Abstract C039: Influence of patient ancestry on homologous recombination repair deficiency in cancer

Abstract Homologous recombination repair deficiency (HRD) is a common driver of tumorigenesis that carries therapeutic implications, particularly in breast, ovarian, prostate, and pancreatic cancers. The influence of genetic ancestry on the incidence of HRD in these tumors remains to be defined. Previous studies have reported a higher incidence of variants of unknown significance (VUS) in individuals of non-European ancestry. Here, we evaluated the frequency of HR-deficiency within a diverse cohort of 566 patients with breast, prostate, ovarian, or pancreatic cancer. Genetic ancestry was estimated from constitutional whole exome sequencing data using a single nucleotide polymorphism weight model containing five ancestral populations: European, Native American, African, East Asian, and South Asian. Frequencies of clinical genetic testing, germline variants in HR-genes, and tumor HRD were compared between individuals of admixed Native American and European ancestry (n=82) and those of European ancestry (n=378). Admixed Native American/European individuals had a younger age at diagnosis compared to individuals of European ancestry (median 52.4 years (range, 20.8-83.6) vs 62.9 years (range, 20.9-87.9), p<0.0001; two-tailed unpaired t-test), driven by a younger age of diagnosis in admixed Native American/European individuals with breast cancer. 22.6% of patients received genetic testing as part of their clinical care, with an increased rate of genetic testing in admixed Native American/European individuals with breast cancer, consistent with the younger age of diagnosis in this population. Among individuals who received clinical germline testing, there was no significant difference based on patient ancestry in the time from cancer diagnosis until germline testing was performed. In the cohort overall, individuals of admixed Native American/European ancestry and those of European ancestry had a similar frequency of both pathogenic/likely-pathogenic (P/LP) (8.5% vs 6.3%) and VUS (17.1% vs 15.1%) germline variants in HR genes. In breast cancer patients who were younger than 50 years at diagnosis, admixed Native American/European individuals showed a trend toward a higher frequency of P/LP events compared to European individuals (17.6% vs 7.0%, p=0.1722). The frequency of somatic variants in HR genes and the rate of tumor HR-deficiency were similar between patients of admixed Native American/European ancestry and those of European ancestry. In summary, in this retrospective analysis, women of admixed Native American/European ancestry showed a younger age of breast cancer diagnosis and a trend toward increased incidence of pathogenic or likely-pathogenic germline variants in HR genes compared to women of European ancestry. These data support a role for genetic ancestry influencing cancer risk and phenotypes. Additional studies evaluating the impact of genetic ancestry on HRD are needed to reduce disparities in genetic testing and improve application of therapies targeting HRD in diverse cancer populations. Citation Format: Sara A. Byron, Guangfa Zhang, Kimber Slater, Jiaming Zhang, Tyler Izatt, Bryce Turner, Xiao-Yu Xia, Rick A. Kittles, Jonathan J. Keats, Jeffrey M. Trent, Nicholas J. Schork, Lorna Rodriguez-Rodriguez. Influence of patient ancestry on homologous recombination repair deficiency in cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C039.