Original article| Volume 22, ISSUE 6, P611-618, August 2022

Characterization of Weakly Hormone Receptor (HR)-Positive, HER2-Negative Breast Cancer and Current Treatment Strategies



      Hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status is critical for determining management of breast cancer. Previous reports of small cohorts with weak HR-positive (HR+)/HER2-negative (HER2-) disease showed similar rates of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) as triple negative breast cancer (TNBC). This study aims to further characterize this group, focusing on pCR rates following NAC.

      Patients and Methods

      Patients with stage I-III, HR+/HER2- breast cancer were identified using the University of Wisconsin Hospital Cancer Registry. Medical records were reviewed for demographics, tumor characteristics with quantification level of estrogen and progesterone receptor (≤33%), treatment, and follow-up data.


      Data was reviewed from 2,900 patients and a total of 64 patients met inclusion criteria. Eighty percent received chemotherapy, about half with NAC (n = 30, 48%). Of 28 patients who received NAC followed by breast and axillary surgery, 12 (43%; 95% CI 25%-63%) had pCR (ypT0/Tis/ypN0). Of the 11 patients who had biopsyproven nodal disease at diagnosis and NAC followed by axillary surgery, 7 (64%, 95% CI 31%-89%) patients had pCR at the axilla. Only one patient with pCR developed recurrent disease. For those that recurred, median time to recurrence was 13.6 (5.6-48.7) months.


      Breast cancers that are HER2- and weakly HR+ treated with NAC demonstrated pCR rate more similar to TNBC than breast cancers that are strong HR+. Neoadjuvant approaches may improve pCR rates, which provides important prognostic information. Clinical trials should be developed to focus on this unique patient cohort.


      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 Clinical Breast Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hammond M.
        • Elizabeth H.
        • Hayes D.
        • et al.
        American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version).
        Arch Pathol Lab Med. 2010; 134: e48-e72
        • Early Breast Cancer Trialists' Collaborative Group
        Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
        Lancet North Am Ed. 2005; 365: 1687-1717
        • Waks Adrienne G.
        • Winer Eric P.
        Breast cancer treatment: a review.
        JAMA. 2019; 321: 288-300
        • Pan Hongchao
        • Gray R.
        • Braybrooke J.
        • et al.
        20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years.
        N Engl J Med. 2017; 377: 1836-1846
        • Denkert Carsten
        • Liedtke C.
        • Tutt A.
        • et al.
        Molecular alterations in triple-negative breast cancer—the road to new treatment strategies.
        Lancet North Am Ed. 2017; 389: 2430-2442
        • Foulkes W.D.
        • Smith I.E.
        • Reis-Filho J.S.
        Triple-negative breast cancer.
        N Engl J Med. 2010; 363: 1938-1948
        • Blum Joanne L.
        • et al.
        Anthracyclines in Early Breast Cancer: The ABC Trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology).
        J Clin Oncol. 2017; 35: 2647-2655
        • Heitz F.
        • Kümmel S.
        • Lederer B.
        • et al.
        Impact of nuclear oestrogen receptor beta expression in breast cancer patients undergoing neoadjuvant chemotherapy.
        Geburtshilfe Frauenheilkd. 2019; 79: 1110-1117
        • Boughey J.C.
        • McCall L.M.
        • Ballman K.V.
        • et al.
        Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) Prospective Multicenter Clinical Trial.
        Ann Surg. 2014; 260: 608-616
        • Schmid P.
        • Cortes J.
        • Pusztai L.
        • et al.
        Pembrolizumab for early triple-negative breast cancer.
        N Engl J Med. 2020; 382: 810-821
        • Santonja A.
        • Sánchez-Muñoz A.
        • Lluch A.
        • et al.
        Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant chemotherapy.
        Oncotarget. 2018; 9: 26406-26416
        • Mittendorf E.A.
        • Zhang H.
        • Barrios C.H.
        • et al.
        Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.
        Lancet North Am Ed. 2020; 396: 1090-1100
        • Liedtke C.
        • Mazouni C.
        • Hess K.R.
        • et al.
        Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer.
        J Clin Oncol. 2008; 26: 1275-1281
        • Kuerer H.M.
        • Newman L.A.
        • Buzdar A.U.
        • et al.
        Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer.
        Am J Surg. 1998; 176: 502-509
        • Cortazar P.
        • Zhang L.
        • Untch M.
        • et al.
        Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
        Lancet North Am Ed. 2014; 384: 164-172
        • Kilbride Kandice E.
        • Lee M.C.
        • Nees A.V.
        • et al.
        Axillary staging prior to neoadjuvant chemotherapy for breast cancer: predictors of recurrence.
        Ann Surg Oncol. 2008; 15: 3252-3258
        • Rouzier Roman
        • Extra J.M.
        • Klijanienko J.
        • et al.
        Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes.
        J Clin Oncol. 2002; 20: 1304-1310
        • Rastogi Priya
        • Anderson S.J.
        • Bear H.D.
        • et al.
        Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27.
        J Clin Oncol. 2008; 26: 778-785
        • Ding Y.
        • Ding K.
        • Yu K.
        • et al.
        Prognosis and endocrine therapy selection for patients with low hormone receptorpositive breast cancer following neoadjuvant chemotherapy: A retrospective study of 570 patients in China.
        Oncol Lett. 2019; 18: 6690-6696
        • Schrenk P.
        • Rieger R.
        • Shamiyeh A.
        • Wayand W.
        Morbidity following sentinel lymph node biopsy versus axillary lymph node dissection for patients with breast carcinoma.
        Cancer. 2000; 88: 608-614
        • Kuehn T.
        • Bauerfeind I.
        • Fehm T.
        • et al.
        Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study.
        Lancet Oncol. 2013; 14: 609-618
        • Caudle A.S.
        • Yang W.T.
        • Krishnamurthy S.
        • et al.
        Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: implementation of targeted axillary dissection.
        J Clin Oncol. 2016; 34: 1072-1078
      1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2022.

