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HER2-Low Breast Cancer: a New Subtype?

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Opinion statement

Breast cancer (BC) guidelines subdivide the disease into three main groups, namely hormone receptor (HR)–positive HER2-negative, HER2-positive, and triple-negative BC (TNBC). The natural history of the HER2-positive subtype has changed since the introduction of HER-targeted therapies, which demonstrated benefit only in case of HER2 overexpression (IHC, score 3+) or gene amplification. Such observation may depend on direct drug inhibition of HER2 downstream signaling, which is needed for survival and proliferation in HER2-addicted BC. Clinically focused categories cannot comprehensively describe biology, as almost half of the currently defined HER2-negative BCs show some degree of IHC expression and have been recently renamed as HER2-low. Why? As technological breakthroughs enable the synthesis of antibody-drug conjugates (ADCs), target antigens may be viewed not only as a biological switch to be turned on-off by targeted drugs but also as an anchor for ADC docking and tethering. As trastuzumab deruxtecan (T-DXd) has already proven in the clinical trial DESTINY-Breast04, even fewer HER2 available receptors on cancer cells may be sufficient for a clinical benefit. So, for HR-negative HER2-low subtype (~40% of TNBCs), though only 58 patients had been enrolled in DESTINY-Breast04, the observed benefit, together with the dismal prognosis of TNBC, warrants the use of T-DXd. Notably, another topoisomerase-based ADC, sacituzumab govitecan, has already been granted approval for pretreated TNBC (ASCENT). As no head-to-head comparison has been performed, the choice relies on regulatory approvals at the time of patient assessment, critical appraisal of available evidence, and careful evaluation of possible cross-resistance with sequential use of ADCs. As for HR-positive HER2-low disease (~60% of HR-positive tumors), DESTINY-Breast04 provides solid evidence for T-DXd prioritization in either second or third treatment lines. Although the remarkable activity observed in this setting favorably compares with outcomes observed in treatment-naive patients, the ongoing DESTINY-Breast06 will clarify the role of T-DXd in this population.

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Author Contribution

CCo contributed to the literature search, conception, and design of the article and drafted the first version of the manuscript. FG and EN contributed to the literature search and provided critical revisions of the manuscript. PT and CCr provided critical revisions of the manuscript. GC contributed to conception and design of the article, and provided critical revisions of the manuscript and supervision. Figure 1 was created with biorender.com by CCo. All the authors provided final approval to the submitted work.

Data Availability

The data that support the findings of this narrative review are derived from publicly available sources and published literature, and no original data were generated or analyzed during the writing of this manuscript. All sources used in this review are cited within the text and listed in the references section. The authors confirm that the data supporting the conclusions of this review are available within the cited references, and that any additional data or materials used in the preparation of this manuscript are available upon request.

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Authors and Affiliations

  1. Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141, Milan, Italy

    Chiara Corti MD, Federica Giugliano MD, Eleonora Nicolò MD, Paolo Tarantino MD, Carmen Criscitiello MD, PhD & Giuseppe Curigliano MD, PhD

  2. Department of Oncology and Hematology-Oncology (DIPO), University of Milan, Milan, Italy

    Chiara Corti MD, Federica Giugliano MD, Eleonora Nicolò MD, Paolo Tarantino MD, Carmen Criscitiello MD, PhD & Giuseppe Curigliano MD, PhD

  3. Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Paolo Tarantino MD

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Conflict of Interest

Chiara Corti, Federica Giugliano, and Eleonora Nicolò have no potential conflicts of interest to disclose. Paolo Tarantino reports honoraria from AstraZeneca. Carmen Criscitiello reports personal fees for consulting, advisory role, and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead, and Pfizer. All the competing interests were outside the submitted work. Giuseppe Curigliano reports the following honoraria for speaker’s engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, Mylan; honoraria for writing engagement: Novartis, BMS; honoraria for participation in Ellipsis Scientific Affairs Group; institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, Medimmune. All the competing interests were outside the submitted work.

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Corti, C., Giugliano, F., Nicolò, E. et al. HER2-Low Breast Cancer: a New Subtype?. Curr. Treat. Options in Oncol. 24, 468–478 (2023). https://doi.org/10.1007/s11864-023-01068-1

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