BRAF-Mutated Colorectal Cancer: Early Frustrations and Future Optimism

James M. Cleary MD, PhD
Published: Friday, Aug 22, 2014

Abstract

The V600E BRAF mutation occurs in 5% to 15% of colorectal cancer patients and is a negative prognostic feature. BRAF-directed therapies in metastatic melanoma have shown great promise. However, unlike BRAF-mutated melanoma, single-agent BRAF inhibition has been an ineffective strategy in BRAF-mutated colorectal cancer. In recent years, preclinical experiments have increased our knowledge of BRAF-mutated colorectal cancer. This review highlights that preclinical data and discusses several ongoing clinical trials that are leveraging this information to explore new therapeutic strategies in targeting BRAF-mutated colorectal cancer.
 
Dr. James M. Cleary

James M. Cleary MD, PhD

Introduction

In recent years, one of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF- mutated melanoma. In addition to BRAF-mutated melanoma, there have been reports of significant responses to BRAF inhibitors in patients with BRAF-mutated lung cancers, thyroid cancers, and hairy cell leukemia.1-4 Unfortunately, to date, attempts to target BRAF-mutated colorectal cancer have been largely unsuccessful. In this article, we will review the molecular and clinical characteristics of BRAF-mutated colorectal cancers and ongoing research efforts to target this aggressive molecular subtype.

Pathologic and Prognostic Characteristics of BRAF-Mutated Colorectal Cancers

Colorectal adenocarcinoma is classically thought to develop from adenomatous polyps.5 Recent work has demonstrated that colorectal cancers can also arise from serrated polyps.6-8 Serrated polyps, which include sessile serrated adenomas and traditional serrated adenomas, differ from traditional adenomas in that they have a sawtooth (ie, serrated) appearance. Colorectal cancers harboring BRAF mutations predominantly develop from these serrated polyps.6,9 Many tumors arising from serrated polyps demonstrate the CpG island methylator (CIMP) phenotype.6,8

BRAF mutations occur in approximately 5% to 15% of colorectal cancers.10-15 BRAF-mutated colorectal cancers are located predominantly in the right side of the colon and are typically poorly differentiated.13,14 In addition, BRAF-mutated colorectal cancers occur more commonly in older patients, and predominantly in females.13,14 Multiple studies have demonstrated that BRAF-mutated tumors carry a poor prognosis. This is especially true in microsatellite stable (MSS) colorectal cancers that harbor a BRAF mutation.10-12,14 Roth et al and Popovici et al found that V600E BRAF mutations were a negative prognostic feature in MSS stage II and III colorectal cancers.14,16 The prognosis of BRAF-mutated colorectal cancers with high levels of microsatellite instability (MSI-H) is still unclear. Two recent studies suggested that the prognosis of BRAF-mutated MSI-H colorectal cancers is favorable compared with BRAF-mutated MSS colorectal cancers.10,11

BRAF Signal Transduction and Murine Models of BRAF-Mutated Colorectal Cancer

The RAF oncogene was discovered in 1983 when it was observed that retroviruses carrying the RAF oncogene transformed murine and avian cells in vitro and in vivo.17,18 Mutations in the BRAF oncogene have now been described in multiple cancers including melanoma, adenocarcinoma of the lung, papillary thyroid cancer, testicular cancer, and hairy cell leukemia.19,20 The V600E BRAF mutation is the most common form of BRAF mutation and results in the constitutive activation of the BRAF kinase domain.19,21

V600E BRAF mutations drive colorectal cancer by causing sustained activation of the MAPK pathway. BRAF is serine/threonine kinase that is downstream of KRAS and is immediately upstream of MEK (Figure). Demonstrative of the importance of the MAPK in colorectal cancer, BRAF and KRAS mutations are mutually exclusive in colorectal cancer and only a few exceptions to this mutual exclusivity have been described.22


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