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An Overview of Clinical Development of Agents for Metastatic or Advanced Breast Cancer Without ERBB2 Amplification (HER2-Low)

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Importance  Erb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 [human epidermal growth factor receptor 2]) is an important prognostic and predictive factor in breast cancer. Anti-ERBB2 therapies have improved outcomes in ERBB2-positive breast cancer. However, based on current definitions, tumors with low ERBB2 expression are included in the ERBB2-negative subtype, and therefore, are ineligible for anti-ERBB2 therapies; patients with ERBB2-low (immunohistochemistry [IHC] 1 positive [+] or IHC 2+/in situ hybridization [ISH] negative [−]) tumors account for up to approximately 50% of breast cancer cases. Although the prognostic role of ERBB2-low needs to be defined, ERBB2 offers a potential therapeutic target in these patients.

Observations  Most breast cancer tumors have some ERBB2 expression, with ERBB2-low being more common in hormone receptor–positive than in hormone receptor–negative breast cancer. Although an early clinical study failed to demonstrate benefit of adjuvant trastuzumab for ERBB2-low disease, several novel anti-ERBB2 therapies have shown efficacy in ERBB2-low breast cancer, including the antibody-drug conjugate trastuzumab deruxtecan in a phase 3 trial, and trastuzumab duocarmazine and the bispecific antibody zenocutuzumab in early-phase studies. Although reports are conflicting, some differences in biology and patient outcomes have been found between ERBB2-low and ERBB2 IHC-0 breast cancer. Currently, no established guidelines exist for scoring ERBB2-low expression in breast cancer because the focus has been on binary classification as ERBB2-positive or ERBB2-negative. Additional interpretive cutoffs may be needed to select patients for treatment with effective agents in ERBB2-low breast cancer, along with standardized laboratory quality assurance programs to ensure consistent patient identification for eligibility for ERBB2-low targeting agents.

Conclusions and Relevance  This review suggests that ERBB2-low may be a distinct, clinically relevant breast cancer entity warranting reassessment of traditional diagnostic and therapeutic paradigms. Ongoing clinical trials and further investigations may provide optimized strategies for diagnosing and treating ERBB2-low breast cancer, including reproducible, consistent definitions to identify patients in this diagnostic category and demonstration of benefits of emerging therapies.

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Article Information

Accepted for Publication: July 26, 2022.

Published Online: September 15, 2022. doi:10.1001/jamaoncol.2022.4175

Corresponding Author: Aleix Prat, MD, PhD, Hospital Clinic of Barcelona, Villarroel 170, Escalera 2, Planta 5, 08036 Barcelona, Spain (alprat@clinic.cat).

Conflict of Interest Disclosures: Dr Prat reported grants and personal fees from Daiichi Sankyo, AstraZeneca, and Pfizer during the conduct of the study; and personal fees from Amgen, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Nanostring Technologies, Novartis, Oncolytics Biotech, Puma Biotechnology, and Roche outside the submitted work. In additional, Dr Prat is a cofounder and stock owner of Reveal Genomics and reports 2 patents licensed to Reveal Genomics (HER2DX and WO 2018/103834). Dr Bardia reported grants and consulting fees from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Sankyo/AstraZeneca, Eli Lilly, and Foundation Medicine during the conduct of the study. Dr Curigliano reported advisory board membership and personal fees from AstraZeneca, Daiichi Sankyo, Bristol Myers Squibb, Roche, and Seagen; speaking fees from Novartis, Eli Lilly, Pfizer, and Gilead; and grants from Foundation One and Merck, all outside the submitted work. Dr Hammond reported personal fees from Daiichi Sankyo during the conduct of the study. Dr Loibl reported advisory board membership fees and/or funded research paid to the institute by Seagen, AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, EirGenix, GlaxoSmithKline, Gilead, Eli Lilly, Merck, Molecular Health, Novartis, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen, all outside the submitted work. In addition, Dr Loibl reported patents for EP14153692.0 (pending immunsignature in TNBC), EP21152186.9 (pending signature for CDK 4/6 inhibitor), EP15702464.7 (issued predicting response to an anti-ERBB2 containing therapy), EP19808852.8 (pending), and Digital Ki67 Evaluator (royalties paid from VM Scope GmbH to institute). Dr Tolaney reported grants and honoraria from AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Gilead, Exelixis, Bristol Myers Squibb, Eisai, Nanostring, Puma Biotechnology, Cyclacel, Sanofi, Odonate, Seagen, and Daiichi Sankyo; and personal fees from Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Samsung Bioepis, CytomX, Certara, Mersana Therapeutics, Ellipses Pharma, 4D Pharma, OncoSec Medical, Chugai Pharmaceuticals, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, and ZetaGen, all outside the submitted work. Dr Viale reported consulting fees from AstraZeneca and Agilent; advisory board fees from Daiichi Sankyo, Roche, and Merck Sharp & Dohme Oncology during the conduct of the study; and grants from AstraZeneca, all outside the submitted work.

Funding/Support: Financial support for the writing of the manuscript was provided by AstraZeneca, which in March 2019 entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (DS-8201).

Additional Contributions: Medical writing support was provided by Jackie Highland, PhD (Articulatescience) and funded by AstraZeneca in accordance with Good Publication Practice guidelines. The manuscript was reviewed for medical accuracy by AstraZeneca and Daiichi Sankyo; however, the authors retained full control of the content and made the final decisions for all aspects of this article.

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