Original Research| Volume 148, P159-170, May 2021

Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors – An analysis of 2765 patients from neoadjuvant clinical trials

Published:March 17, 2021DOI:


      • Low positive hormone receptor breast cancer responses to neoadjuvant chemotherapy were analysed.
      • Low positive hormone receptor breast cancer has worse survival than strong positive.
      • Low positive hormone receptor breast cancer mostly expresses basal-like features.



      To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC.


      We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1–9%) and strong-positive (ER or PR 10–100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38).


      Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87–1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78–1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23–0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33–0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33–0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%).


      Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Fisher B.
        • Redmond C.
        • Legault-Poisson S.
        • et al.
        Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16.
        J Clin Oncol. 1990; 8: 1005-1018
        • Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
        Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
        Lancet. 2005; 365: 1687-1717
        • Senkus E.
        • Kyriakides S.
        • Ohno S.
        • et al.
        Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2015; 26: v8-v30
        • Hammond M.E.
        • Hayes D.F.
        • Dowsett M.
        • et al.
        American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.
        Arch Pathol Lab Med. 2010; 134: 907-922
        • McGuire W.L.
        Current status of estrogen receptors in human breast cancer.
        Cancer. 1975; 36: 638-644
        • Tesch M.
        • Shawwa A.
        • Henderson R.
        The immunohistochemical determination of estrogen and progesterone receptor status in breast cancer.
        Am J Clin Pathol. 1993; 99: 8-12
        • Allred D.C.
        Should immunohistochemical examination replace biochemical hormone receptor assays in breast cancer?.
        Am J Clin Pathol. 1993; 99: 1-3
        • Harvey J.M.
        • Clark G.M.
        • Osborne C.K.
        • Allred D.C.
        Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.
        J Clin Oncol. 1999; 17: 1474-1481
        • Elledge R.M.
        • Green S.
        • Pugh R.
        • et al.
        Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study.
        Int J Canc. 2000; 89: 111-117
        • Goldhirsch A.
        • Glick J.H.
        • Gelber R.D.
        • et al.
        Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005.
        Ann Oncol. 2005; 16: 1569-1583
        • Goldhirsch A.
        • Ingle J.N.
        • Gelber R.D.
        • Coates A.S.
        • Thurlimann B.
        • Senn H.J.
        Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009.
        Ann Oncol. 2009; 20: 1319-1329
        • Yamashita H.
        • Yando Y.
        • Nishio M.
        • et al.
        Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer.
        Breast Cancer. 2006; 13: 74-83
        • Iwamoto T.
        • Booser D.
        • Valero V.
        • et al.
        Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry.
        J Clin Oncol. 2012; 30: 729-734
        • Prabhu J.S.
        • Korlimarla A.
        • Desai K.
        • et al.
        A Majority of low (1-10%) ER positive breast cancers behave like hormone receptor negative tumors.
        J Canc. 2014; 5: 156-165
        • Deyarmin B.1
        • Kane J.L.
        • Valente A.L.
        • et al.
        Effect of ASCO/CAP guidelines for determining ER status on molecular subtype.
        Ann Surg Oncol. 2013; 20: 87-93
        • Allison K.H.
        • Hammond M.E.H.
        • Dowsett M.
        • et al.
        Estrogen and progesterone receptor testing in breast cancer: American Society of clinical oncology/College of American pathologists guideline update.
        Arch Pathol Lab Med. 2020; 144: 545-563
        • Untch M.
        • Loibl S.
        • Bischoff J.
        • et al.
        Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial.
        Lancet Oncol. 2012; 13: 135-144
        • von Minckwitz G.
        • Eidtmann H.
        • Rezai M.
        • et al.
        Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.
        N Engl J Med. 2012; 366: 299-309
        • Untch M.
        • Jackisch C.
        • Schneeweiss A.
        • et al.
        Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial.
        Lancet Oncol. 2016; 17: 345-356
        • Remmele W.
        • Stegner H.E.
        A Proposal for the standardization of the Immunoreactive Score (IRS) for the immunohistochemical demonstration of Estrogen-Receptors (ER-ICA) in breast cancer.
        Pathologe. 1987; 8: 138-140
        • Wolff A.C.
        • Hammond M.E.
        • Schwartz J.N.
        • et al.
        American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.
        J Clin Oncol. 2007; 25: 118-145
        • Hudis C.A.
        • Barlow W.E.
        • Costantino J.P.
        • et al.
        Proposal for standardized definitions for efficacy endpoints in adjuvant breast cancer trials: the STEEP system.
        J Clin Oncol. 2007; 25: 2127-2132
        • Bagnoli J.W.
        • Ziegenhain C.
        • Janjic A.
        • Wange L.E.
        • Vieth B.
        • Parekh S.
        • et al.
        Sensitive and powerful single-cell RNA sequencing using mcSCRB-seq.
        Nat Commun. 2018; 9: 2937
        • Weber J.
        • de la Rosa J.
        • Grove C.S.
        • Schick M.
        • Rad L.
        • Baranov O.
        • et al.
        PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice.
        Nat Commun. 2019; 10: 1415
        • Parekh S.
        • Ziegenhain C.
        • Vieth B.
        • Enard W.
        • Hellmann I.
        zUMIs - a fast and flexible pipeline to process RNA sequencing data with UMIs.
        GigaScience. 2018; 7
        • Love M.I.
        • Huber W.
        • Anders S.
        Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
        Genome Biol. 2014; 15: 550
        • Leek J.T.
        • Johnson W.E.
        • Parker H.S.
        • Jaffe A.E.
        • Storey J.D.
        The sva package for removing batch effects and other unwanted variation in high-throughput experiments.
        Bioinformatics. 2012; 28
        • Paquet E.R.
        • Hallett M.T.
        Absolute assignment of breast cancer intrinsic molecular subtype.
        J Natl Cancer Inst. 2014; 4: 107
        • Yi M.
        • Huo L.
        • Koenig K.B.
        • et al.
        Which threshold for ER positivity? a retrospective study based on 9639 patients.
        Ann Oncol. 2014; 25: 1004-1011
        • Gloyeske N.C.
        • Dabbs D.J.
        • Bhargava R.
        Low ER+ breast cancer: is this a distinct group?.
        Am J Clin Pathol. 2014; 141: 697-701
        • Fujii T.
        • Kogawa T.
        • Dong W.
        • et al.
        Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer.
        Ann Oncol. 2017; 28: 2420-2428
        • Landmann A.
        • Farrugia D.J.
        • Zhu L.
        • et al.
        Low Estrogen Receptor (ER)–positive breast cancer and neoadjuvant systemic chemotherapy: is response similar to typical ER-positive or ER-negative disease?.
        Am J Clin Pathol. 2018; 150: 34-42