Advertisement

Evolution of low HER2 expression between early and advanced-stage breast cancer

Published:January 13, 2022DOI:https://doi.org/10.1016/j.ejca.2021.12.022

      Highlights

      • HER2-low expression is emerging as an actionable biomarker in breast cancer.
      • HER2 IHC score increased from primary to metastatic tumour in 44% of the patients.
      • HER2-low to HER2-zero evolution was observed in 22% of the patients.
      • HER2-low expression is dynamic and may be enriched in the advanced-stage setting.

      Abstract

      Background

      Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications.

      Methods

      We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour.

      Results

      232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21–0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19–0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours.

      Conclusions

      HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression.

      Keywords

      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:

      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

      References

        • von Minckwitz G.
        • Huang C.S.
        • Mano M.S.
        • Loibl S.
        • Mamounas E.P.
        • Untch M.
        • et al.
        Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
        N Engl J Med. 2019; 380: 617-628
        • Piccart M.
        • Procter M.
        • Fumagalli D.
        • de Azambuja E.
        • Clark E.
        • Ewer M.S.
        • et al.
        Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 Years' follow-up.
        J Clin Oncol. 2021; 39: 1448-1457
        • Swain S.M.
        • Miles D.
        • Kim S.B.
        • Im Y.H.
        • Im S.A.
        • Semiglazov V.
        • et al.
        Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
        Lancet Oncol. 2020; 21: 519-530
        • Tarantino P.
        • Hamilton E.
        • Tolaney S.M.
        • Cortes J.
        • Morganti S.
        • Ferraro E.
        • et al.
        HER2-Low breast cancer: pathological and clinical landscape.
        J Clin Oncol. 2020; 38: 1951-1962
        • Wolff A.C.
        • Hammond M.E.H.
        • Allison K.H.
        • Harvey B.E.
        • Mangu P.B.
        • Bartlett J.M.S.
        • et al.
        Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American pathologists clinical practice guideline focused update.
        Arch Pathol Lab Med. 2018; 142: 1364-1382
        • Gianni L.
        • Lladó A.
        • Bianchi G.
        • Cortes J.
        • Kellokumpu-Lehtinen P.L.
        • Cameron D.A.
        • et al.
        Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of Pertuzumab, a HER2 dimerization inhibitor, in patients with HER2-negative metastatic breast cancer.
        J Clin Oncol. 2010; 28: 1131-1137
        • Fehrenbacher L.
        • Cecchini R.S.
        • Geyer C.E.
        • Rastogi P.
        • Costantino J.P.
        • Atkins J.N.
        • et al.
        Abstract GS1-02: NSABP B-47 (NRG oncology): phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with no.
        Cancer Res. 2018; 78 (GS1-02-GS1-02)
        • Burris 3rd, H.A.
        • Rugo H.S.
        • Vukelja S.J.
        • Vogel C.L.
        • Borson R.A.
        • Limentani S.
        • et al.
        Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) -positive breast cancer after prior HER2-directed therapy.
        J Clin Oncol. 2010; 29: 398-405
        • Modi S.
        • Park H.
        • Murthy R.K.
        • Iwata H.
        • Tamura K.
        • Tsurutani J.
        • et al.
        Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low–expressing advanced breast cancer: results from a phase Ib study.
        J Clin Oncol. 2020; 38: 1887-1896
        • Banerji U.
        • van Herpen C.M.L.
        • Saura C.
        • Thistlethwaite F.
        • Lord S.
        • Moreno V.
        • et al.
        Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study.
        Lancet Oncol. 2019; 2045: 1-12
        • Wang J.
        • Liu Y.
        • Zhang Q.
        • Feng J.
        • Fang J.
        • Chen X.
        • et al.
        RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: a pooled analysis of two studies.
        J Clin Oncol. 2021; 39 (1022–1022)
        • Modi S.
        • Ohtani S.
        • Lee C.
        • Wang Y.
        • Saxena K.
        • Cameron D.A.
        Abstract OT1-07-02: a phase 3, multicenter, randomized, open-label trial of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) vs investigator's choice in HER2-low breast cancer (DESTINY-Breast04).
        in: SABCS 2019 OT1-07-02-OT1-07–02. American Association for Cancer Research, 2020https://doi.org/10.1158/1538-7445.sabcs19-ot1-07-02
        • Bardia A.
        • Barrios C.
        • Dent R.
        • Hu X.
