Homologous recombination deficiency in primary ER-positive and HER2-negative breast cancer

TL;DR

This study finds that HRD is rare in ER-positive HER2-negative breast cancer and does not significantly affect patient outcomes after standard treatment.

Contribution

The study provides the first comprehensive analysis of HRD in ER-positive HER2-negative breast cancer using whole-genome sequencing and clinical data.

Findings

HRD occurs in 8.4% of ER-positive HER2-negative breast cancer cases, much less than in triple-negative breast cancer.

HRD in these tumors is mainly caused by alterations in BRCA1/BRCA2/RAD51C/PALB2 genes.

HRD tumors do not show distinct gene expression or DNA methylation profiles and do not consistently predict worse outcomes with standard therapy.

Abstract

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, adjuvant treatment, and outcome data.

We show that HRD is much less frequent in ERpHER2n BC (8.4%) compared to TNBC, though induced by similar genetic/epigenetic mechanisms acting on mainly BRCA1/BRCA2/RAD51C/PALB2 together, providing a plausible HR-inactivation mechanism for 71.4% of HRD tumors. Our modelled estimate of HRD in Western European/Nordic BC is ~10-13%. HRD tumors were observed across all PAM50 gene expression subtypes with the exception of Luminal A tumors ( < 1%) and did not exhibit a unique, defining transcriptional or DNA methylation profile. While HRD status was not statistically associated with differences in patient outcome for patients treated with combined chemotherapy and endocrine therapy, a nonsignificant trend of poorer outcome for patients with HRD tumors was observed for patients treated with adjuvant endocrine therapy only.

ERpHER2n HRD tumors show features of aggressive disease, but do not display a distinct transcriptional or DNA methylation profile that clearly differentiates them from HR-proficient tumors. Though numbers are limited, we present early evidence that HRD stratification by WGS could impact therapeutic strategies, as HRD BCs trended to poorer outcomes when not treated with chemotherapy.

In this study, we examined the frequency, causes, molecular features, and clinical relevance of homologous recombination (HR) deficiency (HRD) in primary ER-positive/HER2-negative breast cancer using whole-genome sequencing of 502 tumors. HRD was uncommon ( < 10%) and mainly driven by alterations in well-established DNA repair genes, similar to other breast cancer subtypes. HRD tumors did not show clear differences in gene expression or DNA methylation compared with HR-proficient tumors. Clinically, HRD status was not significantly associated with patient outcomes after adjuvant systemic therapy, although patients with HRD tumors treated with endocrine therapy alone showed a trend toward poorer outcomes.

Davies, Black et al., investigate the frequency, cause, molecular associations, and prognostic implications of homologous recombination deficiency (HRD) in primary estrogen receptor-positive and HER2-negative breast cancer. HRD was less frequent (8.4%), induced mainly by alterations acting on BRCA1/BRCA2/RAD51C/PALB2, but not associated with patient outcome after adjuvant systemic therapy.

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