Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry

Simon Peter Gampenrieder,Sonja Heibl,Michael Knauer,Daniel Egle,Michael Hubalek,Florian Roitner,Andreas Petzer,August Felix Zabernigg,Johannes Andel,Christian Fridolin Singer,Gabriel Rinnerthaler,Marija Balic,Christopher Hager,Richard Greil,Margit Sandholzer,Clemens Schmitt,Christoph Tinchon

doi:10.1186/s13058-021-01492-x

Abstract

BackgroundAbout 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody–drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC).Patients and methodsThe MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan–Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included.ResultsAs of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74–1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68–1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients.ConclusionLow-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.

Highlights

Amplification of human epidermal growth factor receptor 2 (HER2) is a well-established negative prognostic factor both in early and metastatic breast cancer (MBC)
Low HER2 expression did not significantly influence overall survival (OS) neither in the hazard ratios (HR)+ (HR 0.89; 95% Confidence interval (CI) 0.74–1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68–1.25; P = 0.585), when compared to completely HER2-negative disease
Frequency of low HER2 expression As of 11/15/2020, 1,973 patients were included in the Austrian Study Group of Medical Tumor Therapy (AGMT)-MBC-Registry (Fig. 1)

Summary

Introduction

Amplification of human epidermal growth factor receptor 2 (HER2) is a well-established negative prognostic factor both in early and metastatic breast cancer (MBC). In contrast to T-DM1, these new ADCs show a higher bystander killer effect, by using cleavable linkers and a higher drug-to-antibody ratio [8, 9] and are active in HER2-overexpressing tumors [10] and in tumors with low HER2 expression Two of these ADCs have already shown promising activity in phase I trials including HER2-low MBC [11, 12]: trastuzumab deruxtecan and trastuzumab duocarmazine. About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization This low HER2 expression is a promising new target for antibody–drug conjugates (ADCs) currently under investigation. Little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC)

Methods

Results

Discussion

Conclusion