Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases

Abstract

BackgroundCommon low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families.MethodsWe included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known.ResultsThe family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM.ConclusionsOur results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.

Clinical Impact of Polygenic Risk Score for Breast Cancer Risk Prediction in 382 Individuals with Hereditary Breast and Ovarian Cancer Syndrome

“…In a Dutch study, the impact of incorporating the PRS into risk calculations for 1331 non-BRCA1/2 carriers was investigated regarding screening procedures aligned with Dutch IKNL [56], UK NICE [57], and US NCCN [58] BC screening guidelines. The results revealed clinically significant shifts in 32.4%, 36.0%, and 25.7% of individuals (with 30% BC lifetime risk cut-off levels based on the IKNL and NICE BC screening guidelines) [59].…”

Clinical implications of incorporating genetic and non-genetic risk factors in CanRisk-based breast cancer risk prediction

“…Clinical recommendations changed for 31·5 % (58/184) of these women when applying the 20 % eLTR threshold, 15·8 % (29/184) when applying the 30 % eLTR threshold, and 22·4 % (41/183) when applying the 5 % e10YR threshold. Lakeman et al recently described that integrating PRS 313 data in CanRisk-based risk prediction affects clinical recommendations for 26·8 % (635/2369) of women tested non-informative when applying the 20 % eLTR threshold, and 7·1 % (167/2369) when applying the 30 % eLTR threshold [ 19 ]. This is similar to the effects observed in our investigation using the PRS risk estimation model (20 % eLTR: 26·1 %, 48/184; 30 % eLTR: 12·0 %, 22/184, Table 3 ).…”

The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families

“…Firstly, risk effects conferred by CHEK2 and 77 common variants acted multiplicatively [ 16 ] and more recently, two studies including variant status, individual clinical variables and PRS showed meaningful shifts in LTBCR in CHEK2 carriers regardless of a family history of BC [ 24 , 25 ]. In the familial cancer setting, one study on BC risk prediction of non- BRCA1/2 Dutch families showed that the addition of PRS 313 changed clinical management in 58 % of the CHEK2 carriers [ 26 ]. However, a recent study found linkage between two SNPs located on the 22nd chromosome (chr22:29203724:C/T and chr22:29551872:A/G) and the CHEK2 c.1100delC variant, and therefore using PRS 313 would result in an overestimation of BC risk in heterozygotes.…”