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Global Transcriptional Complexity of Estrogen Receptor Low Positive Breast Cancers in a Prospective Swedish Population-based SCAN-B Cohort

Kimbung, Siker LU ; Veerla, Srinivas LU orcid ; Muhammad, Kadum ; Ehinger, Anna LU orcid ; Vallon-Christersson, Johan LU orcid ; Malmberg, Martin LU and Loman, Niklas LU (2025) In Clinical cancer research : an official journal of the American Association for Cancer Research
Abstract

PURPOSE: There is uncertainty whether ER-low tumors with a 1-10% immunohistochemical staining of nuclei represent a distinct molecular biological entity of BC, posing significant challenges for their clinical management and developing novel therapies. We aimed to elucidate ER-low tumor biology.

EXPERIMENTAL DESIGN: We analyzed primary tumors included in a Swedish population-based SCAN-B BC cohort, 2% (n=174) of which were classified ER-low. Transcriptional patterns, tumor inflammatory infiltration and prognosis were compared between ER-low versus ER-negative (ER-neg; 0%) and ER-positive (ER-pos; >10%) tumors.

RESULTS: The transcriptomes of ER-low and ER-neg tumors remarkably overlapped; displaying predominantly... (More)

PURPOSE: There is uncertainty whether ER-low tumors with a 1-10% immunohistochemical staining of nuclei represent a distinct molecular biological entity of BC, posing significant challenges for their clinical management and developing novel therapies. We aimed to elucidate ER-low tumor biology.

EXPERIMENTAL DESIGN: We analyzed primary tumors included in a Swedish population-based SCAN-B BC cohort, 2% (n=174) of which were classified ER-low. Transcriptional patterns, tumor inflammatory infiltration and prognosis were compared between ER-low versus ER-negative (ER-neg; 0%) and ER-positive (ER-pos; >10%) tumors.

RESULTS: The transcriptomes of ER-low and ER-neg tumors remarkably overlapped; displaying predominantly non-luminal PAM50 subtypes and down-regulated ER signaling. All TNBC molecular subtypes were represented within ER-low/HER2-negative BC. Unsupervised clustering algorithms failed to segregate ER-low/HER2-negative from TNBC tumors and only 2 genes were significantly differentially expressed above 1.5 fold-difference between the groups. However, borderline ER-low tumors (with exactly10% ER) were mostly assigned labels associated with luminal disease biology suggesting possible endocrine responsiveness. Lymphocyte infiltration was comparable between ER-low and ER-neg but was significantly higher relative to ER-pos tumors. Within ER-low/HER2-negative disease, HR-positivity and low/intermediate PAM50 ROR score inferred from RNAseq data and lymphocyte fraction ≥30%, were respectively associated with better prognosis.

CONCLUSIONS: ER-low/HER2-negative is not a distinct BC molecular biological entity but an integral part of TNBC deserving similar treatments. Nonetheless, a few borderline cases with moderately active ER-signaling can potentially respond to ET. HR-related signatures and TILs may stratify ER-low/HER2-negative tumors according to risk for recurrence. The true benefit of ET in ER-low BC requires prospective investigation.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Clinical cancer research : an official journal of the American Association for Cancer Research
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:40227228
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-24-3435
language
English
LU publication?
yes
id
4fc60b87-2561-49de-86b8-2bcefadda90c
date added to LUP
2025-04-18 09:34:13
date last changed
2025-04-22 08:08:46
@article{4fc60b87-2561-49de-86b8-2bcefadda90c,
  abstract     = {{<p>PURPOSE: There is uncertainty whether ER-low tumors with a 1-10% immunohistochemical staining of nuclei represent a distinct molecular biological entity of BC, posing significant challenges for their clinical management and developing novel therapies. We aimed to elucidate ER-low tumor biology.</p><p>EXPERIMENTAL DESIGN: We analyzed primary tumors included in a Swedish population-based SCAN-B BC cohort, 2% (n=174) of which were classified ER-low. Transcriptional patterns, tumor inflammatory infiltration and prognosis were compared between ER-low versus ER-negative (ER-neg; 0%) and ER-positive (ER-pos; &gt;10%) tumors.</p><p>RESULTS: The transcriptomes of ER-low and ER-neg tumors remarkably overlapped; displaying predominantly non-luminal PAM50 subtypes and down-regulated ER signaling. All TNBC molecular subtypes were represented within ER-low/HER2-negative BC. Unsupervised clustering algorithms failed to segregate ER-low/HER2-negative from TNBC tumors and only 2 genes were significantly differentially expressed above 1.5 fold-difference between the groups. However, borderline ER-low tumors (with exactly10% ER) were mostly assigned labels associated with luminal disease biology suggesting possible endocrine responsiveness. Lymphocyte infiltration was comparable between ER-low and ER-neg but was significantly higher relative to ER-pos tumors. Within ER-low/HER2-negative disease, HR-positivity and low/intermediate PAM50 ROR score inferred from RNAseq data and lymphocyte fraction ≥30%, were respectively associated with better prognosis.</p><p>CONCLUSIONS: ER-low/HER2-negative is not a distinct BC molecular biological entity but an integral part of TNBC deserving similar treatments. Nonetheless, a few borderline cases with moderately active ER-signaling can potentially respond to ET. HR-related signatures and TILs may stratify ER-low/HER2-negative tumors according to risk for recurrence. The true benefit of ET in ER-low BC requires prospective investigation.</p>}},
  author       = {{Kimbung, Siker and Veerla, Srinivas and Muhammad, Kadum and Ehinger, Anna and Vallon-Christersson, Johan and Malmberg, Martin and Loman, Niklas}},
  issn         = {{1078-0432}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Clinical cancer research : an official journal of the American Association for Cancer Research}},
  title        = {{Global Transcriptional Complexity of Estrogen Receptor Low Positive Breast Cancers in a Prospective Swedish Population-based SCAN-B Cohort}},
  url          = {{http://dx.doi.org/10.1158/1078-0432.CCR-24-3435}},
  doi          = {{10.1158/1078-0432.CCR-24-3435}},
  year         = {{2025}},
}