Targeting HER2 heterogeneity in breast cancer

Published:September 01, 2021DOI:https://doi.org/10.1016/j.ctrv.2021.102286

      Highlights

      • Low/heterogeneous expression of HER2 impacts benefit from anti-HER2 therapies.
      • Newer HER2-targeted therapies may be effective against HER2-low tumors.
      • Important to refine definition of HER2 expression status to optimize treatment.
      • Validation of techniques to detect HER2 heterogeneity required.
      • Novel treatments effective against HER2 heterogeneous tumors needed.

      Abstract

      The identification of Human epidermal growth factor receptor 2 (HER2) as a target in breast cancer and the subsequent development of HER2-targeted therapies has revolutionized the treatment of patients with HER2-positive breast cancer. However, there is an increasing awareness of how frequently tumors have low or heterogeneous expression of HER2. It is now recognized that this impacts the degree of benefit from HER2-targeted therapies. With the advent of novel and more potent antibody drug conjugates, targeting HER2 in traditional HER2-negative tumors with “HER2-low” expression is becoming possible. It is essential to refine the nomenclature around HER2 expression to enable clinicians to optimize treatment for patients across the HER2 expression spectrum in breast cancer. HER2 heterogeneity can be detected by conventional IHC, gene expression profiling or other methods and numerous studies have documented the correlation between the presence of HER2 heterogeneity and shorter disease-free survival (DFS) and overall survival (OS). Validation of techniques to identify HER2 heterogeneity in the clinic and concurrent development of agents to effectively treat tumors with non-uniform HER2 expression is needed.

