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Aiming at a Tailored Cure for ERBB2-Positive Metastatic Breast CancerA Review

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To identify the key insights or developments described in this article
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Importance  Metastatic breast cancer (MBC) has traditionally been considered incurable. Accordingly, current treatment algorithms are aimed at maintaining quality of life and improving overall survival, rather than at complete eradication of the disease. Attempts to achieve cure with high-dose chemotherapy were conducted in the 1990s, with no observed long-term benefit compared with conventional chemotherapy. Nonetheless, Erb-B2 receptor tyrosine kinase 2 (ERBB2, formerly HER2)-targeted biologic treatments, developed in the past 2 decades, are currently challenging this paradigm. Indeed, a fraction of patients with ERBB2-positive MBC achieve long-lasting responses to chemotherapy and ERBB2-blockade, resembling a cure. In this setting, the challenge of identifying the optimal curable population has emerged, including identifying populations in whom treatment escalation strategies may be beneficial, while avoiding overtreatment in patients with incurable disease.

Observations  A number of clinical and pathologic features allow physicians to identify patients with ERBB2-positive MBC who are more likely to experience a long-lasting response to chemotherapy and ERBB2-blockade. Long-term responders tend to be de novo metastatic, have a reduced disease burden, and tend to show deep responses to systemic treatment. In pathologic terms, features associated with long-term response are high ERBB2 expression, lack of detrimental genomic aberrations, and antitumor immune activation. This population of patients may potentially derive benefit from a tailored escalation of frontline treatment with novel anti-ERBB2 drugs, such as trastuzumab deruxtecan, tucatinib, or margetuximab. Additional recent therapeutic and diagnostic advancements could further aid in the path toward a cure for ERBB2-positive MBC.

Conclusions and Relevance  Careful implementation of novel diagnostic and treatment tools could potentially expand the population of patients with ERBB2-positive MBC experiencing long-lasting disease response. Trials are in preparation to confirm this paradigm, and hopefully lead to a new era of precision therapy for breast cancer.

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Article Information

Accepted for Publication: October 5, 2021.

Published Online: January 13, 2022. doi:10.1001/jamaoncol.2021.6597

Corresponding Author: Sara M. Tolaney, MD, MPH, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 (sara_tolaney@dfci.harvard.edu).

Author Contributions: Dr Tarantino had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tarantino, Curigliano, Parsons, Krop, Winer, Tolaney.

Acquisition, analysis, or interpretation of data: Tarantino, Curigliano, Lin, Mittendorf, Waks, Tolaney.

Drafting of the manuscript: Tarantino, Curigliano, Mittendorf, Tolaney.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Tarantino, Curigliano, Tolaney.

Supervision: Tarantino, Curigliano, Parsons, Krop, Tolaney.

Conflict of Interest Disclosures: Dr Tarantino has served as an adviser/consultant to AstraZeneca and is supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship. Dr Curigliano received honoraria for speaker, consultancy, or advisory roles from Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, Daiichi Sankyo, and Samsung. Dr Parsons is a paid consultant for Foundation Medicine. Dr Lin reports research support (to institution) from Genentech, Merck, Pfizer, and Seattle Genetics; consultant/advisory board: Puma, Seattle Genetics, Daiichi Sankyo, AstraZeneca, Denali Therapeutics, California Institute for Regenerative Medicine, and Prelude Therapeutics. Dr Krop reports research support (to institution) from Genentech/Roche and Pfizer, has received fees from Novartis and Merck for Data Monitoring Board participation, received honoraria from Celltrion, and has received consulting fees from Bristol Myers Squibb, Daiichi/Sankyo, Macrogenics, Context Therapeutics, Taiho Oncology, Genentech/Roche, Seattle Genetics, and AstraZeneca. Dr Mittendorf has received research support from GlaxoSmithKline; honoraria from Physician Education Resource; compensation for serving on advisory boards for AstraZeneca, Exact Sciences, Merck, Peregrine Pharmaceuticals, Roche/Genentech, Sellas Lifesciences, and TapImmune; institutional support from AstraZeneca, EMD Serono, Galena Biopharma, and Roche/Genentech; and has served as an uncompensated steering committee member for Bristol Myers Squibb, Lilly and Roche/Genentech. Dr Waks receives institutional research funding from Genentech/Roche. Dr Winer is a scientific advisory board member for Leap, and reports consultancy fees from Garrick Therapeutics, G1 Therapeutics, Roche Genentech, Genomic Health, GlaxoSmithKline, Jounce, Lilly, Novartis, Seattle Genetics, and Syros, outside the submitted work. Dr Tolaney receives institutional research funding from AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, Exelixis, Bristol Myers Squibb, Eisai, Nanostring, Cyclacel, Odonate, and Seattle Genetics; has served as an adviser/consultant to AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, Bristol Myers Squibb, Eisai, Nanostring, Puma, Sanofi, Puma, Silverback Therapeutics, G1 Therapeutics, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, Ellipsis, Infinity, 4D Pharma, Samsung Bioepsis, Inc, Chugai Pharmaceuticals, BeyondSpring Pharmaceuticals, OncXerna, OncoSec Medical Incorporated, Certara, Mersana Therapeutics, CytomX, Seattle Genetics.

Additional Contributions: We thank Kate Bifolck, BA, for her editorial and submission assistance (full-time employee of Dana-Farber Cancer Institute).

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