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The clinical and biological significance of estrogen receptor-low positive breast cancer

Makhlouf, Shorouk; Althobi, Maryam; Toss, Michael; Muftah, Abir A; Mongan, Nigel P; Lee, Andrew H S; Green, Andrew R; Rakha, Emad A

The clinical and biological significance of estrogen receptor-low positive breast cancer Thumbnail


Shorouk Makhlouf

Maryam Althobi

Michael Toss

Abir A Muftah

Professor of Oncology

Andrew H S Lee

Professor of Breast Cancer Pathology


Estrogen Receptor (ER) status in breast cancer (BC) is determined using immunohistochemistry (IHC) with nuclear expression in ≥1% of cells defined as ER-positive. BC with 1-9% expression (ER-low positive), is a clinically and biologically unique subgroup. In this study, we hypothesized that ER-low positive BC represents a heterogeneous group with a mixture of ER-positive and ER-negative tumor, which may explain their divergent clinical behavior. A large BC cohort (n=8171) was investigated and categorized into three groups: ER-low positive (1-9%), ER-positive (≥10%) and ER-negative (<1%) where clinicopathological and outcome characteristics were compared. A subset of ER-low positive cases was further evaluated using IHC, RNAscope and RT-PCR. PAM50 subtyping and ESR1 mRNA expression levels were assessed in ER-low positive cases within The Cancer Genome Atlas dataset. The reliability of image analysis software in assessment of ER expression in the ER-low positive category was also assessed. ER-low positive tumors constituted <2% of BC cases examined and showed significant clinicopathological similarity to ER-negative tumors. Most of these tumors were non-luminal types showing low ESR1 mRNA expression. Further validation of ER status revealed that 45% of these tumors were ER-negative with repeated IHC staining and confirmed by RNAscope and RT-PCR. ER-low positive tumors diagnosed on needle core biopsy were enriched with false positive ER staining. BCs with 10% ER behaved similarly to ER-positive, rather than ER-negative or low positive BCs. Moderate concordance was found in assessment of ER-low positive tumors, and this was not improved by image analysis. Routinely diagnosed ER-low positive BC includes a proportion of ER-negative cases. We recommend repeat testing of BC showing 1-9% ER expression and using a cut-off ≥10% expression to define ER positivity to help better inform treatment decisions.

Journal Article Type Article
Acceptance Date Jul 13, 2023
Online Publication Date Jul 18, 2023
Publication Date Oct 1, 2023
Deposit Date Jul 17, 2023
Publicly Available Date Jul 26, 2023
Journal Modern Pathology
Print ISSN 0893-3952
Peer Reviewed Peer Reviewed
Volume 36
Issue 10
Article Number 100284
Keywords low expression, pitfalls, assessment, Breast cancer, estrogen receptor
Public URL
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