Trastuzumab Specific Epitope Evaluation as a Predictive and Prognostic Biomarker in Gastric Cancer Patients

Jiwon Koh,Keon-Wook Kang,Ho-Young Lee,Chan-Young Ock,Keun-Wook Lee,Do-Youn Oh,Jin Won Kim,Soo Kyung Nam,Sang-Hoon Ahn,Hyung-Ho Kim,Hye Seung Lee,Woo Ho Kim,Youn Woo Lee

doi:10.3390/biom9120782

Abstract

While human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) antibodies bind to the intracellular domain, trastuzumab binds to the extracellular epitope of HER2 receptor: target of drug action. We aimed to evaluate clinical significance of the new IHC method assessing the target of trastuzumab in gastric cancer (GC) patients and compare with conventional methods. Sixty-nine trastuzumab-treated GC patients were enrolled from two different cohorts. Additionally, we enrolled 528 consecutive GC patients to evaluate prognostic implications of HER2 test methods. HER2 status was assessed by trastuzumab IHC, HER2 IHC (4B5), and HER2 silver in situ hybridization (SISH). HER2 IHC showed 3+ in 48/69 trastuzumab-treated patients (69.6%), however, trastuzumab IHC showed 3+ in 25 (36.2%). Patients with trastuzumab IHC ≥2+ had significantly better progression-free survival (PFS) and overall survival (OS) than their counterpart (p = 0.014). In univariate analysis, trastuzumab IHC ≥2+ and HER2 IHC 3+ were only significant predictive factors for OS in trastuzumab-treated patients. Of the 528 consecutive GCs, patients with trastuzumab IHC ≥2+ had shorter disease-free survival (DFS) and OS (p = 0.008 and 0.031, respectively), while conventional methods failed to reveal any significant survival differences. HER2 assessment by trastuzumab IHC was different from conventional HER2 test results. Trastuzumab IHC was suggested to be a significant predictive factor for trastuzumab responsiveness and prognostic factor for consecutive GCs.

Highlights

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide [1]
Evaluation of human epidermal growth factor receptor 2 (HER2) and Trastuzumab IHC. For both HER2 and trastuzumab IHC, we evaluated IHC staining intensity according to the recommendations from the DAKO HercepTestTM guidelines (DAKO) for GC [20,24] as follows: 0, no reactivity or membrane staining in
Results of HER2 IHC and trastuzumab IHC are shown in Table 2 and Figure 1

Summary

Introduction

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide [1]. HER2 over-expressing status is consistently reported as a poor prognostic factor in breast cancer [6,7], the prognostic role of HER2 in GC remains controversial [8,9,10]. Trastuzumab is the first humanized anti-HER2 monoclonal antibody and is widely used as a targeted therapy for HER2-positive breast cancer [6]. Following the success of trastuzumab for a GC (ToGA) trial in 2010 [11], trastuzumab-based therapy has become the standard therapy for HER2-overexpressing gastric cancer [12]. In light of its clinical implications, various methods of assessing HER2 status have been developed, including HER2 immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and silver in situ hybridization (SISH). No single method is a complete gold standard, HER2 IHC is the most widely used assessment technique [14]

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Methods

Results

Discussion

Conclusion