Discovery of HER2-Low and the Need for Precise Diagnostics

In the past, breast cancer treatment focused solely on HER2-positive patients with HER2 protein overexpression. However, the advent of innovative antibody-drug conjugates (ADCs) has completely changed the landscape. Enhertu (trastuzumab deruxtecan), co-developed by AstraZeneca and Daiichi Sankyo, gained FDA approval in August 2022 after a Phase 3 trial (DESTINY-Breast04), opening up a new frontier for HER2-low. Consequently, the Hellenic Cooperative Oncology Group (HeCOG) conducted a large, retrospective analysis to establish precise diagnostic criteria encompassing both genomics and the immune environment, moving beyond the limitations of conventional diagnostics.

Luminal B Subtype Defined Based on Data from 7 Clinical Trials

This study was based on data from 2,751 early breast cancer (eBC) patients who participated in seven prospective adjuvant chemotherapy trials led by HeCOG. The analysis revealed that HER2-low breast cancer patients exhibited a significantly higher proportion (51.0%) of the Luminal B subtype, characterized by rapid cell proliferation, compared to the HER2-zero group (41.6%). This finding provides crucial evidence supporting the rationale for administering potent targeted therapies, such as ADCs, early on, rather than relying solely on hormone therapy for HER2-low patients.

Personalized Treatment Strategies Based on Genomic Variation Analysis

Researchers performed next-generation sequencing (NGS) on 1,120 tumor tissues to identify genomic variations. The analysis showed that the frequency of PIK3CA gene mutations, a well-known prognostic factor for poor outcomes in breast cancer, was higher in the HER2-zero group (33.6%) than in the HER2-low group (24.7%). Conversely, HER2-low tumors exhibited a pattern of gradually increasing ERBB2 copy number, demonstrating a correlation between genetic activity. These differences will serve as important evidence for clinicians in determining whether to prioritize Enhertu or competing drugs, such as Trodelvy (sacituzumab govitecan) from Gilead Sciences, based on the patient's specific mutations.

Analysis of the Immune Microenvironment and the Potential for Combination Therapy

Tumor-infiltrating lymphocytes (TILs), which reflect the immune status of the tumor microenvironment, were also a key focus of this study. In particular, the study quantitatively demonstrated that the triple-negative breast cancer (TNBC) subtype, known for its high immunogenicity and challenging treatment, exhibits active immune responses. This finding can be a valuable clue for designing next-generation combination clinical trials that involve administering immune checkpoint inhibitors and HER2-targeted ADCs to early-stage breast cancer patients.

Projected USD 3.2 Billion Market for HER2-Low

The HER2-low breast cancer treatment market, based on the major seven countries (7MM), reached approximately USD 3.2 billion in 2024, and its size is expected to grow rapidly as the indications for ADCs expand to earlier stages. Amid this commercial potential, HeCOG's study provides a scientific foundation for refining treatment responses based on the unique tumor genomics of patients, going beyond simply observing drug responses. As a result, it will play a significant role in accelerating the entry of new drugs into early-stage clinical trials and maximizing clinical success rates for global pharmaceutical companies.