The distinctive molecular, pathological and clinical characteristics of BRAF-mutant colorectal tumors

Abstract

Several clinical series have demonstrated a notably low overall survival for colorectal cancer patients diagnosed with a BRAF-mutant tumor. A potentially interesting predictive role has also been suggested for BRAF-mutant colorectal cancer receiving anti-EGFR monoclonal antibodies. Although a global consensus exists in indicating BRAF as a prognostic factor with a possible predictive activity, the clinical use of BRAF mutational status in colorectal tumors is still controversial. This article reviews the current knowledge on the use and implications of BRAF mutational status in colorectal tumors, in order to define its present role in the clinical practice. Also suggested are possible treatment strategies in this prognostically challenging group of patients. Finally, a comprehensive outlook on future developments for specifically directed anti-BRAF therapy is illustrated.

Keywords:

• BRAF
• cetuximab
• colon cancer
• dabrafenib
• encorafenib
• panitumumab
• trametinib
• vemurafenib

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• A BRAF mutation is present in approximately 10% of all colorectal tumors.

• BRAF-mutant tumors represent a distinct biological and molecular group among colorectal cancer patients.

• Clinical series unanimously reported that patients harboring a BRAF-mutant colorectal tumor experienced an impressively worse clinical outcome, particularly median overall survival.

• Therapeutic strategies for BRAF-mutant colorectal cancer patients are limited by the aggressiveness of this disease determining resistance to therapy, early progression and death.

• When clinically feasible, a therapeutic approach using a triplet chemotherapy regimen in combination with biologicals such as the FOLFOXIRI plus bevacizumab regimen might be a possible option in carefully selected cases.

• The efficacy of BRAF inhibitors in BRAF-mutant colorectal cancer is limited by the early occurrence of resistance mechanism involving the activation of the EGFR, PI3K and MEK–driven molecular pathways.

• The novel treatment strategies now explored are those combining a simultaneous pharmacological blockade of BRAF, EGFR and/or PI3K and/or MEK.