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

Abstract

PurposeTo investigate the frequency of germline pathogenic variants (PVs) in women with bilateral breast cancer.MethodsWe undertookBRCA1/2andCHEK2c.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 withBRCA1/BRCA2PVs.Results764 women with bilateral breast cancer have undergone testing ofBRCA1/2andCHEK2; 407 were also tested forPALB2and 177 forATM. Detection rates wereBRCA111.6%,BRCA214.0%,CHEK22.4%,PALB21.0%,ATM1.1% and, for a subset of mainly very early onset tumours,TP534.6% (9 of 195). The highest PV detection rates were for triple negative cancers forBRCA1(26.4%), grade 3 ER+HER2 forBRCA2(27.9%) and HER2+ forCHEK2(8.9%). ER status of the first primary inBRCA1andBRCA2PV heterozygotes was strongly predictive of the ER status of the second contralateral tumour since ~90% of second tumours were ER− inBRCA1heterozygotes, and 50% were ER− inBRCA2heterozygotes if the first was ER−.ConclusionWe have shown a high rate of detection ofBRCA1andBRCA2PVs in triple negative and grade 3 ER+HER2− first primary diagnoses, respectively. High rates of HER2+ were associated withCHEK2PVs, and women ≤30 years were associated withTP53PVs. First primary ER status inBRCA1/2strongly predicts the second tumour will be the same ER status even if unusual for PVs in that gene.