Prognostic Value and Molecular Landscape of HER2 Low-Expressing Metastatic Colorectal Cancer

Masataka Yagisawa,Kentaro Sawada,Yoshiaki Nakamura,Satoshi Fujii,Satoshi Yuki,Yoshito Komatsu,Takayuki Yoshino,Naoya Sakamoto,Hiroya Taniguchi

doi:10.1016/j.clcc.2020.11.002

Abstract

BackgroundThe prognostic value and molecular landscape of human epidermal growth factor receptor 2 (HER2) low-expressing (HER2-L) metastatic colorectal cancer (mCRC) remain unclear. Patients and MethodsThis study enrolled patients with mCRC who had undergone surgical resection of primary tumor. Using the specimen, we evaluated HER2 expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 positivity was defined as follows: HER2 positivity (HER2-Pos) as IHC 3 + or IHC 2+/FISH positive, HER2-L as IHC 2+/FISH negative or IHC 1+, and HER2 negativity (HER2-Neg) as IHC 0+. Gene alterations were determined by next-generation sequencing. ResultsBetween 2005 and 2015, a total of 370 patients were analyzed, comprising 15 patients (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg disease. The clinicopathologic characteristics among groups had no differences. HER2-L had a significantly higher proportion of coaltered RAS mutation than HER2-Pos (P = .037). With a median follow-up of 101.8 months, HER2-L had a significantly better median overall survival than HER2-Pos (P = .029) (18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 patients harboring wild-type RAS and receiving anti-EGFR antibody therapy, HER2-L had a better median progression-free survival tendency than HER2-Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.1 in HER2-Neg (P = .036). ConclusionHER2-L mCRC showed a better prognosis than HER2-Pos mCRC, and it is similar to HER2-Neg mCRC. Hence, HER2-L mCRC might have different biologic behavior in terms of prognostic value and molecular landscape of mCRC, suggesting the possibility of implementation of HER2-guided clinical development against HER2-expressing mCRC.

Highlights

The human epidermal growth factor receptor 2 (HER2), which is a 185 kDa transmembrane glycoprotein with an intracellular domain with tyrosine kinase catalytic activity, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases.[1]
HER2-low expression (HER2-L) tumors was identified in 6% of metastatic colorectal cancer (mCRC), and the overall survival (OS) was significantly longer than in those with HER2-Pos and similar to those with HER2-Neg
The molecular characteristics of HER2-L mCRC were different from HER2-Pos and similar to HER2-Neg: higher frequency of RAS mutations and less enrichment of alterations in receptor tyrosine kinases (RTKs) in HER2-L and HER2-Neg mCRCs

Summary

Introduction

The human epidermal growth factor receptor 2 (HER2), which is a 185 kDa transmembrane glycoprotein with an intracellular domain with tyrosine kinase catalytic activity, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases.[1]. RAS is at the top of these cascades and acts as a self-inactivating signal transducer. A wide range of different tumor types demonstrates overexpression and/ or amplification of HER2.3 The HER2-targeted therapy for HER2positive breast and gastric cancers had improved clinical outcomes in the last 2 decades.[4,5] Recently, HER2 dual blockade has shown potential in several clinical trials even in patients with HER2-positive metastatic colorectal cancer (mCRC).[6,7,8,9,10] The prevalence of HER2positive mCRC is approximately up to 4% of unselected mCRC11; in RAS/BRAF wild-type mCRC cases, the prevalence is enriched up to 5% to 14%.6,12,13. We aimed to investigate the clinicopathologic and biologic features of HER2-low expressed mCRC with the goal of clarifying the molecular landscape and prognostic value of HER2-low expression on mCRC as a prelude to the development of rational therapeutic strategies

Objectives

Methods

Results

Conclusion