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

Next-generation sequencing study results have revealed significant heterogeneity in the molecular nature of this cancer type. Several drugs targeting key molecular drivers of CRC have yielded significant survival gains in the past decade when added to chemotherapy in the frontline setting and beyond in patients with metastatic disease. The epidermal growth factor receptor (EGFR) antibodies, cetuximab (Erbitux) and panitumumab (Vectibix), and the antiangiogenic drug, bevacizumab (Avastin), which targets the vascular endothelial growth factor (VEGF), are all approved for first-line treatment in metastatic settings.3

To date, the only established predictive molecular biomarker to aid treatment selection for patients with mCRC is the presence of activating mutations in the KRAS or NRAS oncogenes, which predict lack of response to EGFR-targeted therapy.4

Another molecular driver of CRC is the BRAF gene, which encodes a serine/threonine protein kinase that is an integral part of the mitogenactivated protein kinase (MAPK) pathway, which governs cellular proliferation, differentiation, and survival. The MAPK pathway is activated downstream of extracellular growth signals transmitted via membrane-bound receptor tyrosine kinases (RTKs), such as the EGFR.

Inside the cell, these RTKs activate RAS proteins, which in turn stimulate the RAF family members, including BRAF, ultimately triggering the MEK and ERK proteins, which transduce the signal into the nucleus to effect changes to a range of cellular processes (Figure5 ).3-6

 

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

Best characterized, however, is the association of BRAF mutations with poor prognosis in CRC. Numerous reports have demonstrated a lack of response to standard therapies and reduced survival in advanced-stage patients with BRAF mutations. The impact of BRAF mutations in earlier-stage disease is not as clear-cut; some studies suggest a similar poorer prognosis, while others show no effect.11


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