Contralateral breast cancer risks for BRCA1, BRCA2, PALB2, CHEK2, and ATM pathogenic variant carriers in two large cohort studies

All breast cancer (BC) patients have a risk of developing contralateral BC (CBC). This will be higher in women carrying a BC susceptibility gene pathogenic variant (PV), but specific risk estimates are lacking. We addressed this in a study-level meta-analysis of two large, recent cohort studies that used Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES) project and Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium data. We used population risks from the Netherlands to estimate 10-year cumulative CBC risks for BRCA1, BRCA2, PALB2, CHEK2 , and ATM PV carriers. We estimated pooled hazard ratios (HRs) in meta-analyses using the generic inverse-variance method and assuming random effects. We stratified by first BC estrogen receptor (ER) status. Among 462 BRCA1 , 590 BRCA2 , 796 CHEK2 , 297 PALB2 , and 345 ATM PV carriers, we estimated 10-year cumulative CBC risks of 10.1% (95% confidence interval (CI):7.5–13.6%) for BRCA1 , 10.2% (95%CI:7.4–13.9%) for BRCA2 , 7.1% (95%CI:3.4–14.3%) for PALB2 , 8.0% (95%CI:5.7–11.1%) for CHEK2 (any PV), 8.5% (95%CI:5.9–12.3%) for CHEK2 del.1100 C, and 4.5% (95%CI:2.5–8.0%) for ATM PV carriers. We found elevated HRs in BRCA1 (HR:2.8, 95%CI:2.1–3.6), BRCA2 (HR:2.8, 95%CI:2.1–3.7), and CHEK2 PV carriers (all PVs: HR:2.1, 95%CI:1.6–2.9. del.1100 C PVs only: HR:2.3, 95%CI:1.6–3.3). We found no significantly elevated risks in PALB2 (HR:1.9, 95%CI:0.9–3.8) or ATM (HR:1.2, 95%CI:0.7–2.1) PV carriers. We saw increased risks in BRCA1/2 and CHEK2 PV carriers following ER-positive BC, and in BRCA1/2 and PALB2 PV carriers following ER- negative BC. BC survivors carrying BRCA1, BRCA2 , and CHEK2 PVs and ER-negative BC survivors carrying PALB2 PVs are at two-fold or higher CBC risks. These estimates may assist clinical decision making for management of the contralateral breast.