        • Gapstur S.M.
        • Dupuis J.
        • Gann P.
        • Collila S.
        • Winchester D.P.
        Hormone receptor status of breast tumors in black, Hispanic, and non-Hispanic white women: An analysis of 13,239 cases.
        Cancer. 1996; 77: 1465-1471
        • McCarty Jr K.S.
        • Silva J.S.
        • Cox E.B.
        • et al.
        Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast.
        Ann Surg. 1983; 197: 123-127
        • 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
        • Dieci M.V.
        • Griguolo G.
        • Bottosso M.
        • et al.
        Impact of estrogen receptor levels on outcome in non-metastatic triple negative breast cancer patients treated with neoadjuvant/adjuvant chemotherapy.
        NPJ Breast Cancer. 2021; 7: 1-7
        • Schrodi S.
        • Braun M.
        • Andrulat A.
        • et al.
        Outcome of breast cancer patients with low hormone receptor positivity: analysis of a 15-year population-based cohort.
        Ann Oncol. 2021; 32: 1410-1424
        • Paakkola N.M.
        • Karakatsanis A.
        • Mauri D.
        • Foukakis T.
        • Valachis A.
        The prognostic and predictive impact of low estrogen receptor expression in early breast cancer: a systematic review and meta-analysis.
        ESMO open. 2021; 6100289
        • Jatoi I.
        • Anderson W.F.
        • Jeong J.H.
        • Redmond C.K.
        Breast cancer adjuvant therapy: time to consider its time-dependent effects.
        J Clin Oncol. 2011; 29: 2301-2304
        • Dent R.
        • Trudeau M.
        • Pritchard K.I.
        • et al.
        Triple-negative breast cancer: clinical features and patterns of recurrence.
        Clin Cancer Res. 2007; 13: 4429-4434
        • Wu Q.
        • Li J.
        • Zhu S.
        • et al.
        Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study.
        Oncotarget. 2017; 8: 27990-27996
        • Boughey J.C.
        • Suman V.J.
        • Mittendorf E.A.
        • et al.
        Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial.
        JAMA. 2013; 310: 1455-1461
        • Ververs J.M.M.A.
        • Roumen R.M.H.
        • Vingerhoets A.J.J.M.
        • et al.
        Risk, severity and predictors of physical and psychological morbidity after axillary lymph node dissection for breast cancer.
        Eur J Cancer. 2001; 37: 991-999
        • Hack T.F.
        • Cohen L.
        • Katz J.
        • Robson L.S.
        • Goss P.
        Physical and psychological morbidity after axillary lymph node dissection for breast cancer.
        J Clin Oncol. 1999; 17: 143-149
        • Allison K.H.
        • Hammond M.E.H.
        • Dowsett M.
        • et al.
        Estrogen and Progesterone Receptor Testing in Breast Cancer.
        ASCO/CAP Guideline Update, 2020
        • 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
        • Cai Y.W.
        • Shao Z.M.
        • Yu K.D.
        De-escalation of five-year adjuvant endocrine therapy in patients with estrogen receptor-low positive (immunohistochemistry staining 1%-10%) breast cancer: Propensity-matched analysis from a prospectively maintained cohort.
        Cancer. 2022; 128: 1748-1756
        • Poterala J.E.
        • Wisinski K.B.
        Abbreviated endocrine therapy duration for low estrogen receptor-positive breast cancer: The counter to extended endocrine therapy.
        Cancer. 2022; 128: 1724-1726