Refining HER2-Negative Breast Cancer: Distinct Survival Profiles of HER2-Low and HER2-Ultralow Tumors

Jul 9, 2026

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Retrospective analysis evaluates the clinical, pathological, and prognostic value of HER2-low versus HER2-ultralow expression in 171 HER2-negative breast cancer cases reclassified by immunohistochemistry as HER2-low, HER2-ultralow, or IHC 0. Cohort composition, Ki-67, hormone receptor status, treatments, and stage were assessed using Welch’s ANOVA, Kaplan–Meier landmark survival, and Cox regression. HER2-ultralow showed the best overall survival, with subgroup vulnerability in HER2-low/HR-negative tumors. Findings support further subclassification, while emphasizing validation needs.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

Introduction

Materials and Methods

Results

Cohort distribution and clinicopathological comparisons

Survival analyses and multivariable risk factors

Subgroup findings

Conclusion

Pathology-Research and Practice 274 (2025) 156140 Contents lists available at ScienceDirect Pathology - Research and Practice journal [homepage: www.elsevier.com/locate/prp](homepage: www.elsevier.com/locate/prp) | Refining HER2-Negative breast cancer: distinct survival profiles of HER2-Low and HER2-Ultralow tumors | | | | | --- | --- | --- | --- | | Dido Eliphas Lea˜o de Alencar a,*,1 , Giuliano Rizzotto Guimara˜es b,2, Adriana Vial Roehe c,3 a Pathology Graduate Program-Universidade Federal de Ciˆencias da Saúde de Porto Alegre, Porto Alegre, Brazil b Universidade Federal de Ciˆencias da Saúde de Porto Alegre, Porto Alegre, Brazil c Pathology Graduate Program-Universidade Federal de Ciˆencias da Saúde de Porto Alegre, Porto Alegre, Brazil | | | | | A R T I C L E I N F O | | A B S T R A C T | | | Keywords: Breast Neoplasms Receptor ErbB-2 Prognosis Immunohistochemistry Molecular Pathology | | Purpose: To evaluate the clinical, pathological, and prognostic significance of HER2-low and HER2-ultralow expression in breast cancer. Methods: In this retrospective study, 171 HER2-negative breast cancer cases were reclassified by immunohistochemistry as HER2-low, HER2-ultralow, or HER2 IHC 0. Clinicopathological variables, Ki-67 index, hormone receptor (HR) status, and treatment data were analyzed. Welch’s ANOVA, Kaplan–Meier survival with a 60-month landmark, and Cox regression were applied. Results: The cohort included 49.1 % HER2-low, 27.5 % HER2-ultralow, and 23.4 % HER2 IHC 0 cases. No significant differences were found in clinical stage, histologic grade, or treatment distribution. Ki-67 index was lower in HER2 IHC 0 tumors (p = 0.047). Overall survival (OS) differed significantly: HER2-ultralow patients had the best outcomes (median OS: 47.5 months), followed by HER2 IHC 0 (37.5) and HER2-low (33.0) (log-rank p < 0.05). In multivariable Cox analysis, HER2-low status was independently associated with worse OS versus HER2-ultralow (HR = 1.86; p = 0.006), while HER2 IHC 0 showed no significant difference (HR = 1.42; p = 0.212). Higher Ki-67 and negative ER status were also linked to worse prognosis. Subgroup analysis revealed the poorest outcomes in HER2-low/HR-negative tumors. Conclusion: HER2-ultralow tumors were associated with better survival than HER2-low, suggesting clinical relevance in further subclassifying HER2-negative breast cancers. Although the retrospective design and minor proportional hazard violations warrant caution, these findings may guide treatment for more individualized approaches. Future multicenter studies, supported by molecular profiling and AI-assisted HER2 scoring, are essential to validate these findings and improve reproducibility in low-level HER2 assessment. | | 1. Introduction Breast cancer is the most incident type of cancer worldwide, accounting for approximately 12 % of all new cases and representing the leading cause of death among women [1]. Projections suggest that, without significant advances in early detection and treatment access, the annual number of deaths may exceed one million women by 2040. Five-year survival rates vary considerably: they surpass 90 % in highincome countries but fall to 66 % in India and 40 % in South Africa, while in Brazil, the estimated five-year survival is 59.6 %[2,3]. Brazilian List of Abbreviations: AC-T, Doxorubicin Adriamycin + Cyclophosphamide followed by Paclitaxel; ADC, Antibody–Drug Conjugate; ANOVA, Analysis of Variance; CAP/ASCO, College of American Pathologists / American Society of Clinical Oncology; CI, Confidence Interval; DFS, Disease-Free Survival; ER, Estrogen Receptor; FISH, Fluorescence In Situ Hybridization; HER2, Human Epidermal Growth Factor Receptor 2; HR, Hazard Ratio, Hormone ReceptorHR in statistics; IHC, Immunohistochemistry; ISH, In Situ Hybridization; Jamovi, Open-source statistical software interface; LVI, Lymphovascular Invasion; NHG, Nottingham Histological Grade; OS, Overall Survival;

FAQs

How were HER2-negative breast cancer cases classified into HER2-low, HER2-ultralow, and IHC 0?

The study reclassified 171 HER2-negative cases using immunohistochemistry into HER2-low, HER2-ultralow, or HER2 IHC 0, then compared clinicopathological variables and biomarker data across groups.

What survival differences were observed among HER2-ultralow, HER2-low, and HER2 IHC 0 groups?

Overall survival differed significantly, with HER2-ultralow patients showing the best outcomes (median OS 47.5 months), followed by HER2 IHC 0 (37.5) and HER2-low (33.0).

Which factors were linked to worse prognosis in the multivariable analysis?

Multivariable Cox analysis showed HER2-low status was independently associated with worse overall survival versus HER2-ultralow, while HER2 IHC 0 was not significantly different. Higher Ki-67 and negative ER status were also associated with poorer prognosis, with the worst outcomes in HER2-low/HR-negative tumors.

Jul 9, 2026

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