Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas

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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 ofBRCA1/2and 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 ofBRCA1,BRCA2orRAD51Cconfirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring inBRCA1/2mutant 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.

What's new?

The BRCA1/2 tumor suppressors play a key role in DNA repair by homologous recombination, and inactivation of these factors is associated with high breast and ovarian cancer risk. Here, the authors performed a comprehensive study of breast tumors screening for homologous recombination deficiency (HRD) measured by large-scale chromosomal breaks. They find good overlap between HRD-positivity and BRCA mutations, but also identify a small subset of HRD+ tumors in which the sole determination of BRCA1/2 mutational status is insufficient. This points to HRD determination as a potentially important method to find patients benefiting most from emerging new therapies such as PARP inhibitors.

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