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Background <p>Homologous recombination deficiency (HRD) originating from inactivation of genes like <i>BRCA1</i>/<i>BRCA2</i> 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.</p> Methods <p>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.</p> Results <p>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 <i>BRCA1</i>/<i>BRCA2</i>/<i>RAD51C</i>/<i>PALB2</i> 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 ( &lt; 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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月16日

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  • Helen R. Davies,
  • Daniella Black,
  • Anders Kvist,
  • Kristín Sigurjónsdóttir,
  • Ana Bosch,
  • Ramsay Bowden,
  • Yasin Memari,
  • Ziqian Chen,
  • Giuseppe Rinaldi,
  • Frida Rosengren,
  • Deborah F. Nacer,
  • Srinivas Veerla,
  • Lennart Hohmann,
  • Nicklas Nordborg,
  • Jari Häkkinen,
  • Johan Vallon-Christersson,
  • Åke Borg,
  • Serena Nik-Zainal,
  • Johan Staaf

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.