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

Abstract

Purpose

To investigate the frequency of germline pathogenic variants (PVs) in women with bilateral breast cancer.

Methods

We undertook BRCA1/2and CHEK2c.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 BRCA1/B RCA2PVs.

Results

764 women with bilateral breast cancer have undergone testing of BRCA1/2and CHEK2; 407 were also tested for PALB2and 177 for ATM. Detection rates were BRCA111.6%, 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 for BRCA1(26.4%), grade 3 ER+HER2 for BRCA2(27.9%) and HER2+ for CHEK2(8.9%). ER status of the first primary in BRCA1and BRCA2PV heterozygotes was strongly predictive of the ER status of the second contralateral tumour since ~90% of second tumours were ER− in BRCA1heterozygotes, and 50% were ER− in BRCA2heterozygotes if the first was ER−.

Conclusion

We have shown a high rate of detection of BRCA1and BRCA2PVs in triple negative and grade 3 ER+HER2− first primary diagnoses, respectively. High rates of HER2+ were associated with CHEK2PVs, and women ≤30 years were associated with TP53PVs. First primary ER status in BRCA1/2strongly predicts the second tumour will be the same ER status even if unusual for PVs in that gene.