Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment: a study protocol

Shang-Hung Chen,Yu-Min Yeh,Ching-Wen Huang,Li-Tzong Chen,Jaw-Yuan Wang,Hsiang-Lin Tsai,Jeng-Kai Jiang,Yung-Chuan Sung

doi:10.1186/s12885-019-5826-7

Abstract

BackgroundIn the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy.MethodsA total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed.DiscussionLiquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC.Trial registrationThe date of trial registration (NCT03401957) in this study was January 17, 2018.

Highlights

In the management of patients with RAS wild-type metastatic colorectal cancer, anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival
Sample size calculation The present study aims to identify the frequency of RAS mutations in circulating free DNA (cfDNA) during cetuximab treatment
CtDNA would only account for a certain portion of cfDNA in patients with cancer, circulating nucleic acids from tumor cells could be detected through the development of molecular quantification techniques such as next generation sequencing (NGS) and digital polymerase chain reaction (PCR) [17, 27]

Summary

Introduction

In the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. Mutations at key sites within the RAS family cause constitutive activation of RAS-associated signaling, rendering anti-EGFR therapies ineffective for mCRC. Acquired resistance inevitably appears in some patients after the initial response to cetuximab, limiting the clinical benefit of this anti-EGFR antibody. RAS mutations have been identified after anti-EGFR therapies in approximately 50% of patients with RAS wild-type mCRC [13, 14]. Dynamic monitoring for the emergence of activation mutations of effectors downstream located in EGFR signaling pathway, especially RAS mutations in patients undergoing anti-EGFR therapies can be a useful tool to determine tumor response and ongoing patient care

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