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September 15, 2022

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

Author Affiliations
  • 1Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
  • 2Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
  • 3Department of Medicine, University of Barcelona, Barcelona, Spain
  • 4Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts
  • 5Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
  • 6European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
  • 7Intermountain Healthcare and University of Utah School of Medicine, Salt Lake City, Utah
  • 8German Breast Group, Neu-Isenburg, Germany
  • 9Center for Hematology and Oncology Bethanien, Frankfurt, Germany
  • 10Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
JAMA Oncol. 2022;8(11):1676-1687. doi:10.1001/jamaoncol.2022.4175

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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