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Updated: May 27, 2025
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
HER2-low status as a distinct breast cancer subtype: myth or truth? Analysis of the WSG trials WSG-ADAPT-HR+/HER2-,
Gilda Schmidt1, Oleg Gluz2,3,4, Matthias Christgen5
1Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Medical Center, Homburg, Germany. gilda.schmidt@uks.eu.
Background:
New data show that not only HER2-overexpressing breast cancer (BC) tumors but also HER2-low tumors, classically considered as HER2-negative, respond to HER2-targeting antibody-drug-conjugates. Our objective was to analyze the prevalence of HER2-low BC in a pooled analysis of contemporary early BC trials and to evaluate its role as a prognostic factor in terms of survival in comparison to HER2-zero BC.
Methods:
We evaluated 5598 patients with locally HR + /HER2- BC from the screening cohort of WSG-ADAPT-HR + /HER2-, 2592 patients with HR + /HER2- or HR-/HER2- from the adjuvant WSG-PlanB trial, and 336 patients from the WSG-ADAPT-TN trial. Central HER2 testing was performed prospectively in WSG-ADAPT and retrospectively in WSG-PlanB. Following ASCO/CAP guidelines, HER2-low status was defined as immunohistochemistry (IHC) 1 + or 2 + and in situ hybridization (ISH)-negative, and HER2-zero was defined as IHC 0. Agreement between HER2 assessments was evaluated with Cohen's kappa coefficient, and effects of HER2 status on pathological complete response (pCR) and on survival were analyzed with logistic regression and Cox proportional hazards models, respectively.
Findings:
In WSG-ADAPT-HR + /HER2-, 3198 (64.6%) tumors were HER2-low by the central and 3096 (55.6%) by the local histology (agreement for HER2-low status was 61.0%). In HR + /HER2- cases from WSG-PlanB, 601 tumors (28.7%) were HER2-low. In both cohorts, HER2-low status was significantly associated with higher ERBB2 mRNA expression by Oncotype DX test in comparison to HER2-zero: mean 9.3 vs. 9.1 (p < .001) by local HER2 assessment in WSG-ADAPT and mean 9.2 vs. 8.8 (p < .001) in WSG-PlanB. Furthermore, patients with HER2-low tumors in WSG-ADAPT-HR + /HER2- significantly less often had a pCR compared to the HER2-zero tumors (p = .015). No significant difference was observed in (invasive and/or distant) disease-free survival (DFS) between centrally HER2-low and HER2-zero tumors in both HR + /HER2- cohorts (WSG-ADAPT-HR + /HER2- distant DFS: unadjusted HR = 1.06, 95%CI 0.83-1.36, similar results for local assessment; WSG-PlanB DFS: unadjusted HR = 1.28, 95%CI 0.91-1.82). In the HR-/HER2- WSG-PlanB cohort, centrally HER2-low tumors (10.5%) were associated with better DFS (unadjusted HR = 0.21, 95%CI 0.05-0.83), this association was not observed in the WSG-ADAPT-TN.
Conclusion:
The prevalence of HER2-low status varied between the analyzed trials. Our results show that survival does not differ between HER2-low and HER2-zero tumors in HR + /HER2- cohorts; however, HER2-low status appears to have an inconsistent impact on survival in TNBC. Therefore, our findings do not support the characterization of HER2-low status as a distinct BC subtype.
Insights
HER2-low breast cancer (BC) shows similar survival to HER2-zero BC in HR-positive/HER2-negative cohorts, but its prognostic role in triple-negative BC is inconsistent. These findings do not support classifying HER2-low as a distinct BC subtype.
Area of Science:
- Oncology
- Genomics
- Pathology
Background:
- Emerging data indicate HER2-low breast cancer (BC) responds to HER2-targeting antibody-drug conjugates, challenging its prior classification as HER2-negative.
- The prevalence and prognostic significance of HER2-low BC in contemporary early BC trials require further investigation.
Purpose of the Study:
- To determine the prevalence of HER2-low BC in pooled early breast cancer trials.
- To evaluate HER2-low BC as a prognostic factor for survival compared to HER2-zero BC.
Main Methods:
- Pooled analysis of 8555 patients from WSG-ADAPT-HR+/HER2-, WSG-PlanB, and WSG-ADAPT-TN trials.
- Central and local HER2 testing using immunohistochemistry (IHC) and in situ hybridization (ISH) according to ASCO/CAP guidelines.
- Statistical analysis of HER2 status agreement, pathological complete response (pCR), and disease-free survival (DFS) using logistic regression and Cox models.
Main Results:
- HER2-low status prevalence varied across trials (e.g., 64.6% central in WSG-ADAPT-HR+/HER2-).
- HER2-low tumors showed significantly higher ERBB2 mRNA expression than HER2-zero tumors (p < .001).
- No significant difference in DFS was observed between HER2-low and HER2-zero tumors in HR+/HER2- cohorts; however, HER2-low status was associated with better DFS in HR-/HER2- (triple-negative) BC (unadjusted HR = 0.21).
Conclusions:
- HER2-low BC prevalence differs across early breast cancer trials.
- Survival outcomes do not differ between HER2-low and HER2-zero tumors in HR+/HER2- cohorts.
- The prognostic impact of HER2-low status in triple-negative breast cancer is inconsistent, thus not supporting its classification as a distinct BC subtype.
