Abstract P1-09-04: Association between a breast cancer polygenic risk score and contralateral breast cancer risk

Abstract

Background Breast cancer patients are at significant risk of a second contralateral, breast cancer (CBC). Identification of women at high or low CBC risk could improve patient management decisions. Previous research has shown that breast cancer-associated single nucleotide polymorphisms (SNPs) summarized in a polygenic risk score (PRS) predict the risk of a first breast cancer with an odds ratio (OR) per 1 SD of 1.55 (95% confidence interval (95%CI)=1.52-1.58) (77-SNP PRS). The aim of this study was to evaluate the association between a recently developed PRS and CBC risk. Methods We identified 19 studies from the Breast Cancer Association Consortium (BCAC) with follow-up information on participating patients and at least 10 patients diagnosed with CBC. This included 38,228 females of European ancestry diagnosed with first invasive breast cancer since 1990. Genotyping was done using the iCOGS array or OncoArray, with genotypes for SNPs not on the arrays estimated by imputation. We used a 313-SNP PRS, optimized for prediction of overall (first) breast cancer in the BCAC dataset. Metachronous CBC risk by PRS was quantified using univariable and multivariable Cox regression analyses stratified by country and adjusted for multiple patient, tumor, and treatment characteristics. We assessed PRS interaction with age, family history, adjuvant systemic therapy, and ER-status. Results Median time to develop a CBC (N=1,046) after a first breast cancer was 5.8 years (range 0.3-21.9). Higher PRS was associated with increased CBC risk: hazard ratio (HR) per 1 SD=1.31 (95%CI=1.23-1.39). Patients in the highest and lowest 5% of the PRS had 1.95 fold and 0.67 fold risks of CBC, respectively, compared with patients in the middle quintile. Adjustments for age, year of diagnosis, family history, tumor size, nodal status, ER-status, or treatment (chemotherapy, endocrine therapy, radiotherapy) did not substantially alter these results. We found an interaction with age at first breast cancer diagnosis (Pinteraction=.002); the PRS was associated with an increased CBC risk for patients aged ≥40 years (HR=1.37, 95%CI=1.28-1.47), but not for patients <40 years (HR=1.06, 95%CI=0.93-1.21). Conclusion The PRS is predictive for the development of CBC in patients ≥40 years at first breast cancer diagnosis. For this group, the PRS could be incorporated in CBC risk prediction models to help define high and low risk patients, and hence optimize screening and treatment strategies. Citation Format: Kramer I, Hooning MJ, Breast Cancer Association Consortium (BCAC), Mavaddat N, Canisius S, Keeman R, van den Broek AJ, Steyerberg E, Hauptmann M, Pharoah PD, Easton DF, Hall P, Schmidt MK. Association between a breast cancer polygenic risk score and contralateral breast cancer risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-04.

The risk of contralateral breast cancer: a SEER-based analysis

“…Compared to women who scored at the 50th percentile, the odds ratios were 0.75 and 1.33 for those in the 10th percentile and 90th percentile, respectively. 27 The authors did not calculate the actuarial risk of contralateral breast cancer in this case-control study, but if we assume a 25-year risk of 10%, then the great majority of women would fall within three percentage points of this mean. It is yet to be shown that providing a PRS for contralateral breast cancer will influence a woman's surgical decision.…”

“…SEER also does not capture information on commonly occurring single-nucleotide polymorphisms (SNPs) that have been reported to influence the risk for contralateral breast cancer. 26,27 In a large case-control study conducted by the Breast Cancer Association Consortium, Kramer et al reported on the impact of a personal risk score (PRS) based on 313 SNPs on the relative risk of developing metachronous contralateral breast cancer. Compared to women who scored at the 50th percentile, the odds ratios were 0.75 and 1.33 for those in the 10th percentile and 90th percentile, respectively.…”

Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival

“…As previously described, adjustment for type of array was not needed because of the high correlation of PRS 313 between the two platforms. 12,13 All participants provided written informed consent, and all studies were approved by the relevant institutional review boards. BCAC data were centrally harmonized and cleaned in consultation with the study data managers and principal investigators.…”

“…12 PRS 313 is also associated with a higher risk of contralateral breast cancer with a HR per SD of 1.25 (95% CI, 1.18 to 1.33). 13 PRS for subtypespecific disease (estrogen receptor [ER]-positive and ER-negative disease) have also been established, although currently the risk prediction for ER-positive disease is better than for ER-negative disease. 7,12 One of the most promising clinical applications for PRS is to provide a personalized risk assessment to individualize breast cancer screening.…”

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants inATM,BRCA1,BRCA2,CHEK2, andPALB2

“…The risk of contralateral breast cancer (CBC) among women with breast cancer in the general population is estimated to be 0.5% per year, 1,2 with germline mutation status, race/ethnicity, age at diagnosis, and menopausal status significantly influencing the risk. [3][4][5][6] Germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are detected in 5%-7% of women with breast cancer in the general population and are associated with a significantly increased risk of breast cancer in unaffected women. [7][8][9][10] The CBC risk among carriers of germline PVs, especially for ATM, CHEK2, and PALB2 PV carriers, is not well-defined.…”