Rates of potentially actionable germline variants in homologous recombination repair genes in a large international cohort outside of the United States.

10590 Background: Identification of pathogenic germline variants (PGVs) in homologous recombination repair (HRR) genes among patients (pts) with breast (BC), ovarian (OC), pancreatic (PaC), and prostate cancer (PrC) is critical to determine potential eligibility for targeted therapies such as PARP inhibitors (PARPi). It is important to evaluate the frequency and patterns of PGVs across different regions of the World to help inform the counseling of pts and implementation of precision medicine. Methods: A retrospective analysis of pts with BC, OC, PaC, and/or PrC cancer undergoing GGT through a single laboratory was conducted. The location of the ordering provider determined the assigned region, which included: Asia-Pacific (APAC), Latin America (LATAM), Middle East and African (MEA), and United Kingdom and Europe (UKEU). Analyses were limited to pts tested for PARPi-eligible (in the US) HRR genes and PGV analysis to the 10 most frequent genes for that cancer type. Descriptive statistics and Chi square with Yates correction were utilized. Significance was set at p<0.05. Results: The cohort consisted of 40,539 pts with an average age at testing of 51 years, the majority of whom had BC (81%) (Table). The median number of genes tested ranged from 14-85 (Table). BRCA1 and BRCA2 were the most frequent genes with PGVs (3,358 pts, 8%). LATAM BC pts had significantly higher rates of BRCA1/2 PGVs (10%) than the other 3 regions ( p <0.0007). OC BRCA1/2 rates were high, and statistically similar, across regions (15-17%, p>0.08). Rates of BRCA1/2 and PALB2 in PaC pts did not differ between regions (4-7%, p>0.08), nor did rates of BRCA1/2, CHEK2, ATM, and PALB2 in PrC pts (7-11%, p>0.16) (Table). In sum, 3,434 pts (9% of those tested for the eligible genes) had PGVs in the above PARPi-eligible HRR genes. A notable limitation is that pts were ascertained by cancer type but information on other PARPi eligibility, namely metastatic/advanced disease, was not available. Conclusions: 1 in 12 pts were found to carry PARPi-eligible PGVs across the 4 cancer types and regions analyzed. Knowledge of these PGVs can help inform public health policies, current and future treatment strategies, and identify at-risk family members. In some countries, GGT may represent a more cost-effective and accessible pathway to targeted therapies compared to tumor profiling due to ease of sample collection and lower cost of testing. [Table: see text]