Abstract P3-02-07: Breast Cancer Polygenic Risk Score and Patient Survival Outcomes Among Caucasians

Abstract Introduction: Genome-wide association studies have identified many common, low-penetrance variants associated with breast cancer risk. This has led to the development of polygenic scores (PGS) to aggregate the effects of individual variants for risk prediction. However, the genetic determinants of breast cancer-related outcomes remain largely unknown. We hypothesize that breast cancer patients with high PGS are at an increased risk of experiencing a second breast-related adverse event, such as recurrence, contralateral breast cancer, or death. Methods: The study is based on the Pathways Study, which is a prospective cohort study of breast cancer survivors enrolled shortly after diagnosis in 2006-2013 at Kaiser Permanente Northern California, with ongoing follow-up. Genome-wide genotype data were available from 3,995 patients for calculation of 4 PGS, including PGS313, PGS4k, PGS5k and PGS6m. Scores were categorized into tertiles to investigate their associations with 7 survival outcomes including recurrence, contralateral second primary breast cancer, other second primary cancer, and death. Hazard ratios (HR) and 95% confidence intervals (CI) were derived from multivariable Cox proportional hazards regression models. The models were adjusted for age at diagnosis, race and ethnicity group, tumor stage, tumor grade, IHC subtype, surgery, radiotherapy, chemotherapy, and endocrine therapy. Results: The median age at diagnosis was 60 (23.6-94.8) years and most (68%, n= 2696) patients self-identified as Non-Hispanic whites. Many women had estrogen receptor (ER)+ (83.4%), stage I and II tumors (89%), with 13.3% HER2+ tumors. The majority (60%) received lumpectomy and some type of adjuvant therapy (44.3% radiotherapy, 47.0% chemotherapy, and 74.6% received hormonal therapy). By December 31, 2021, the median follow-up time was 10.5 (0.2-14.2) years. In the overall cohort, there were 504 recurrences, 419 total second primary cancers (146 contralateral and 237 non-breast), and 762 deaths (352 breast cancer-specific). Among Non-Hispanic whites, there were 333 recurrences, 322 total second primary cancers (113 contralateral and 184 non-breast), and 558 deaths (224 breast cancer-specific). In the overall cohort, breast cancer patients with high (T3) PGS313 had a higher risk of recurrence (HR 1.29, 95% CI: 1.02-1.61, p=0.04), all-cause death (HR 1.28, 95% CI: 0.96-1.31, p=0.03), total breast cancer events (HR 1.29, 95% CI: 1.04-1.54, p=0.02) and invasive breast cancer events (HR 1.34, 95% CI: 1.09-1.63, p=0.006) compared to those with low (T1) PGS313. Although breast cancer-specific death was observed to be higher among those with high PGS313 in the overall cohort, it was not statistically significant (HR 1.34, 95% CI: 0.99-1.73, p=0.007). In the subgroup analysis, it was observed that Non-Hispanic White breast cancer patients with high (T3) PGS313 had similar higher risk of recurrence (HR 1.29, 95% CI: 1.06-1.83, p=0.04) but not contralateral breast cancer (HR 1.22, 95% CI: 0.76-1.94, p=0.58) or other second primary cancers (HR 1.01, 95% CI: 0.77-1.34, p=0.86). They also had a higher risk of all-cause death (HR 1.30, 95% CI: 0.99-1.41, p=0.04), breast cancer-specific death (HR 1.53, 95% CI: 1.08-2.15, p=0.03), and invasive breast cancer (HR 1.33, 95% CI: 1.06-1.71, p=0.02). The other three PGS were not associated with survival outcomes in either the overall or Non-Hispanic White cohorts examined. Conclusions: Breast cancer patients with higher PGS313 scores were found to have an elevated risk of recurrence, invasive breast cancer events, and death. These results suggest that breast cancer PGS may have additional prognostic utility in patients diagnosed with the disease, indicating the need for further investigation. Citation Format: Arya Mariam Roy, Nur Zeinomar, Haiyang Sheng, Janise M. Roh, Cecile A. Laurent, Isaac J. Ergas, Jennifer Delmerico, Qianqian Zhu, Marilyn L. Kwan, Lawrence H. Kushi, Christine B. Ambrosone, Song Yao. Breast Cancer Polygenic Risk Score and Patient Survival Outcomes Among Caucasians [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-02-07.