      Keywords

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      References

        • King C.R.
        • Kraus M.H.
        • Aaronson S.A.
        Amplification of a novel v-erbB-related gene in a human mammary carcinoma.
        Science. 1985; 229: 974-976https://doi.org/10.1126/science.2992089
        • Slamon D.J.
        • Clark G.M.
        • Wong S.G.
        • Levin W.J.
        • Ullrich A.
        • McGuire W.L.
        Human breast cancer: correlation of relapse and survival with amplification of the HER-2/ neu oncogene.
        Science. 1987; 235: 177-182https://doi.org/10.1016/S0960-9776(11)70289-2
        • Pegram M.
        • Hsu S.
        • Lewis G.
        • Pietras R.
        • Beryt M.
        • Sliwkowski M.
        • et al.
        Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers.
        Oncogene. 1999; 18: 2241-2251https://doi.org/10.1038/sj.onc.1202526
        • Slamon D.J.
        • Leyland-Jones B.
        • Shak S.
        • Fuchs H.
        • Paton V.
        • Bajamonde A.
        • et al.
        Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
        N Engl J Med. 2001; 344: 783-792https://doi.org/10.1056/NEJM200103153441101
        • Murthy R.K.
        • Loi S.
        • Okines A.
        • Paplomata E.
        • Hamilton E.
        • Hurvitz S.A.
        • et al.
        Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.
        N Engl J Med. 2020 Feb 13; 382: 597-609https://doi.org/10.1056/NEJMoa1914609
        • Burris H.A.
        • Tibbits J.
        • Holden S.N.
        • Sliwkowski M.X.
        • Lewis Phillips G.D.
        Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer.
        Clin Breast Cancer. 2011 Oct; 11: 275-282https://doi.org/10.1016/j.clbc.2011.03.018
        • Verma S.
        • Miles D.
        • Gianni L.
        • Krop I.E.
        • Welslau M.
        • Baselga J.
        • et al.
        Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer.
        N Engl J Med. 2012; 367: 1783-1791https://doi.org/10.1056/NEJMoa1209124
        • Yver A.
        • Agatsuma T.
        • Soria J.-C.
        The art of innovation: clinical development of trastuzumab deruxtecan and redefining how antibody-drug conjugates target HER2-positive cancers.
        Ann Oncol. 2020 Mar; 31: 430-434https://doi.org/10.1016/j.annonc.2019.11.019
        • Modi S.
        • Saura S.
        • Yamashita T.
        • Park Y.H.
        • Kim S.B.
        • Tamura K.
        • et al.
        Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.
        N Engl J Med. 2020 Feb 13; 382: 610-621https://doi.org/10.1056/NEJMoa1914510
        • Wolff A.C.
        • Hammond M.E.
        • Hicks D.G.
        • Dowsett M.
        • McShane L.M.
        • Allison K.H.
        • et al.
        Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.
        J Clin Oncol. 2013; 31: 3997-4013https://doi.org/10.1200/JCO.2013.50.9984
        • Wolff A.C.
        • Hammond M.E.H.
        • Allison K.H.
        • Harvey B.E.
        • Mangu P.B.
        • Bartlett J.M.S.
        Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update.
        J Clin Oncol. 2018; 36: 2105-2122https://doi.org/10.1200/JCO.2018.77.8738
        • Eiger D.
        • Agostinetto E.
        • Saúde-Conde R.
        • de Azambuja E.
        The Exciting New Field of HER2-Low Breast Cancer Treatment.
        Cancers. 2021; 13: 1015https://doi.org/10.3390/cancers13051015
        • Agostinetto E.
        • Rediti M.
        • Fimereli D.
        • Debien V.
        • Piccart M.
        • Aftimos P.
        HER2-Low Breast Cancer: Molecular Characteristics and Prognosis.
        Cancers. 2021; 13: 2824https://doi.org/10.3390/cancers13112824
        • Allison K.H.
        • Dintzis S.M.
        • Schmidt R.A.
        Frequency of HER2 heterogeneity by fluorescence in situ hybridization according to CAP expert panel recommendations: time for a new look at how to report heterogeneity.
        Am J Clin Pathol. 2011; 136: 864-871https://doi.org/10.1309/AJCPXTZSKBRIP07W
        • Ohlschlegel C.
        • Zahel K.
        • Kradolfer D.
        • Hell M.
        • Jochum W.
        HER2 genetic heterogeneity in breast carcinoma.
        J Clin Pathol. 2011; 64: 1112-1116https://doi.org/10.1136/jclinpath-2011-200265
        • Seol H.
        • Lee H.J.
        • Choi Y.
        • Lee H.E.
        • Kim Y.J.
        • Kim J.H.
        • et al.
        Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance.
        Mod Pathol. 2012; 25: 938-948https://doi.org/10.1038/modpathol.2012.36
        • Lee H.J.
        • Seo A.N.
        • Kim E.J.
        • Jang M.H.
        • Suh K.J.
        • Ryu H.S.
        • et al.
        HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer.
        Am J Clin Pathol. 2014; 142: 755-766https://doi.org/10.1309/AJCPIRL4GUVGK3YX
        • Hanna W.M.
        • Rüschoff J.
        • Bilous M.
        • Coudry R.A.
        • Dowsett M.
        • Osamura R.Y.
        • et al.
        HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity.
        Mod Pathol. 2014; 27: 4-18https://doi.org/10.1038/modpathol.2013.103
        • Kurozumi S.
        • Padilla M.
        • Kurosumi M.
        • Matsumoto H.
        • Inoue K.
        • Horiguchi J.
        • et al.
        HER2 intratumoral heterogeneity analyses by concurrent HER2 gene and protein assessment for the prognosis of HER2 negative invasive breast cancer patients.
        Breast Cancer Res Treat. 2016; 158: 99-111https://doi.org/10.1007/s10549-016-3856-2
        • Paik S.
        • Kim C.
        • Wolmark N.
        HER2 status and benefit from adjuvant trastuzumab in breast cancer.
        N Engl J Med. 2008 Mar 27; 358: 1409-1411https://doi.org/10.1056/NEJMc0801440
        • Perez E.A.
        • Reinholz M.M.
        • Hillman D.W.
        • Tenner K.S.
        • Schroeder M.J.
        • Davidson N.E.
        • et al.
        HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial.
        J Clin Oncol. 2010 Oct 1; 28: 4307-4315https://doi.org/10.1200/JCO.2009.26.2154
        • Dowsett M.
        • Procter M.
        • McCaskill-Stevens W.
        • de Azambuja E.
        • Dafni U.
        • Rueschoff J.
        • et al.
        Disease-free survival according to degree of HER2 Amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA trial.
        J Clin Oncol. 2009; 27: 2962-2969https://doi.org/10.1200/JCO.2008.19.7939
        • Fehrenbacher L.
        • Cecchini R.S.
        • Geyer Jr, C.E.
        • Rastogi P.
        • Costantino J.P.
        • Atkins J.N.
        • et al.
        NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2.
        J Clin Oncol. 2020 Feb 10; 38: 444-453https://doi.org/10.1200/JCO.19.01455
        • Network C.G.A.
        Comprehensive molecular portraits of human breast tumours.
        Nature. 2012 Oct 4; 490: 61-70https://doi.org/10.1038/nature11412
        • Prat A.
        • Parker J.S.
        • Fan C.
        • Perou C.M.
        PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer.
        Breast Cancer Res Treat. 2012; 135: 301-306https://doi.org/10.1007/s10549-012-2143-0
        • Parker J.S.
        • Mullins M.
        • Cheang M.C.U.
        • Leung S.
        • Voduc D.
        • Vickery T.
        • et al.
        Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes.
        J Clin Oncol. 2009; 27: 1160-1167https://doi.org/10.1200/JCO.2008.18.1370
        • Prat A.
        • Carey L.A.
        • Adamo B.
        • Vidal M.
        • Tabernero J.
        • Cortés J.
        • et al.
        Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer. JNCI.
        J Natl Cancer Inst. 2014; 106: dju152https://doi.org/10.1093/jnci/dju152
        • Prat A.
        • Perou C.M.
        Deconstructing the molecular portraits of breast cancer.
        Mol Oncol. 2011; 5: 5-23https://doi.org/10.1016/j.molonc.2010.11.003
        • Llombart-Cussac A.
        • Cortes J.
        • Pare L.
        • Galvan P.
        • Bermejo B.
        • Martinez N.
        • et al.
        HER2- enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial.
        Lancet Oncol. 2017; 18: 545-554https://doi.org/10.1016/S1470-2045(17)30021-9
        • Cejalvo J.M.
        • Pascual T.
        • Fernandez-Martinez A.
        • Brasó-Maristany F.
        • Gomis R.R.
        • Perou C.M.
        • et al.
        Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer.
        Cancer Treat Rev. 2018; 67: 63-70https://doi.org/10.1016/j.ctrv.2018.04.015
        • Mittendorf E.A.
        • Wu Y.
        • Scaltriti M.
        • Meric-Bernstam F.
        • Hunt K.K.
        • Dawood S.
        • et al.
        Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes.
        Clin Cancer Res. 2009; 15: 7381-7388https://doi.org/10.1158/1078-0432.CCR-09-1735
      1. Branco FP, Machado D, Silva FF, André S, Catarino A, Madureira R, et al., Loss of HER2 and disease prognosis after neoadjuvant treatment of HER2+ breast cancer. Am J Transl Res. 2019 Sep 15;11(9):6110-16. PMID: 31632579; PMCID: PMC6789273.

