Abstract P3-13-01: Association of polygenic risk score with 2 year risk of poor prognosis breast cancer
Authors: McCarthy Anne Marie , Manning Alisa K. , Hsu Sarah , Moy Beverly , Lehman Constance D. , Armstrong Katrina 
Published: March 2022

Introduction: Mammography reduces breast cancer mortality, however, there is controversy surrounding when and how often women should undergo mammography screening. Knowledge of short-term risk of developing breast cancer, particularly poor prognosis breast cancer, would help direct more intensive screening to those at highest risk. Polygenic risk scores (PRS) are emerging as a powerful tool to predict breast cancer risk, however, few studies have evaluated the associations of breast cancer PRS with short-term risk or with risk of poor prognosis breast cancers specifically. Methods: Using a mammography screening cohort at Massachusetts General Hospital, we identified women who had a negative mammogram (BI-RADS assessment 1 or 2) from 2006 to 2015. We linked the cohort to a research biobank to obtain genetic information. In addition, we recruited 205 patients who developed breast cancer within 2 years of a negative mammogram to provide a DNA sample. Women with a prior history of breast cancer, with breast implants, and who were not residents of Massachusetts were excluded. Samples were genotyped using the Illumina Multi-Ethnic GWAS/Exome SNP (MEGA) array. Genotypes were imputed using TOPMed (Version r2 2020). Patients whose saliva DNA samples had low concentration or that failed quality control procedures were excluded. Ancestry specific principal components were generated and used as a covariate. We generated the 313-SNP breast cancer PRS, the estrogen receptor positive (ER+) PRS and the estrogen receptor negative (ER-) PRS using established methods. (PMID: 30554720) Breast cancers were defined as poor prognosis if they were metastatic, had positive lymph nodes, were ER/PR+HER2- and &gt 2cm or ER/PR/HER2- or HER2+ and &gt 1cm. (PMID: 33169794) Logistic regression was used to estimate the odds ratios for standardized PRS measures, adjusted for age, breast density, race/ethnicity, year of screening, and ancestry principal components. Results: After exclusions, 308 breast cancers and 3329 non-cases were analyzed. Of the breast cancers, 86% were ER/PR+ (264/308) and 14% were ER/PR- (42/308), and 137 (44%) were poor prognosis. The majority of patients were non-Hispanic White (87%) and the mean age was 57 years and was similar for cancers and non-cancers. Cancer cases were more likely than non-cases to have higher breast density and a family history of breast cancer. First, we examined the overall breast cancer PRS, and found the PRS was significantly associated with breast cancer diagnosed within two years of a negative mammogram (OR=1.39, 95% CI 1.23-1.57, p &lt 0.001). The PRS was also significantly associated specifically with diagnosis of poor prognosis disease (OR=1.21, 95% CI 1.01-1.45, p=0.037). In addition, the ER+ PRS was significantly associated with ER/PR+ breast cancer (OR=1.41, 95% CI 1.24-1.61, p &lt 0.001), and the ER- PRS was significantly associated with ER- breast cancer (OR=1.48, 95% CI 1.08-2.02, p=0.015). Conclusion: Even after adjusting for breast density and other risk factors, breast cancer PRS was significantly associated with diagnosis of both breast cancer overall and poor prognosis breast cancer within two years of a negative mammogram. Furthermore, the subtype specific PRS were significantly associated with short-term risk of ER+ and ER- disease. These results suggest that PRS may be useful in guiding decisions about screening interval and supplemental screening, given the association of PRS with risk of poor prognosis disease in the short term.

Table 1.Logistic Regression of PRS and cancer diagnosis within 2 years of a negative mammogramOR95% CIp-valueAll Cancers (N=308), Overall PRS1.391.23-1.571.78x10-7Poor prognosis (N=147), Overall PRS1.211.01-1.450.037ER+ cancers (N=264), ER+ PRS1.421.24-1.621.87x10-7ER- cancers (N=42), ER- PRS1.521.11-2.090.008

Citation Format: Anne Marie McCarthy, Alisa K. Manning, Sarah Hsu, Beverly Moy, Constance D. Lehman, Katrina Armstrong. Association of polygenic risk score with 2 year risk of poor prognosis breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-01.