Emerging role of human epidermal growth factor 2-low status in the prognosis and management of triple-negative breast cancer: a narrative review

Background and Objective: Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes. Lack of targeted therapies in TNBC mandates identification of novel molecular and therapeutic vulnerabilities. Human epidermal growth factor 2 (HER2)-low breast cancer, defined by immunohistochemistry (IHC) score 1+ or 2+ with negative in situ hybridization (ISH), represents an intermediate phenotype between HER2-positive and HER2-negative disease. This manuscript aims at summarizing the biology, epidemiology, and clinical management of HER2-low TNBC, discussing recent advances, challenges, and future directions.

Methods: We queried the PubMed database, Google Scholar and other databases for studies published in English (up to April 2026) and available online, using search terms (such as TNBC, breast cancer, HER2-low, HER2-ultralow, trastuzumab deruxtecan, T-DXd, T-DM1), and selected publications based on their relevance to the topic. We also hand-searched reference lists of relevant papers to provide the most updated and comprehensive review of the topic, and utilized “ClinicalTrials.gov” to identify studies exploring anti-HER2 directed treatments in HER2-low and HER2-ultralow breast cancers, with an emphasis on TNBC.

Key Content and Findings: HER2-low TNBC represents a relatively large proportion of TNBC cases, and is gaining recognition as a distinct therapeutic and biological subtype, affecting clinical management. In HER2-low TNBC patients, utilization of anti-HER2 targeted therapies, similar to those in HER2-positive breast cancer patients, has been recently shown to offer clinical advantages. Namely, antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd), confers survival benefits in patients with HER2-low breast cancer, including HER2-low TNBC patients with metastatic disease. Ongoing clinical trials investigate T-DXd in various clinical settings as a monotherapy or in combination with chemotherapeutic, immunotherapeutic and targeted drugs in patients with hormone (HR) receptor-negative and HER2-low expressing breast cancer. New HER2-directed ADCs are also being developed, with several being investigated in clinical trials.

Conclusions: The development of new HER2-directed treatments is revolutionizing the management of TNBC patients, and mandates further research to better detect and target clinically meaningful HER2-positive signals. This manuscript provides analysis and synthesis of current literature to potentially guide future research and clinical efforts directed at improving outcomes of patients with TNBC.