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

D Gareth Evans, George J Burghel, Helene Schlecht, Elaine F Harkness, Ashu Gandhi, Sacha J Howell, Anthony Howell, Claire Forde, Fiona Lalloo, William G Newman, Miriam Jane Smith, Emma Roisin Woodward

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

Methods We undertook BRCA1/2 and CHEK2 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 BRCA1/BRCA2 PVs.

Results 764 women with bilateral breast cancer have undergone testing of BRCA1/2 and CHEK2; 407 were also tested for PALB2 and 177 for ATM. Detection rates were BRCA1 11.6%, BRCA2 14.0%, CHEK2 2.4%, PALB2 1.0%, ATM 1.1% and, for a subset of mainly very early onset tumours, TP53 4.6% (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 BRCA1 and BRCA2 PV heterozygotes was strongly predictive of the ER status of the second contralateral tumour since ~90% of second tumours were ER− in BRCA1 heterozygotes, and 50% were ER− in BRCA2 heterozygotes if the first was ER−.

Conclusion We have shown a high rate of detection of BRCA1 and BRCA2 PVs in triple negative and grade 3 ER+HER2− first primary diagnoses, respectively. High rates of HER2+ were associated with CHEK2 PVs, and women ≤30 years were associated with TP53 PVs. First primary ER status in BRCA1/2 strongly predicts the second tumour will be the same ER status even if unusual for PVs in that gene.
Original languageEnglish
JournalJournal of Medical Genetics
Early online date13 Apr 2023
Publication statusE-pub ahead of print - 13 Apr 2023


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