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Towards personalized treatment for early stage HER2-positive breast cancer

Abstract

Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the duration of HER2-targeted therapy. Indeed, dual HER2-targeted therapies and extended-duration anti-HER2 therapy, as well as adjuvant therapy with the anti-HER2 antibody–drug conjugate T-DM1, have all been approved for clinical use. Emerging evidence suggests, however, that some patients do not derive sufficient benefit from these additional therapies to offset the associated toxicities and/or costs. Similarly, the universal use of chemotherapy might not benefit all patients, and treatment de-escalation through omission of chemotherapy has shown promise in clinical trials and is currently being explored further. The future of precision medicine should therefore involve tailoring of therapy based on the genetics and biology of each tumour and the clinical characteristics of each patient. Predictive biomarkers that enable the identification of patients who will benefit from either escalated or de-escalated treatment will be crucial to this approach. In this Review, we summarize the available HER2-targeted agents and associated mechanisms of resistance, and describe the current therapeutic landscape of early stage HER2-positive breast cancer, focusing on strategies for treatment escalation or de-escalation.

Key points

  • Advances in HER2-targeted therapy have improved the outcomes of patients with HER2-positive breast cancer; however, intrinsic and acquired resistance to such treatment remain a major clinical challenge.

  • Emerging preclinical and clinical evidence suggests that simultaneous therapeutic blockade of the HER2 and oestrogen receptor signalling pathways in tumours co-expressing both of these receptors should be considered in order to improve patient outcomes.

  • In the era of precision medicine, treatment based on the biological and molecular characteristics of the tumour and the clinical characteristics of the patient is a logical approach.

  • The development of a molecular approach to differentiate patients who are likely to benefit from HER2-targeted therapy with less or no chemotherapy (treatment de-escalation) from those who require chemotherapy or need additional treatment (escalation) remains an overarching challenge.

  • Prospective testing and validation of risk-stratified biomarker-driven treatment approaches will pave the way towards personalized therapy for patients with HER2-positive breast cancer.

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Fig. 1: Signalling by HER2 and other HER family members and the clinically approved HER2-targeted agents.
Fig. 2: Major mechanisms of resistance to HER2-targeted therapy.
Fig. 3: pCR rates stratified by ER status and treatment arm in clinical trials of neoadjuvant HER2-targeted therapy for HER2+ breast cancer.

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Acknowledgements

The work of the authors is supported, in part, by the Department of Defense grants W81XWH-17-1-0579 (to M.F.R.) and W81XWH-17-1-0580 (to R.S.), the NIH SPORE grant P50 CA186784 (to R.S., C.K.O. and M.F.R.); the Cancer Center grant P30 CA125123 (principal investigator C.K.O.); the Breast Cancer Research Foundation grant BCRF-17-143 (to R.S and C.K.O); the Cancer Prevention & Research Institute of Texas grant CPRIT RP 140102 (to C.De A.); and the Translational Breast Cancer Research Consortium (TBCRC).

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K.G., J.V., M.F.R., and R.S wrote the manuscript. All authors made substantial contributions to researching data for the manuscript and to discussions of content, and reviewed and/or edited the manuscript prior to submission.

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Correspondence to Mothaffar F. Rimawi or Rachel Schiff.

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C.K.O. has received research funding from AstraZeneca and GlaxoSmithKline, has served on advisory boards for AstraZeneca, Genentech and Tolmar Pharmaceuticals, has been a data monitoring committee member for Eli Lilly, and is a stockholder of GeneTex. M.F.R. receives research support from GlaxoSmithKline via his institution and has been a consultant for Daiichi, Genentech, Macrogenics and Novartis. R.S. has received research funding from AstraZeneca, Gilead Sciences, GlaxoSmithKline and PUMA Biotechnology, and has been a consultant or advisory committee member for Eli Lilly and Macrogenics. The other authors declare no competing interests.

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Goutsouliak, K., Veeraraghavan, J., Sethunath, V. et al. Towards personalized treatment for early stage HER2-positive breast cancer. Nat Rev Clin Oncol 17, 233–250 (2020). https://doi.org/10.1038/s41571-019-0299-9

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