BRAF-Mutated Colorectal Cancer

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The collection of data suggests that BRAF-mutations result in a poor prognosis for patients with colorectal cancer (CRC). In the 80405 study, approximately 8% of patients rapidly progressed with very aggressive disease. Although the analysis has not yet been conducted, lead investigator Alan P. Venook, MD, suspects that BRAF-mutations will be implicated in this poor response to therapy.

BRAF is downstream from KRAS, suggesting that an alteration in BRAF could render EGFR inhibitors ineffective, even in KRAS wild-type tumors. As a result of this poor prognosis, patients with BRAF mutations experience a much shorter median overall survival, when compared to patients with BRAF wild-type CRC, notes Venook.

To address this unmet need, studies are looking at targeted therapies geared toward patients with BRAF mutations. Unfortunately, clinical trials exploring single-agent BRAF inhibitors have not been successful in patients with CRC. Additionally, studies exploring the combination of a BRAF and MEK inhibitor have also not shown dramatic benefits, Venook notes.

Several studies have explored combination approaches for patients with BRAF-mutated CRC, notes Johanna Bendell, MD. These analyses have explored various combinations with EGFR, BRAF, and MEK inhibitors or EGFR, BRAF, and PI3 kinase inhibitors. Additionally, studies have explored BRAF inhibitors with chemotherapy. In early data, studies exploring the 3 drug regimens have shown promising response rates between 35% and 40%, notes Bendell.

BRAF mutational analysis should be added to standard expanded RAS testing for clinical trial eligibility and effective treatment planning, believes Al B. Benson III, MD. In general, 5% to 10% of patients test positive for a BRAF mutation, notes Venook. To further cull this out, the next analysis from the 80405 study will assess this hard to treat population.