The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Lakeman, I.M.M.; Broek, A.J. van den; Vos, J.A.M.; Barnes, D.R.; Adlard, J.; Andrulis, I.L.; ... ; KconFab Investigators (2021)

Article / Letter to editor

Purpose To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

• All authors: Lakeman, I.M.M.; Broek, A.J. van den; Vos, J.A.M.; Barnes, D.R.; Adlard, J.; Andrulis, I.L.; Arason, A.; Arnold, N.; Arun, B.K.; Balmana, J.; Barrowdale, D.; Benitez, J.; Borg, A.; Caldes, T.; Caligo, M.A.; Chung, W.K.; Claes, K.B.M.; Collee, J.M.; Couch, F.J.; Daly, M.B.; Dennis, J.; Dhawan, M.; Domchek, S.M.; Eeles, R.; Engel, C.; Evans, D.G.; Feliubadalo, L.; Foretova, L.; Friedman, E.; Frost, D.; Ganz, P.A.; Garber, J.; Gayther, S.A.; Gerdes, A.M.; Godwin, A.K.; Goldgar, D.E.; Hahnen, E.; Hake, C.R.; Hamann, U.; Hogervorst, F.B.L.; Hooning, M.J.; Hopper, J.L.; Hulick, P.J.; Imyanitov, E.N.; Isaacs, C.; Izatt, L.; Jakubowska, A.; James, P.A.; Janavicius, R.; Jensen, U.B.; Jiao, Y.; John, E.M.; Joseph, V.; Karlan, B.Y.; Kets, C.M.; Konstantopoulou, I.; Kwong, A.; Legrand, C.; Leslie, G.; Lesueur, F.; Loud, J.T.; Lubinski, J.; Manoukian, S.; McGuffog, L.; Miller, A.; Gomes, D.M.; Montagna, M.; Mouret-Fourme, E.; Nathanson, K.L.; Neuhausen, S.L.; Nevanlinna, H.; Yie, J.N.Y.; Olah, E.; Olopade, O.I.; Park, S.K.; Parsons, M.T.; Peterlongo, P.; Piedmonte, M.; Radice, P.; Rantala, J.; Rennert, G.; Risch, H.A.; Schmutzler, R.K.; Sharma, P.; Simard, J.; Singer, C.F.; Stadler, Z.; Stoppa-Lyonnet, D.; Sutter, C.; Tan, Y.Y.; Teixeira, M.R.; Teo, S.H.; Teule, A.; Thomassen, M.; Thull, D.L.; Tischkowitz, M.; Toland, A.E.; Tung, N.; Rensburg, E.J. van; Vega, A.; Wappenschmidt, B.; Devilee, P.; Asperen, C.J. van; Bernstein, J.L.; Offit, K.; Easton, D.F.; Rookus, M.A.; Chenevix-Trench, G.; Antoniou, A.C.; Robson, M.; Schmidt, M.K.; GEMO Study Collaborators; EMBRACE Collaborators; OCGN Investigators; HEBON Investigators; KconFab Investigators
• Date: 2021-06-10
• Journal: Genetics in Medicine
• Volume: 23
• Issue: 9
• Pages: 1726 - 1737
• DOI: doi:10.1038/s41436-021-01198-7
• Link: https://www.nature.com/articles/s41436-021-01198-7.pdf