        • O'Shaughnessy J.
        • Yonemori K.
        • et al.
        Abstract OT-03-09: trastuzumab deruxtecan (T-DXd; DS-8201) vs investigator's choice of chemotherapy in patients with hormone receptor-positive (HR+), HER2 low metastatic breast cancer whose disease has progressed on endocrine therapy in the metastatic set.
        in: SABCS 2020 OT-03-09-OT-03-09. American Association for Cancer Research, 2021https://doi.org/10.1158/1538-7445.SABCS20-OT-03-09
        • Kan S.
        • Koido S.
        • Okamoto M.
        • Hayashi K.
        • Ito M.
        • Kamata Y.
        • et al.
        Gemcitabine treatment enhances HER2 expression in low HER2-expressing breast cancer cells and enhances the antitumor effects of trastuzumab emtansine.
        Oncol Rep. 2015; 34: 504-510
        • Knowlden J.M.
        • Hutcheson I.R.
        • Jones H.E.
        • Madden T.
        • Gee J.M.
        • Harper M.E.
        • et al.
        Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells.
        Endocrinology. 2003; 144: 1032-1044
        • Cao N.
        • Li S.
        • Wang Z.
        • Ahmed K.M.
        • Degnan M.E.
        • Fan M.
        • et al.
        NF-κB-Mediated HER2 overexpression in radiation-adaptive resistance.
        Radiat Res. 2009; 171: 9-21
        • Allison K.H.
        • Hammond M.E.H.
        • Dowsett M.
        • McKernin S.E.
        • Carey L.A.
        • Fitzgibbons P.L.
        • et al.
        Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update.
        J Clin Oncol. 2020; 38: 1346-1366
        • Bao K.K.H.
        • Sutanto L.
        • Tse S.S.W.
        • Man Cheung K.
        • Chan J.C.H.
        The association of ERBB2 -low expression with the efficacy of cyclin-dependent kinase 4/6 inhibitor in hormone receptor–positive, ERBB2 -negative metastatic breast cancer.
        JAMA Netw Open. 2021; 4e2133132
        • Scaltriti M.
        • Verma C.
        • Guzman M.
        • Jimenez J.
        • Parra J.L.
        • Pedersen K.
        • et al.
        Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity.
        Oncogene. 2009; 28: 803-814
        • Thomson T.A.
        • Hayes M.M.
        • Spinelli J.J.
        • Hilland E.
        • Sawrenko C.
        • Phillips D.
        • et al.
        HER-2/neu in breast cancer: interobserver variability and performance of immunohistochemistry with 4 antibodies compared with fluorescent in situ hybridization.
        Mod Pathol. 2001; 14: 1079-1086
        • Khoury T.
        Delay to formalin fixation (cold ischemia time) effect on breast cancer molecules.
        Am J Clin Pathol. 2018; 149: 275-292
        • Press M.F.
        • Cordon-Cardo C.
        • Slamon D.J.
        Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues.
        Oncogene. 1990; 5: 953-962
        • Miglietta F.
        • Griguolo G.
        • Bottosso M.
        • Giarratano T.
        • Lo Mele M.
        Evolution of HER2-low expression from primary to recurrent breast cancer.
        npj Breast Cancer. 2021; 7
        • Schettini F.
        • Chic N.
        • Brasó-Maristany F.
        • Paré L.
        • Pascual T.
        Clinical, pathological and gene expression features of HER2-low breast cancer.
        Ann Oncol. 2020; 31: S15-S41
        • de Moura Leite L.
        • Cesca M.G.
        • Tavares M.C.
        • Santana D.M.
        • Saldanha E.F.
        • Guimarães P.T.
        • et al.
        HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer.
        Breast Cancer Res Treat. 2021; https://doi.org/10.1007/s10549-021-06365-7
        • Agostinetto E.
        • Rediti M.
        • Fimereli D.
        • Debien V.
        • Piccart M.
        • Aftimos P.
        • et al.
        HER2-Low breast cancer: molecular characteristics and prognosis.
        Cancers (Basel). 2021; 13: 2824
        • Hein A.
        • Hartkopf A.D.
        • Emons J.
        • Lux M.P.
        • Volz B.
        • Taran F.A.
        • et al.
        Prognostic effect of low-level HER2 expression in patients with clinically negative HER2 status.
        Eur J Cancer. 2021; 155: 1-12
        • Schettini F.
        • Chic N.
        • Brasó-Maristany F.
        • Paré L.
        • Pascual T.
        • Conte B.
        • et al.
        Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer.
        npj Breast Cancer. 2021; 7
        • Mutai R.
        • Barkan T.
        • Moore A.
        • Sarfaty M.
        • Shochat T.
        • Yerushalmi R.
        • et al.
        Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer.
        Breast. 2021; 60: 62-69
        • Denkert C.
        • Seither F.
        • Schneeweiss A.
        • Link T.
        • Blohmer J.U.
        • Just M.
        • et al.
        Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials.
        Lancet Oncol. 2021; 22: 1151-1161

      Linked Article