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Dual HER2 inhibition: mechanisms of synergy, patient selection, and resistance

  • Review Article
  • Published:

From Nature Reviews Clinical Oncology

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Abstract

HER2-targeted therapies for patients with HER2+ breast cancer are rapidly evolving, offering a range of more complex and personalized treatment options. Currently, an array of anti-HER2 monoclonal antibodies, tyrosine kinase inhibitors and antibody–drug conjugates are administered, sometimes alongside chemotherapy or endocrine therapy, both in curative and palliative contexts. However, the heterogeneous nature of HER2+ breast cancer demands a deeper understanding of disease biology and its role in responsiveness to novel HER2-targeted agents, as well as non-HER2-targeted therapies, in order to optimize patient outcomes. In this Review, we revisit the mechanisms of action of HER2-targeted agents, examine the evidence supporting the use of dual HER2 blockade in patients with HER2-amplified tumours, and explore the role of biomarkers in guiding future treatment strategies. We also discuss potential implications for the future treatment of patients with HER2+ breast cancer.

Key points

  • HER2-targeted therapies function by blocking activation of the oncogenic tyrosine kinase signalling pathways downstream of HER2 and inducing immune-mediated cell death.

  • Dual HER2 inhibition can overcome resistance to single-agent blockade through several mechanisms, including more potent inhibition of downstream signalling pathways, overcoming limited HER2 binding, and augmenting HER2 receptor downregulation and degradation.

  • Regimens including trastuzumab plus pertuzumab improve pathological complete response and long-term event rates in patients with stage II–III HER2+ breast cancer receiving neoadjuvant or adjuvant therapy, respectively, compared with trastuzumab monotherapy.

  • Compared with single-agent HER2 inhibition, dual inhibition improves the outcomes of patients with HER2+ metastatic breast cancer in both the first-line and treatment-refractory settings, thus underscoring the importance of oncogenic HER2 signalling throughout the course of disease.

  • HER2+ breast cancer is a biologically heterogeneous disease. Biomarkers including level of HER2 expression, luminal biology, tumour cell proliferation and tumour immune infiltration all merit further investigation as possible methods of guiding the selection of HER2-targeted therapies.

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Fig. 1: Timeline of approvals for HER2-targeted agents for use in patients with HER2+ advanced-stage cancers.
Fig. 2: Mechanisms of action of FDA-approved HER2-targeted agents.
Fig. 3: The biological spectrum of treatment responsiveness in HER2+ breast cancers.

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Acknowledgements

The authors thank A. Garcia (bio-graphics scientific visualization, Barcelona, Spain) for assistance with preparation of Fig. 3, and V. Hope Goldstein (Dana-Farber Cancer Institute, Boston, MA) for editorial assistance.

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Author notes

  1. These authors contributed equally: Sara M. Tolaney, Aleix Prat.

Authors and Affiliations

  1. Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Adrienne G. Waks, Paolo Tarantino & Sara M. Tolaney

  2. Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA

    Adrienne G. Waks, Paolo Tarantino & Sara M. Tolaney

  3. Harvard Medical School, Boston, MA, USA

    Adrienne G. Waks & Sara M. Tolaney

  4. Cancer Institute, Hospital Clinic of Barcelona, Barcelona, Spain

    Olga Martínez-Sáez, Fara Braso-Maristany, Tomás Pascual & Aleix Prat

  5. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Olga Martínez-Sáez, Fara Braso-Maristany, Tomás Pascual & Aleix Prat

  6. Department of Medicine, University of Barcelona, Barcelona, Spain

    Olga Martínez-Sáez, Tomás Pascual & Aleix Prat

  7. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Paolo Tarantino

  8. SOLTI Cancer Research Group, Barcelona, Spain

    Tomás Pascual

  9. International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, Spain

    Javier Cortés

  10. IOB Madrid, Hospital Beata Maria Ana, Madrid, Spain

    Javier Cortés

  11. Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain

    Javier Cortés

  12. Breast Cancer Unit, IOB-QuirónSalud, Barcelona, Spain

    Aleix Prat

  13. Reveal Genomics, Barcelona, Spain

    Aleix Prat

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Contributions

A.G.W., P.T. and O.M.-S. researched data for the manuscript, all authors made a substantial contribution to discussion of content, A.G.W., P.T. and O.M.-S. wrote the manuscript, and all authors reviewed and/or edited the manuscript before submission.