        • Niikura N.
        • Tomotaki A.
        • Miyata H.
        • Iwamoto T.
        • Kawai M.
        • Anan K.
        • et al.
        Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry.
        Ann Oncol. 2016 Mar; 27: 480-487https://doi.org/10.1093/annonc/mdv611
        • Brasó-Maristany F.
        • Griguolo G.
        • Pascual T.
        • Paré L.
        • Nuciforo P.
        • Llombart-Cussac A.
        • et al.
        Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade.
        Nat Commun. 2020 Jan 20; 11: 385https://doi.org/10.1038/s41467-019-14111-3
        • Cortazar P.
        • Zhang L.
        • Untch M.
        • Mehta K.
        • Costantino J.P.
        • Wolmark N.
        • et al.
        Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
        Lancet. 2014; 384: 164-172https://doi.org/10.1016/S0140-6736(13)62422-8
        • Denkert C.
        • Lambertini C.
        • Fasching P.S.
        • Pogue-Geile K.L.
        • Mano M.S.
        • Untch M.
        • et al.
        Biomarker data from KATHERINE: a phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer [abstract].
        J Clin Oncol. 2020; 38(15_Suppl):502https://doi.org/10.1200/JCO.2020.38.15_suppl.502
        • Dzimitrowicz H.
        • Berger M.
        • Vargo C.
        • Hood A.
        • Abdelghany O.
        • Raghavendra A.S.
        • et al.
        T-DM1 activity in metastatic human epidermal growth factor receptor 2–positive breast cancers that received prior therapy with Trastuzumab and Pertuzumab.
        J Clin Oncol. 2016; 34: 3511-3517https://doi.org/10.1200/JCO.2016.67.3624
        • Vici P.
        • Pizzuti L.
        • Michelotti A.
        • Sperduti I.
        • Natoli C.
        • Mentuccia L.
        • et al.
        A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience.
        Oncotarget. 2017; 8: 56921-56931https://doi.org/10.18632/oncotarget.18176
        • Bon G.
        • Pizzuti L.
        • Laquintana V.
        • Loria R.
        • Porru M.
        • Marchiò C.
        • et al.
        Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.
        J Exp Clin Cancer Res. 2020 Dec 10; 39: 279https://doi.org/10.1186/s13046-020-01797-3
        • Shafi H.
        • Astvatsaturyan K.
        • Chung F.
        • Mirocha J.
        • Schmidt M.
        • Bose S.
        Clinicopathological significance of HER2/neu genetic heterogeneity in HER2/neu non-amplified invasive breast carcinomas and its concurrent axillary metastasis.
        J. Clin. Pathol. 2013; 66: 649-654https://doi.org/10.1136/jclinpath-2012-201403
        • Hosonaga M.
        • Arima Y.
        • Sampetrean O.
        • Komura D.
        • Koya I.
        • Sasaki T.
        • et al.
        HER2 Heterogeneity Is Associated with Poor Survival in HER2-Positive Breast Cancer.
        Int J Mol Sci. 2018 Jul 24; 19: 2158https://doi.org/10.3390/ijms19082158
        • Metzger Filho O.
        • Viale G.
        • Stein S.
        • Trippa L.
        • Yardley D.A.
        • Mayer I.A.
        • et al.
        Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab.
        Cancer Discov. 2021 May 3:candisc.1557.2020.; https://doi.org/10.1158/2159-8290.CD-20-1557
        • Hurvitz S.A.
        • Martin M.
        • Jung K.H.
        • Huang C.S.
        • Harbeck N.
        • Valero V.
        • et al.
        Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study.
        J Clin Oncol. 2019 Sep 1; 37: 2206-2216https://doi.org/10.1200/JCO.19.00882
      2. de Haas SL, Hurvitz SA, Martin M, Kiermaier A, Lewis Phillips G, Xu J, et al. Biomarker analysis from the neoadjuvant KRISTINE study in HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-09. DOI: 10.1158/1538-7445.SABCS16-P6-07-09.

