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. 2018 Sep;26(8):539-544.
doi: 10.1097/PAI.0000000000000475.

RAS-expanded Mutations and HER2 Expression in Metastatic Colorectal Cancer: A New Step of Precision Medicine

Anna M Valentini  1 , Elisabetta Cavalcanti, Marianna Di Maggio, Maria L Caruso
Affiliations

RAS-expanded Mutations and HER2 Expression in Metastatic Colorectal Cancer: A New Step of Precision Medicine

Anna M Valentini et al. Appl Immunohistochem Mol Morphol. 2018 Sep.

Abstract

Cetuximab and panitumumab monoclonal antibodies are a milestone in the history of treatment of metastatic colorectal cancer (mCRC) and point toward future directions for personalized treatment. Recent studies have shown that broader RAS testing is needed to select patients for targeted therapy. The objectives of our study were to identify the prevalence of RAS mutations and evaluate human epidermal growth factor receptor 2 (HER2) expression in KRAS exon 2 wild-type (WT) mCRC patients, correlating the findings with objective response rate, progression-free survival, and overall survival. In total, 29 mCRC patients undergoing treatment with cetuximab therapy were enrolled in this study. By pyrosequencing, mutations were found in 17% of nonresponder patients, in KRAS codon 146 and NRAS codon 12. HER2 positivity was limited to only 1 responder carcinoma specimen. There was no correlation between RAS mutation, HER2/neu expression, and clinicopathologic findings. We highlighted significantly the differences between objective response rate and RAS gene status. The overall survival and progression-free survival of RAS WT patients were higher compared with those with RAS-mutated disease. Clinical response to cetuximab therapy is impaired in the presence of RAS-expanded mutations. In fact, our finding of 5 mutations in RAS-expanded genes allowed us to understand the resistance to cetuximab in 33% of KRAS WT exon 2 nonresponder patients. HER2 does not seem to be a potential biomarker for cetuximab-targeted therapy. These analyses suggest that the assessment of other biomarkers is needed to determine the best treatment for patients with mCRC, to maximize benefit and minimize harm.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
The distribution of KRAS and NRAS mutations in 5 nonresponder patients.
FIGURE 2
FIGURE 2
Kaplan-Meier survival analysis for progression-free survival time of patients with and without RAS mutation.
FIGURE 3
FIGURE 3
Kaplan-Meier survival analysis for overall survival time according to RAS status.
FIGURE 4
FIGURE 4
HER2 immunohistochemistry showing a moderate membranous staining pattern in neoplastic cells. Score 2+.
FIGURE 5
FIGURE 5
Image representing an HER2 gene amplified (red clusters) specimen (HER2/CEN-17 ratio >2.0).
See this image and copyright information in PMC

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