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Correspondence to Aleix Prat.

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Competing interests

A.G.W. has acted as a speaker for AstraZeneca and as a consultant/adviser to AMBRX and AstraZeneca and has received institutional research funding from Genentech, Gilead, Macrogenics and Merck. P.T. has acted as an adviser and/or consultant to AstraZeneca, Daiichi Sankyo, Genentech, Gilead, Lilly, Menarini/Steamline, Novartis and Roche, and has received institutional research funding from AstraZeneca. F.B.-M. reports patents filed as a co-inventor (PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369), and part-time employment by Reveal Genomics. T.P. has acted as a speaker for AstraZeneca, Pfizer and Novartis, and has acted as a consultant to Novartis. J.C. has acted as a consultant and/or adviser to Abbvie, AstraZeneca, Bioasis, Biocon, BioInvent, Biontech, Boehringer Ingelheim, BridgeBio, Circle Pharma, Clovis Oncology, Daiichi Sankyo, Ellipses, Expres2ion Biotechnologies, Gemoab, Gilead, Hibercell, Jazz Pharmaceuticals, Lilly, Merck Sharp & Dohme, Menarini, Reveal Genomics, Roche, Seattle Genetics, Scorpion Therapeutics and Zymeworks; has received honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Stemline Therapeutics; has received institutional research funding from Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai, Guardant Health, Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Queen Mary University of London and Roche Iqvia; owns stock in MAJ3 Capital (and a relative owns stock in Leuko); has received travel support from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Merck Sharp & Dohme, Novartis, Pfizer, Roche and Stemline Therapeutics; and is listed as a co-inventor on patents WO 2014/199294A and US 2019/ 0338368 A1. S.M.T. has acted as a consultant and/or adviser to Aadi Bio, Artios Pharma, Arvinas, AstraZeneca, Bayer, BioNTech, Blueprint Medicines, Bristol Myers Squibb, Circle Pharma, Cullinan Oncology, CytomX Therapeutics, Daiichi Sankyo, eFFECTOR, Eisai, Eli Lilly, Genentech/Roche, Gilead, Hengrui USA, Incyte Corp, Jazz Pharmaceuticals, Johnson & Johnson, Menarini/Stemline, Merck, Natera, Novartis, Pfizer (SeaGen), Reveal Genomics, Sanofi, Systimmune, Sumitovant Biopharma, Tango Therapeutics, Umoja Biopharma, Zentalis and Zymeworks; has received institutional research funding from AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Gilead, Jazz Pharmaceuticals, Lilly, Merck, NanoString Technologies, Novartis, OncoPep, Pfizer and Seattle Genetics; and travel support from Eli Lilly, Gilead, Jazz Pharmaceuticals, Pfizer and Sanofi. A.P. has acted as an adviser and/or consultant to Amgen, Bristol Myers Squibb, Guardant Health, Lilly, MSD, Novartis, Oncolytics Biotech, Peptomyc, Pfizer, Puma, Reveal Genomics, Roche and SL; has acted as a speaker for Amgen, Bristol Myers Squibb, Daiichi Sankyo, Nanostring Technologies, Novartis, Pfizer and Roche; has received institutional research funding from Astellas, Celgene, Boehringer, Medica Scientia Innovation Research, Nanostring, Novartis, Pfizer, Roche, SL and Sysmex Europa GmbH; holds stocks in Reveal Genomics and SL; and is listed as a co-inventor on patent applications (CT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369). The other authors declare no competing interests.

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Waks, A.G., Martínez-Sáez, O., Tarantino, P. et al. Dual HER2 inhibition: mechanisms of synergy, patient selection, and resistance. Nat Rev Clin Oncol (2024). https://doi.org/10.1038/s41571-024-00939-2

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