      3. Baselga J, Lewis Phillips GD, Verma S, Ro J, Huober J, Guardino AE, et al. Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer. Clin Cancer Res. 2016 Aug 1;22(15):3755-63. doi: 10.1158/1078-0432.CCR-15-2499. Epub 2016 Feb 26. Erratum in: Clin Cancer Res. 2018 Nov 1;24(21):5486.

      4. Wulfkuhle JD, Wolf DM, Yau C, Gallagher RI, Swigart LM, Hirst GL, et al. HER family protein expression and activation predicts response to combination T-DM1/pertuzumab in HER2+ patients in the I-SPY 2 TRIAL. J Clin Oncol 37, 2019 (suppl; abstr 3133). 10.1200/JCO.2019.37.15_suppl.3133.

        • 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 Jun 10; 38 (Epub 2020 Apr 24 PMID: 32330069): 1951-1962https://doi.org/10.1200/JCO.19.02488
        • Schalper K.A.
        • Kumar S.
        • Hui P.
        • Rimm D.L.
        • Gershkovich P.
        A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: Impact of 2007 American Society of Clinical Oncology/College of American Pathologists criteria.
        Arch Pathol Lab Med. 2014 Feb; 138: 213-219https://doi.org/10.5858/arpa.2012-0617-OA
        • 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; 20: 1124-1135https://doi.org/10.1016/S1470-2045(19)30328-6
      5. Modi S, Park H, Murthy RK, 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 Jun 10;38(17):1887-96. doi: 10.1200/JCO.19.02318. Epub 2020 Feb 14. PMID: 32058843; PMCID: PMC7280051.

      6. Pistilli B, Wildiers H, Hamilton EP, Ferreira AA, Dalenc F, Vidal M, et al. Clinical activity of MCLA-128 (zenocutuzumab) in combination with endocrine therapy (ET) in ER+/HER2-low, non-amplified metastatic breast cancer (MBC) patients (pts) with ET-resistant disease who had progressed on a CDK4/6 inhibitor (CDK4/6i). J Clin Oncol 38: 2020 (suppl; abstr 1037). 10.1200/JCO.2020.38.15_suppl.1037.

        • Hamilton E.
        • Shapiro C.L.
        • Petrylak D.
        • Boni V.
        • Martin M.
        • Del Conte G.
        Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study [abstract]. AACR; Cancer Res, San Antonio, TX. Philadelphia (PA)2021https://doi.org/10.1158/1538-7445.SABCS20-PD3-07