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Br J Cancer. 2017 Nov 7;117(10):1450-1458. doi: 10.1038/bjc.2017.308. Epub 2017 Oct 3.

Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

Author information

1
Department of Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan.
2
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
3
Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
4
Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
5
Department of Gastroenterology, Saitama Cancer Center, Saitama 362-0806, Japan.
6
Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama 791-0280, Japan.
7
Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo 060-8648, Japan.
8
Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba 277-8577, Japan.
9
G&G Science Co. Ltd., Fukushima 960-1242, Japan.
10
Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan.
11
Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan.
12
Department of Biostatistics, National Cancer Center, Kashiwa 277-8577, Japan.
13
Biostatistics Division, Center for Research and Administration and Support, National Cancer Center, Kashiwa 277-8577, Japan.
14
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan.
15
Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
16
Genome Medical Science Project, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan.
17
Third Department of Internal Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
18
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.

Abstract

BACKGROUND:

Patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAFV600E (BRAFnon-V600E mutations) contribute to anti-EGFR antibody resistance.

METHODS:

This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort.

RESULTS:

In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAFV600E (6.0%), and 7 patients with BRAFnon-V600E mutations (4.7%), respectively. The response rates in RAS, BRAFV600E, and BRAFnon-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAFnon-V600E mutations was 2.4 months, similar to that in RAS or BRAFV600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months).

CONCLUSIONS:

Although BRAFnon-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAFnon-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.

PMID:
28972961
PMCID:
PMC5680457
DOI:
10.1038/bjc.2017.308
[Indexed for MEDLINE]
Free PMC Article

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