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The following is a summary of “HER2-low status as a distinct breast cancer subtype: myth or truth? Analysis of the WSG trials WSG-ADAPT-HR+/HER2-, WSG-PlanB, and WSG-ADAPT-TN,” published in the February 2025 issue of Breast Cancer Research by Schmidt et al.

Emerging evidence indicates that HER2-overexpressing not only breast cancer (BC) but also HER2-low tumors—traditionally categorized as HER2-negative—exhibit responsiveness to HER2-targeted antibody-drug conjugates. This study aimed to assess the prevalence of HER2-low BC across multiple contemporary early BC trials and to evaluate its prognostic significance in comparison to HER2-zero BC, particularly in terms of survival outcomes. A pooled analysis was conducted on 5,598 patients with hormone receptor-positive (HR+)/HER2-negative BC from the WSG-ADAPT-HR+/HER2- trial screening cohort, 2,592 patients with HR+/HER2- or HR-/HER2- BC from the adjuvant WSG-PlanB trial, and 336 patients from the WSG-ADAPT-TN trial. Central HER2 testing was prospectively performed in WSG-ADAPT and retrospectively in WSG-PlanB, following ASCO/CAP guidelines. 

HER2-low status was defined as immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization (ISH), while HER2-zero was defined as IHC 0. Agreement between HER2 assessments was analyzed using Cohen’s kappa coefficient, and the impact of HER2 status on pathological complete response and survival was evaluated using logistic regression and Cox proportional hazards models. Among WSG-ADAPT-HR+/HER2- cases, 64.6% (3198) of tumors were classified as HER2-low by central testing, compared to 55.6% (3096) by local histology (agreement: 61.0%). In WSG-PlanB, 28.7% (601) of HR+/HER2- tumors were HER2-low. HER2-low status was significantly correlated with higher ERBB2 mRNA expression in comparison to HER2-zero tumors, with a mean score of 9.3 vs. 9.1 (p < .001) in WSG-ADAPT and 9.2 vs. 8.8 (p < .001) in WSG-PlanB. 

Additionally, in WSG-ADAPT-HR+/HER2-, HER2-low tumors demonstrated a significantly lower pCR rate compared to HER2-zero tumors (p = .015). However, no significant differences in disease-free survival (DFS) or distant DFS were observed between HER2-low and HER2-zero tumors in the HR+/HER2- cohorts (WSG-ADAPT-HR+/HER2- distant DFS: HR = 1.06, 95% CI: 0.83–1.36; WSG-PlanB DFS: HR = 1.28, 95% CI: 0.91–1.82). Interestingly, in the HR-/HER2- cohort from WSG-PlanB, HER2-low tumors (10.5%) were associated with significantly improved DFS (HR = 0.21, 95% CI: 0.05–0.83), but this association was not observed in WSG-ADAPT-TN. These findings indicate variability in HER2-low prevalence across different trials and suggest that HER2-low status does not significantly impact survival in HR+/HER2- BC, although its prognostic role in triple-negative BC (TNBC) remains inconsistent. Consequently, the results do not support the classification of HER2-low BC as a distinct biological subtype, underscoring the need for further research to refine the clinical implications of HER2-low status in BC management.

Source: breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-025-01969-z