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Review
. 2022 Aug 18;14(16):3996.
doi: 10.3390/cancers14163996.

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

Ilana Schlam  1 , Paolo Tarantino  2   3 , Sara M Tolaney  2
Affiliations
Review

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

Ilana Schlam et al. Cancers (Basel). .

Abstract

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for around 15% of all breast cancers and was historically associated with a worse prognosis compared with other breast cancer subtypes. With the development of HER2-directed therapies, the outcomes of patients with HER2-positive disease have improved dramatically; however, many patients present with de novo or acquired resistance to these therapies, which leads to early recurrences or progression of advanced disease. In this narrative review, we discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates. We review mechanisms such as impaired binding to HER2, incomplete receptor inhibition, increased signaling from other receptors, cross-talk with estrogen receptors, and PIK3CA pathway activation. We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.

Keywords: HER2; antibody-drug conjugates; breast cancer; monoclonal antibodies; resistance; tyrosine kinase inhibitors.

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Conflict of interest statement

Ilana Schlam: Nothing to disclose; Paolo Tarantino: Consulting or Advisory Role, AstraZeneca, Daiichi Sankyo; Sara M. Tolaney: Consulting or Advisory Role, Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol-Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics. Institutional Research Funding: Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi, Seattle Genetics.

Figures

Figure 1
Figure 1
Mechanism of action of HER2-targeted therapies. Legend: (A) mechanism of action of trastuzumab and pertuzumab; (B) mechanism of action of margetuximab; (C) mechanism of action of tyrosine kinase inhibitors; (D) mechanism of actions of antibody-drug conjugates with a cleavable linker (Created with BioRender).
Figure 2
Figure 2
Mechanisms of resistance to HER2-targeted agents. Legend: (A) structural modifications of the monoclonal antibody binding site; (B) activating mutations in the HER2/ERBB2 gene; (C) cross-talk between HER2 and estrogen receptors; (D) increased expression of EGFR and HER3. (E) The level of HER2 expression can impact response to certain HER2-targeted therapies; this figure shows that HER2-low tumors do not usually respond to monoclonal antibodies but can respond to antibody-drug conjugates. (F) Increased activity and expression of the drug efflux pump and altered lysosomal transport are unique mechanisms of resistance to antibody-drug conjugates.
See this image and copyright information in PMC

References

    1. Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer statistics, 2022. CA Cancer J. Clin. 2022;72:7–33. doi: 10.3322/caac.21708. - DOI - PubMed
    1. 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;235:177–182. doi: 10.1126/science.3798106. - DOI - PubMed
    1. Slamon D.J., Leyland-Jones B., Shak S., Fuchs H., Paton V., Bajamonde A., Fleming T., Eiermann W., Wolter J., Pegram M., et al. Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2. N. Engl. J. Med. 2001;344:783–792. doi: 10.1056/NEJM200103153441101. - DOI - PubMed
    1. Dodson A., Parry S., Ibrahim M., Bartlett J.M., Pinder S., Dowsett M., Miller K. Breast cancer biomarkers in clinical testing: Analysis of a UK national external quality assessment scheme for immunocytochemistry and in situ hybridisation database containing results from 199 300 patients. J. Pathol. Clin. Res. 2018;4:262–273. doi: 10.1002/cjp2.112. - DOI - PMC - PubMed
    1. Pauletti G., Godolphin W., Press M.F., Slamon D.J. Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene. 1996;13:63–72. - PubMed