Addition of a 161-SNP polygenic risk score to family history-based risk prediction: impact on clinical management in non-BRCA1/2breast cancer families

Abstract

BackgroundThe currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families.Methods101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS.ResultsThe mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively.ConclusionOur results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.

Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field

“…Several studies have examined the effect of PRS on existing risk prediction models, including the Gail Model [39,46,56,[58][59][60][61][62], Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) [46,63,64], Tyrer-Cuzick (TC) [39,41,46,49,52], BRCAPRO [46], and Breast Cancer Surveillance Consortium (BCSC) [30,40,65] (Table 2). These statistical models utilize a range of well-known breast cancer risk factors such as personal and family history, breast pathology, and lifestyle factors to estimate the risk of breast cancer.…”

“…Thus, there is a need to develop new method of risk stratification to inform risk management decisions for women with uninformative results from monogenic testing. Studies assessing the application of polygenic factors for familial cancer have reported that PRS was predictive of breast cancer risk among women from high-risk families with uninformative BRCA1/2 result [7,31,32,34,46,56,64]. Higher PRS has also been reported among women from breast cancer families when compared to those without a family history of the disease [29,31,32], suggesting that breast cancer variants may cluster in affected families.…”

Simplified Breast Risk Tool Integrating Questionnaire Risk Factors, Mammographic Density, and Polygenic Risk Score: Development and Validation

“…Over the past decade our models were built from life course risk factors that include reproductive factors, adiposity at different points in life, age and type of menopause, menopausal hormone therapy, family history of breast cancer, personal history of benign breast disease, and alcohol intake (3)(4)(5)(6). Investigators have added to these models to improve discrimination often measured as the area under the ROC curve (AUC); and include MD (3,(7)(8)(9)(10); endogenous hormones (11); and/or PRS using a variable number of SNPs (12)(13)(14)(15)(16)(17)(18). While combinations of these factors have been evaluated (e.g., lifestyle factors and PRS or lifestyle factors and MD), models that combine measures from all three components (life course risk factors, MD, and PRS) (19)(20)(21) show the highest AUC values at 0.71 (9,22).…”

Clustering of known low and moderate risk alleles rather than a novel recessive high‐risk gene in non‐BRCA1/2 sib trios affected with breast cancer

“…46 With regard to the common low-risk variants, our results are consistent with studies which have found that non-BRCA1/2 familial breast cancer cases have a higher PRS than both cases from the general population and cases who carry a BRCA1 or BRCA2 pathogenic variant. [47][48][49][50] Whether the prevalence of rare missense variants in the known breast cancer genes we observed in our families is causally linked to breast cancer, will need very large case-control studies to substantiate further.…”