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

Davies, Helen R ; Black, Daniella ; Kvist, Anders LU orcid ; Sigurjónsdóttir, Kristín LU ; Bosch, Ana LU ; Bowden, Ramsay ; Memari, Yasin ; Chen, Ziqian ; Rinaldi, Giuseppe and Rosengren, Frida LU , et al. (2026) In Communications medicine 6(1).
Abstract

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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Communications medicine
volume
6
issue
1
article number
118
publisher
Nature Publishing Group
external identifiers
  • scopus:105030198679
  • pmid:41699108
ISSN
2730-664X
DOI
10.1038/s43856-026-01385-0
language
English
LU publication?
yes
id
d9ea6472-a548-4abd-930d-671617a52eda
date added to LUP
2026-02-17 08:56:32
date last changed
2026-07-17 00:53:58
@article{d9ea6472-a548-4abd-930d-671617a52eda,
  abstract     = {{<p>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.</p><p>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.</p><p>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 ( &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><p>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.</p>}},
  author       = {{Davies, Helen R and Black, Daniella and Kvist, Anders and Sigurjónsdóttir, Kristín and Bosch, Ana and Bowden, Ramsay and Memari, Yasin and Chen, Ziqian and Rinaldi, Giuseppe and Rosengren, Frida and Nacer, Deborah F and Veerla, Srinivas and Hohmann, Lennart and Nordborg, Nicklas and Häkkinen, Jari and Vallon-Christersson, Johan and Borg, Åke and Nik-Zainal, Serena and Staaf, Johan}},
  issn         = {{2730-664X}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Communications medicine}},
  title        = {{Homologous recombination deficiency in primary ER-positive and HER2-negative breast cancer}},
  url          = {{http://dx.doi.org/10.1038/s43856-026-01385-0}},
  doi          = {{10.1038/s43856-026-01385-0}},
  volume       = {{6}},
  year         = {{2026}},
}