Risk of Contralateral Breast Cancer in Women with and without Pathogenic Variants in , and Genes in Women with Very Early-Onset (<36 Years) Breast Cancer.

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in carriers diagnosed at very young ages. However, little is published on the risk of carriers. 397 women with breast cancer diagnosed <36 years of age were obtained from three sources: (i) a population-based study of 283 women diagnosed sequentially from 1980-1997 in North-West England, (ii) referrals to the Genomic Medicine Department at St Mary's Hospital from 1990-2018, and (iii) individuals from (i) and the Family History Clinic at Wythenshawe Hospital South Manchester who tested negative for pathogenic variants (PV) in all three genes. Sequencing of , and genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 , 218 , and 132 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in , , and . Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were : 7.03% (4.3%), : 3.57% (1.8%), and : 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in , and PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.