Homologous recombination deficiency in primary ER-positive and HER2-negative breast cancer
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Homologous recombination deficiency (HRD) originating from inactivation of genes like BRCA1 / BRCA2 is a targetable abnormality common in triple-negative breast cancer (TNBC). In estrogen-receptor (ER)-positive HER2-negative (ERpHER2n) breast cancer (BC), HRD prevalence and clinical impact are unclear. We analyzed 502 ERpHER2n tumors from patients recruited via the population-representative Swedish SCAN-B study, by whole genome sequencing (WGS) defining mutational signatures-based HRD, as well as matched transcriptional, DNA methylation, clinicopathological, treatment and outcome data. HRD is much less frequent in ERpHER2n BC (8.4%) compared to TNBC (58.6%), though induced by similar genetic/epigenetic mechanisms acting on mainly BRCA1 / BRCA2 / RAD51C / PALB2 . Our modelled estimate of HRD in Western European BC is ∼10-13%. HRD tumors were observed across all gene expression subtypes and did not exhibit a unique, defining transcriptional or DNA methylation profile. Though numbers are limiting, we present early evidence that HRD stratification by WGS could impact therapeutic strategies, as HRD BCs trended to poorer outcomes, especially when not treated with chemotherapy.
