HER2 Expression Is Predictive of Survival in Cetuximab Treated Patients with RAS Wild Type Metastatic Colorectal Cancer.

Said A Khelwatty,Sharadah Essapen,Alan M Seddon,Izhar Bagwan,Soozana Puvanenthiran,Helmout Modjtahedi

doi:10.3390/cancers13040638

Abstract

Simple SummaryTreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs)—cetuximab and panitumumab—produced clinical benefits in a subset of patients with metastatic colorectal cancer (mCRC). Here, the authors investigated the relative expression and predictive value of HER family members in 144 patients with CRC. They found high levels of expression of HER2 in patients treated with cetuximab; these were associated with shorter progression free survival (PFS). The results provide support for the emergence of HER2 as a therapeutic target in patients with mCRC.The overexpressed HER2 is an important target for treatment with monoclonal antibody (mAb) trastuzumab, only in patients with breast and gastric cancers, and is an emerging therapeutic biomarker in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and panitumumab. In this study, we investigated the relative expression and predictive value of all human epidermal growth factor receptor (HER) family members in 144 cetuximab-treated patients with wild type RAS mCRC. The relative expression of EGFR and HER2 have also been examined in 21-paired primary tumours and their metastatic sites by immunohistochemistry. Of the 144 cases examined, 25%, 97%, 79%, 48%, and 10% were positive for EGFR, HER2, HER3, and HER4 and all four HER family members, respectively. The expression of EGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively. Our results implicate the importance of a large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e., EGFR protein) but also HER2 and other HER family members as therapeutic targets, or for response to therapy with anti-EGFR mAbs and other forms of HER inhibitors, in both the primary tumours and metastatic sites in mCRC.

Highlights

Colorectal cancer (CRC) is a heterogenous disease and one of the leading causes of cancer deaths worldwide [1]
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) bevacizumab, and anti-VEGFR2 mAb ramucirumab are approved for the treatment of patients with metastatic colorectal cancer [5,6,7,8]
We report for the first time the co-expression and predictive value of all human epidermal growth factor receptor (HER) family members in 144 metastatic colorectal cancer (mCRC) patients with RAS wild type, as well as changes in such expression before and post cetuximab treatment, and their association with survival and response to therapy

Summary

Introduction

Colorectal cancer (CRC) is a heterogenous disease and one of the leading causes of cancer deaths worldwide [1]. Identification of cell surface antigens with high levels of expression in colorectal cancer resulted in the development and approval of several monoclonal antibody-based drugs for use in targeted therapy of metastatic colorectal cancer (mCRC) [3,4]. Three checkpoint inhibitors namely antiPD-1 mAb nivolumab alone or in combination with anti-cytotoxic T-lymphocyte-associated protein 4(CTLA-4) mAb ipilimumab and anti-programmed cell death protein 1 (PD-1) pembrolizumab have been approved for the treatment of patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer [9,10]. There is currently no reliable predictive biomarker for the selection of patients who benefit from therapy with anti-EGFR antibodies [4]. There is a need for the identification of more reliable biomarkers for the response to therapy with anti-EGFR antibodies in patients with mCRC [4,13]

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