Solving the BRAF Mystery in CRC: Genomic Clues Lead to Triplets and Immunotherapy

Jane de Lartigue, PhD
Published: Tuesday, Dec 12, 2017
Mutations in the BRAF kinase are found in a relatively small number of patients with metastatic colorectal cancer (mCRC), but they nonetheless have important implications for prognosis and response to standard therapy. Thus far, investigators have struggled to directly target BRAF activity in colorectal cancer (CRC), despite the progress that has been made in melanoma against a seemingly identical oncogenic driver. While searching for explanations for this discrepancy between the 2 tumor types, researchers have fostered a greater understanding of the molecular underpinnings of CRC. Novel treatment strategies including triplet regimens are yielding improved outcomes. Meanwhile, the role of BRAF mutations in CRC continues to be elucidated.

Diverse Molecular Drivers in CRC

In the United States, CRC is the third most common type of cancer and the third leading cause of cancer-related death.1 Surgical resection remains the only curative option for patients with localized tumors. Approximately a quarter of patients present with metastases and another 25% develop them during the course of the disease.2 The standard of care for these patients is influenced by several factors, including their performance status, age, comorbidities, and preferences. It involves the use of combination chemotherapy regimens, typically 5-fluorouracil and leucovorin with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI).3


Figure. Key Elements of BRAF Signaling Pathway5

Figure. Key Elements of BRAF Signaling Pathway5
According to a recent pooled analysis of randomized controlled trials, BRAF mutations are present in approximately 8% of mCRC cases.7 Since their discovery, more than 100 types of BRAF mutations have been described in CRC.8 The most common is a substitution mutation that results in the switching of a valine for a glutamine within the catalytic domain (V600E).9

Clinical Differences in BRAF-Driven CRC

BRAF-mutant CRC constitutes a distinct subset of the disease, with unique clinical characteristics and behavior. It tends to be associated with colon ,rather than rectal tumors, and with tumors that are right-sided, high-grade, or with mucinous histology. Additionally, the mutations are correlated with older age and being female. They also have a different pattern of metastasis; in addition to being associated with multiple metastatic sites, they have higher rates of peritoneal and distant lymph node metastases and fewer lung metastases.10,11
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