Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in <i>ATM</i>, <i>BRCA1</i>, <i>BRCA2</i>, <i>CHEK2</i>, and <i>PALB2</i>.

Abstract

To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in <i>ATM</i>, <i>BRCA1</i>, <i>BRCA2</i>, <i>CHEK2</i>, and <i>PALB2</i>. The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. Germline <i>BRCA1</i>, <i>BRCA2</i>, and <i>CHEK2</i> PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the <i>PALB2</i> PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, <i>ATM</i> PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for <i>BRCA1</i>, 27% for <i>BRCA2</i>, and 13% for <i>CHEK2</i> PV carriers with breast cancer and 35% for <i>PALB2</i> PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for <i>BRCA1</i>, 9% for <i>BRCA2</i>, and 4% for <i>CHEK2</i>. Women diagnosed with breast cancer and known to carry germline PVs in <i>BRCA1</i>, <i>BRCA2</i>, <i>CHEK2</i>, or <i>PALB2</i> are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.