic groups. Ongoing work includes analysis of additional cohorts (lung, any type) and evaluation in community oncology setting with a goal to provide a paradigm to efficiently educate and empower patients while addressing ASCO/ACMG guidelines within the flow of clinical practice. Table 1. Response to video message-specific questions before versus after tumor genomic testing educational video intervention Citation Format: Daniel Stover, Deloris Veney, Lai Wei, Amanda Toland, Carolyn Presley, Tasleem Padamsee, Clara Lee, Heather Hampel, William Irvin, Jawad Francis, Michael Bishop, Shelly Hovick, Leigha Senter. A Video Intervention to Improve Patient Understanding of Tumor Genomic Testing in Patients with Metastatic Breast Cancer: Primary Results of a Prospective Intervention Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-07.
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