Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers.

William Jacot,Jeanne Ramos,Charlotte Sorbs,Florence Boissière-Michot,Aurélie Maran-Gonzalez,Océane Massol,Séverine Guiu,Caroline Mollevi

doi:10.3390/cancers13236059

Abstract

Simple SummaryHER2-low breast cancer is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression using the 2018 ASCO/CAP guidelines for HER2 scoring and its prognostic value in a large retrospective series of 296 patients with non-metastatic TNBC. In this large, homogeneous series of patients with early TNBC, HER2 1+/2+ expression was associated with a lower histological grade and molecular apocrine profile, and a specific subgroup of androgen receptor-expressing TNBC with worse long-term prognosis. Considering the current development of anti-androgens for molecular apocrine-like tumors and anti-HER2 antibody–drug conjugates for this HER2 1+/2+ population, this clinicopathological association could have therapeutic implications. Although rare (2.7% of patients in our series), HER2 2+ TNBC seems to have worse relapse-free survival, advocating a dedicated clinical, biological and therapeutic evaluation of this subgroup.HER2-low breast cancer (i.e., HER 1+ or 2+, without gene amplification) is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression and its prognostic value in a large retrospective series of patients with non-metastatic TNBC (median age: 57.7 years; range: 28.5–98.6). Among the 296 TNBC samples, 83.8% were HER2 0, 13.5% were HER2 1+, and 2.7% were HER2 2+ (HercepTestTM and 2018 ASCO/CAP guidelines for HER2 scoring). CK5/6 and/or EGFR-expressing androgen receptors and FOXA1-expressing tumors were classified as basal-like (63.8%) and molecular apocrine-like (MA, 40.2%), respectively. Compared with HER2 0 tumors, HER2 1+/2+ tumors exhibited a lower histological grade (1/2) (35.4% vs. 18.2%, p = 0.007) and MA profile (57.5% vs. 36.7%, p = 0.008). Moreover, patients with HER2 1+/2+ tumors were older (p = 0.047). After a median follow-up of 9.7 years, HER2 2+ tumors (compared with HER2 0/1+ tumors) were associated with worse relapse-free survival (RFS) (HR = 3.16, 95% CI [1.27; 7.85], p = 0.034) in a univariate analysis. Overall survival (OS) and RFS were not different in the HER2 0 and 1+/2+ groups. HER2 levels were not significantly associated with OS or RFS in a multivariate analysis.

Highlights

Triple-negative breast cancer (TNBC) represents 15% of all breast cancer types, and is defined by the lack of significant estrogen receptor (ER) and progesterone receptor (PR) expression, and the absence of human epidermal receptor 2 (HER2) overexpression/amplification [1,2]
In TNBC, HER2 levels can vary from absent to moderate expression without ERBB2 gene amplification
We evaluated the impact of HER2 expression level (0, 1+, 2+) and its association with clinicopathological features and survival outcomes in a cohort of 296 patients with early TNBC treated at our institution, previously characterized for emerging biomarkers [14,15,16,17]

Summary

Introduction

Triple-negative breast cancer (TNBC) represents 15% of all breast cancer types, and is defined by the lack of significant estrogen receptor (ER) and progesterone receptor (PR) expression, and the absence of human epidermal receptor 2 (HER2) overexpression/amplification [1,2]. HER2 status is routinely assessed in all patients with breast cancer, by immunohistochemistry (IHC) and/or in situ hybridization (ISH). According to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2018 recommendations [4], tumors are considered to be HER2-positive (HER2+) when HER2 overexpression is observed by IHC (score 3+, strong expression), or when ERBB2 gene amplification is detected by fluorescence in situ hybridization (FISH). Tumors with a score of 0 and 1+ (weak expression) are considered to be HER2-negative, and tumors with a score of 2+ (moderate expression) need to be assessed by FISH for confirmation. In TNBC, HER2 levels can vary from absent (score of 0) to moderate expression without ERBB2 gene amplification (score of 2+ ISH−)

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