Discordance in HER2 Status in Gastro-esophageal Adenocarcinomas: A Systematic Review and Meta-analysis

A Creemers,E Ter Veer,L De Waal,G K J Hooijer,M F Bijlsma,N C T Van Grieken,S L Meijer,M G H Van Oijen,H W M Van Laarhoven,P Lodder

doi:10.1038/s41598-017-03304-9

Abstract

Trastuzumab combined with chemotherapy is standard of care for HER2 positive advanced gastro-esophageal cancers. The reported prevalence of HER2 discordance between primary tumors and corresponding metastases varies, hampering uniform patient selection for HER2 targeted therapy. This meta-analysis explores the influence of HER2 assessment methods on this discordance and investigates the prevalence of HER2 discordance in gastro-esophageal adenocarcinomas. PubMed, Embase and Cochrane databases were searched until January 2016. Differences in discordance rate between strict and broad(er) definitions of HER2 status were assessed using random-effect pair-wise meta-analysis. Random-effect single-arm meta-analyses were performed to assess HER2 discordance and the prevalence of positive and negative conversion. A significantly lower discordance rate in HER2 status between primary tumors and corresponding metastases was observed using a strict vs. broad definition of HER2 status (RR = 0.58, 95%CI 0.41–0.82), with a pooled discordance rate of 6.2% and 12.2%, respectively. Using the strict definition of HER2 assessment pooled overall discordance was 7% (95%CI 5–10%). The lowest discordance rates between primary tumors and corresponding metastasis are observed when using a strict method of HER2 positivity. Treatment outcomes of different studies will be better comparable if selection of eligible patients for HER2 targeted therapy is based on this strict definition.

Highlights

Discordance can be observed in two ways: HER2/neu gene (HER2) status may be positive in the primary tumor and negative in the corresponding metastasis – so called negative conversion – or, vice versa, negative in the primary tumor and positive in the metastasis, known as positive conversion
Considering the selection of eligible patients for trastuzumab treatment, it is important to notice that the ToGA trial included patients with either HER2 IHC 3+ scores and/or amplification of the HER2/neu gene by fluorescence in-situ hybridization (FISH)
The strict definition of HER2 detection consists of HER2 IHC scoring according to the consensus scoring system of Hofmann et al.[3] with HER2 positivity defined as IHC score 3+ or IHC score 2+ with an amplification of the HER2/neu gene by in situ hybridization (ISH)

Summary

Introduction

Discordance can be observed in two ways: HER2 status may be positive in the primary tumor and negative in the corresponding metastasis – so called negative conversion – or, vice versa, negative in the primary tumor and positive in the metastasis, known as positive conversion. All specimens scoring IHC 2+ are further investigated by means of in situ hybridization Those IHC 2+ tumors showing amplification of the HER2/neu gene (HER2:CEP17 ratio of 2.0, or when using a single probe >6.0 copies) are likewise confirmed HER2 positive cases and patients may be treated with trastuzumab. This review explores the influence of these different definitions of HER2 assessment on the HER2 status discordance rate between primary tumors and corresponding metastasis in both gastric and esophageal adenocarcinomas. It provides an updated systematic review and meta-analysis of the HER2 discordance rate in gastro-esophageal cancer

Methods

Results

Conclusion