Introduction: Pathogenic variants (PVs) in high- and intermediate-penetrance breast cancer susceptibility genes have large effects on disease risk. While individual PVs are rare, in aggregate, they markedly contribute to breast cancer risk in women of European ancestry in the general population. We examined the association with risk of developing breast cancer in Latinas. Methods: We conducted a pooled case-control analysis of breast cancer in Latinas from the San Francisco Bay Area, Los Angeles, and Mexico (4,172 cases and 3,692 controls). Case ascertainment included 2,095 participants from high-risk breast cancer studies (age below 50 years at breast cancer diagnosis, family history, or bilateral breast cancer) and 5,769 from general population studies. We determined presence of a rare PV in nine known breast cancer risk genes (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, RAD51C, and TP53). We examined associations between PVs in each gene and breast cancer using multivariable logistic regression models, adjusted for age and ancestry. Secondary analyses were stratified by age, family history, or Indigenous American (IA) ancestry. Results: PVs in known risk genes were detected in 7.0% of cases and 1.7% of controls in participants from general population studies. Odds ratios (OR) for breast cancer in those with PVs in BRCA1, BRCA2, CHEK2, PALB2, and TP53 were 15.7 (95% CI: 5.7-64.8), 7.0 (95% CI: 3.7-14.4), 1.9 (95% CI: 1.0-4.0), 6.1 (95% CI: 3.1-13.9), and 3.7 (95% CI: 1.1-16.2) respectively. PVs in ATM (OR: 1.2, 95% CI: 0.7-2.1), BARD1 (OR: 1.5, 95% CI: 0.3-10.4), PTEN (PVs in 4 cases and 0 controls), and RAD51C (OR: 1.5, 95% CI: 0.2-11.5) were not significantly associated with breast cancer. Among cases, those with age<50 at diagnosis or with family history of breast cancer had increased odds of having a PV, with ORs of 1.4 (95% CI: 1.0-1.9) and 2.3 (95% CI: 1.4-4.0), respectively. IA above the median was associated with increased odds of having a PV among cases (OR: 1.8; 95% CI: 1.4-2.5) but not among controls. Discussion: Among Latina participants, having a PV in any of the nine genes was associated with increased risk of breast cancer. As expected, cases who were younger or had a family history of breast cancer were more likely to have a PV. In addition, cases but not controls with high IA were more likely to have a PV. The higher prevalence of PVs among high IA cases but not controls may be due to the younger age of these women and/or lower prevalence of other environmental risk factors. Our PV prevalence estimates among Latinas were similar to those previously found among European ancestry participants. Our results suggest that there may be clinical utility in testing for rare PVs in breast cancer risk genes among those in the general population.

Citation Format: Jovia L Nierenberg, Aaron Adamson, Yuan C. Ding, Yiwey Shieh, Donglei Hu, Scott Huntsman, Esther M. John, Gabriela Torres-Mejia, Christopher A. Haiman, Lawrence H. Kushi, Charite N. Ricker, Linda Steele, Robin Lee, Jeffrey N. Weitzel, Laura Fejerman, Elad Ziv, Susan L. Neuhausen. Pathogenic variants in breast cancer risk genes in Latinas [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-164.