Clinicopathologic features and treatment efficacy of Chinese patients with BRAF-mutated metastatic colorectal cancer: a retrospective observational study

Xicheng Wang,Yanyan Li,Jifang Gong,Lin Shen,Jian Li,Jing Gao,Jie Li,Qing Wei

doi:10.1186/s40880-017-0247-y

Xicheng Wang, Yanyan Li + Show 6 more

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https://doi.org/10.1186/s40880-017-0247-y

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Abstract

BackgroundThe prognostic role of the V600E mutation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) in metastatic colorectal cancer (mCRC) is well established, but the therapeutic regimen targeting this disease is lacking. This study aimed to analyze the clinicopathologic features of and treatment efficacy of commonly used regimens on BRAF-mutated mCRCs.MethodsWe collected and reviewed the medical records of mCRC patients treated at Peking University Cancer Hospital & Institute (Beijing, China) between July 2011 and July 2016. Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and BRAF mutational status was assayed using direct sequencing. The details of clinicopathologic characteristics of patients and their responses to FOLFOXIRI regimen or standard therapy were obtained by reviewing the medical records. The progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analysis and compared using the log-rank test.ResultsOf 1694 patients studied, 75 had BRAF exon 15 mutations. Of these 75 patients, 71 had V600E mutation, 1 had D594G mutation, 2 had K601E mutation, and 1 had a novel T599_V600insAGA alteration. No patients had KRAS or NRAS mutations. Of 63 patients with BRAF V600E-mutated mCRC and sufficient clinical data, 27 (42.9%) had right-sided colon tumors, 19 (30.2%) had left-sided colon tumors, and 17 (26.9%) had rectal tumors; 26 (41.3%) had peritoneal metastases, and 50 (79.4%) had distant lymph node metastases. The patients with BRAF K601E- and T599_V600insAGA-mutated tumors had similar clinicopathologic features to those with BRAF V600E-mutated tumors. Patients with the BRAF V600E mutation benefited more from FOLFOXIRI regimen compared with patients who underwent standard therapy (overall response rate 83.3% vs. 14.0%; median PFS 6.4 months vs. 2.8 months, P = 0.220; median OS 11.0 months vs. 6.9 months, P = 0.048).ConclusionsBRAF V600E mutations were commonly identified in right-sided tumors and showed a high incidence of peritoneal and distant lymph nodes metastases. This subtype of mCRC was characterized by short OS and unique patterns of metastasis. Compared with standard treatment regimens, the FOLFOXIRI regimen had acceptable and manageable toxicities and favorable efficacy on patients with BRAF-mutated mCRC.

Highlights

The prognostic role of the V600E mutation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) in metastatic colorectal cancer is well established, but the therapeutic regimen targeting this disease is lacking
The BRAF V600E mutation is negatively associated with prognosis in patients with metastatic colorectal cancer, distinguishing them as a subgroup that obtains modest benefit from standard treatments [5,6,7]
We investigated the efficacy of FOLFOXIRI compared with standard doublet-agent treatment (FOLFOX/CapeOX or FOLFIRI) for patients with unresectable BRAF-mutated metastatic colorectal cancer (mCRC)

Summary

Introduction

The prognostic role of the V600E mutation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) in metastatic colorectal cancer (mCRC) is well established, but the therapeutic regimen targeting this disease is lacking. This study aimed to analyze the clinicopathologic features of and treatment efficacy of commonly used regimens on BRAF-mutated mCRCs. V-raf murine sarcoma viral oncogene homolog B1 (BRAF), a principal downstream effector of the mitogenactivated protein kinase (MAPK)/extracellular signalregulated kinase (ERK) pathway, is mutated in 5%–10% of colorectal cancer (CRC) cases [1]. It was reported that a thymine to adenine single-base change at position 1799 accounts for 90% of BRAF mutations [2]. This missense mutation, located in exon 15, results in a change at codon 600 that substitutes glutamine for valine (V600E) [2]. The BRAF V600E mutation is negatively associated with prognosis in patients with metastatic colorectal cancer (mCRC), distinguishing them as a subgroup that obtains modest benefit from standard treatments [5,6,7]

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