Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas

Abstract

Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large‐scale State Transitions) genomic signature previously validated for triple‐negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2‐overexpressing (HER2+) tumors. The LST genomic signature related to the number of large‐scale chromosomal breakpoints in SNP‐array tumor profile was applied to identify HRD in in‐house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in‐house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild‐type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5–8%) and 2% (1/59, 95%CI: 2–9%), respectively. In TNBC cisplatin‐based neo‐adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors.