164P Incorporation of the polygenic risk score (PRS) in breast cancer (BC) risk estimation among carriers of a moderate penetrance pathogenic variant (MPPV)

Women with MPPV in BC genes have broad risk estimates. Follow-up and prevention guidelines often employ a one-size-fits-all approach. However, the PRS may help stratify the risk. We aimed to evaluate the change in risk stratification when adding the PRS to the classical BC risk factors in healthy women harboring a MPPV. Multicentric study of women aged 30-70 with a germline pathogenic variant in PALB2, CHEK2, ATM, BARD1, or RAD51C/D and available breast density (BD). Genotyping employed the PRiSma-268 array. Cumulative 10-year risk was calculated using the BOADICEA v.6 model: the baseline model included personal, family history, and BD; and the full model incorporated the PRS. BC risk was categorized as average, moderate, and high based on NICE guidelines (8%, respectively). Descriptive statistics were used. We included 133 women with a median age of 49 years (30–67.5), with most harboring pathogenic variants in ATM (36%), PALB2 (24%), and CHEK2 (20.3%). Median Z score was 0.27 -2.72–3.45, with the highest in CHEK2 (0.89 -1.83-2.44) and the lowest in RAD51C (-0.21 -1.31-3.45). Overall, median 10-year risk was 6% 0.7–22.7 in the baseline model and 5.6% 2.6–22.7 in the full model. After adding the PRS, risk group classification shifted in 28% of women, with 15% increasing and 13% decreasing their respective categories. In ATM and RAD51C, 23% and 56% of women were categorized as average risk with the full model. However, results should be interpreted with caution due to the limited sample size (Table).Table: 164PGeneAll carriersPALB2ATMCHEK2BARD1RAD51CRAD51DN (%)133 (100)32 (24)48 (36)27 (20,3)5 (3,7)16 (12)5 (3,7)Median age49 30-67,547,1 30,7-64,350 36,8-68,149 32,2-6246,6 42,9-65,156,5 32,4-66,943,1 33,1-62Median Z score0,27 -2,7-3,40,01 -2,5-1,90,06 -2,7-3,10,89 -1,8-2,40,49 0,5-0,8-0,21-1,3-3,40,40 0,01-1,7Basal/Full model (%) Average Moderate High17/20,354/44,329/35,33/628/2569/6912,5/2375/5212,5/2530/1537/5233/330/060/6040/4037,5/5662,5/380/620/2080/600/20Total risk group change (%) Increase Decrease Stable27,81512,872,228,112,515,671,931,316,714,668,822,214,87,477,800010037,512,52562,52020080 Open table in a new tab Adding the PRS to BC risk estimation in carriers of MPPV significantly modifies BC risk stratification, which may provide valuable information for making informed decisions regarding preventive measures and screening strategies.