Biomarkers in Colorectal Cancer

For biomarkers in colorectal cancer, recent advances made in next generation sequencing have facilitated driven clinical management. These include tumor markers to help early diagnosis, mutation specific therapeutic interventions and markers that predict prognosis.

Biomarkers in Colorectal Cancer also provide information for patient risk stratification. Currently, clinically actionable genomic abnormalities with FDA approved drugs for colorectal cancer include alterations in the following genes: KRAS (wildtype), NRAS (wildtype), BRAF, microsatellite instability (MSI-H), tumor mutational burden (TMB-H), and NTRK fusions.

What are the Biomarkers in Colorectal Cancer?

There are many biomarkers identified in colorectal cancer patients. The most common include:

KRAS mutations:

KRAS is a cancer-causing gene that is frequently mutated in pancreatic, lung and colon cancers. KRAS mutations are detected in approximately 40% of the colorectal cancer patients. KRAS mutations in colorectal cancer are somatic, non-inherited mutations and are primarily located on codons 12, 13, and 61 of the gene. Oncogenic KRAS mutations activate the PI3K and RAS/MEK pathways resulting in tumor initiation and progression. KRAS testing is typically recommended for stage IV colorectal cancer patients. KRAS activating mutations confer resistance to EGFR monoclonal antibodies cetuximab and panitumumab. Conversely, colorectal cancer patients that are wildtype (without any mutations) in KRAS can be treated with FDA approved cetuximab and panitumumab. Advanced stage colorectal cancer patients that are considered for EGFR therapy should be tested to confirm absence of KRAS mutations prior to therapy. Clinical trials are currently underway targeting KRAS mutations with specific RAS inhibitors in colorectal cancer.

NRAS mutations:

NRAS encodes a membrane associated protein that controls MAPK and PI3K signaling pathways that are pivotal to cancer cell division, proliferation, and migration. While NRAS mutations are very common in melanoma, its prevalence is comparatively rarer in colorectal cancer. NRAS mutations are detected in approximately 6% of the colorectal cancer patients. National Comprehensive Cancer Network (NCCN) has recommended testing for NRAS mutations (along with KRAS mutations) in advanced stage metastatic colorectal cancer patients. As with KRAS mutations, patients with mutations in NRAS will not respond to EGFR monoclonal antibodies cetuximab and panitumumab.

BRAF mutations:

While BRAF mutations are commonly associated with melanoma and thyroid cancer, they are also present in approximately 12% of colorectal cancer patients. BRAF mutations, in particular the V600E mutation, mediates tumorigenesis by activating cancer forming molecular pathways. Patients with BRAF mutations have a poor prognosis, especially in a metastatic setting with aggressive tumor behavior. Colorectal cancer patients with BRAF mutations may not respond to monotherapy with EGFR inhibitors cetuximab and panitumumab. However, FDA has approved encorafenib in in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with BRAF V600E mutations as detected by an FDA approved test. BRAF testing is typically recommended for stage IV metastatic colorectal cancer patients.

Microsatellite instability (MSI-H):

Microsatellite instability refers to a hypermutated phenotype caused by genetic defects in the mismatch repair (MMR) pathway resulting in genomic instability. MSI-H phenotype can occur due to mutations in MLH1, MSH2, MSH6 and PMS1. Approximately 15% of colorectal cancer are MSI-H. 3% of the MSI-H colorectal cases are accounted by Lynch syndrome patients that carry germline mutations of the DDR genes. Patients diagnosed with MSI associated Lynch syndrome should encourage first degree family members to get tested for MSI status. MSI-H has been associated with a better prognosis in early stage colorectal cancer. FDA has approved pembrolizumab and nivolumab for colorectal cancer patients with a MSI-H phenotype.

Tumor mutational burden (TMB-H):

Tumor mutational burden is a measure of number of mutations in a tumor and TMB-high (TMB-H) represents a hypermutational phenotype. TMB-H tumors respond well to checkpoint inhibitors and the FDA has approved pembrolizumab to treat solid tumors with TMB-H.

NTRK fusions:

Fusions in NTRK1, NTRK2, and NTRK3 have been identified in various cancer types. NTRK fusions can send cellular signals to trigger unregulated cell growth in many different cancers. The FDA has approved larotrectinib and entrectinib for all solid tumors with NTRK fusions agnostic of the cancer type.

ERBB2 amplification:

Amplification of human epidermal growth factor receptor-2 (ERRB2 or HER2) has been detected in approximately 4% of colorectal cancer patients and are more common in KRAS wildtype cancers. ERBB2 amplification is associated uncontrolled cell growth and can be targeted by anti-HER2 agents including trastuzumab and lapatinib.