Detection of pathogenic variants in breast cancer susceptibility genes in bilateral breast cancer.

Abstract

To investigate the frequency of germline pathogenic variants (PVs) in women with bilateral breast cancer. We undertook <i>BRCA1/2</i> and <i>CHEK2</i> c.1100delC molecular analysis in 764 samples and a multigene panel in 156. Detection rates were assessed by age at first primary, Manchester Score, and breast pathology. Oestrogen receptor (ER) status of the contralateral versus first breast cancer was compared on 1081 patients with breast cancer with <i>BRCA1</i>/B<i>RCA2</i> PVs. 764 women with bilateral breast cancer have undergone testing of <i>BRCA1/2</i> and <i>CHEK2</i>; 407 were also tested for <i>PALB2</i> and 177 for <i>ATM</i>. Detection rates were <i>BRCA1</i> 11.6%, <i>BRCA2</i> 14.0%, <i>CHEK2</i> 2.4%, <i>PALB2</i> 1.0%, <i>ATM</i> 1.1% and, for a subset of mainly very early onset tumours, <i>TP53</i> 4.6% (9 of 195). The highest PV detection rates were for triple negative cancers for <i>BRCA1</i> (26.4%), grade 3 ER+HER2 for <i>BRCA2</i> (27.9%) and HER2+ for <i>CHEK2</i> (8.9%). ER status of the first primary in <i>BRCA1</i> and <i>BRCA2</i> PV heterozygotes was strongly predictive of the ER status of the second contralateral tumour since ~90% of second tumours were ER- in <i>BRCA1</i> heterozygotes, and 50% were ER- in <i>BRCA2</i> heterozygotes if the first was ER-. We have shown a high rate of detection of <i>BRCA1</i> and <i>BRCA2</i> PVs in triple negative and grade 3 ER+HER2- first primary diagnoses, respectively. High rates of HER2+ were associated with <i>CHEK2</i> PVs, and women ≤30 years were associated with <i>TP53</i> PVs. First primary ER status in <i>BRCA1/2</i> strongly predicts the second tumour will be the same ER status even if unusual for PVs in that gene.