Molecular profiling has become essential for the treatment of metastatic colorectal cancer (CRC) when surgery cannot be considered and systemic therapy is recommended. CRC has several potential mutations that are diagnostic, prognostic, and predictive. National Comprehensive Cancer Network (NCCN) guidelines recommend that advanced practice providers conduct RAS, BRAF, HER2, and MSI testing as part of a full molecular panel, review the results, and acted on them prior to starting patients on systemic therapy.

The three human RAS genes (KRAS, NRAS, and HRAS) are mutated in about 45% of colorectal cancers. Patients who do not have a RAS mutation (“wild type”) may respond to anti-EGFR therapy, including cetuximab or panitumumab. KRAS and BRAF mutations are mutually exclusive.

BRAF mutations are present in 5%–15% of CRC, with a higher incidence in right-sided colon cancer. Patients with BRAF mutations are more likely to be female, have right-sided tumors, or have peritoneal or node metastasis but less likely to have lung metastasis. BRAF-mutant CRC contends a poor prognosis, but the mechanism is not well understood.

According to the results of BEACON CRC, an open-label, phase III trial, a combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer progression-free survival, overall survival, and higher response rate than standard therapy in patients with metastatic CRC with BRAF mutations. The trial enrolled 665 patients with BRAFV600E- mutations with disease progression after one to two lines of therapy. The triple combination was generally well tolerated, with the most common adverse effects were diarrhea and skin events.

About 15% of colorectal cancers will display high-level microsatellite instability (MSI-H). MSI status has become a crucial biomarker to define a patient’s options for treatment, with several studies currently ongoing. NCCN guidelines support frontline use of nivolumab or pembrolizumab or combination therapy for patients with MSI-H CRC.

Patients with HER2-positive and RAS wild-type CRC may respond to dual therapy with trastuzumab and lapatinib, according to the phase II HERACLES trial data published in 2016. Larotrectinib is a treatment option for patients with CRC that is NTRK gene fusion positive.

Refer to the NCCN guidelines for a full overview of systemic therapy options and details and schedule of treatment.