The long and winding road to useful predictive factors for anti-EGFR therapy in metastatic colorectal carcinoma: the KRAS/BRAF pathway.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with metastatic colorectal carcinoma. Among patients not carrying activating mutations in the KRAS gene, only a limited number will experience tumor response to these therapeutic agents. The role of BRAF mutations in determining resistance to this treatment is emerging through preclinical and clinical studies. Standardization and validation of laboratory mutation analysis is needed to allow an optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Clinical single-arm and randomized studies were conducted both in first-line and refractory settings to evaluate the correlation of KRAS mutational status and efficacy of cetuximab and panitumumab. The main trials on first-line regiments are CRYSTAL, which is looking at FOLFIRI (folinic acid, fluorouracil, irinotecan) + cetuximab, and OPUS, which is evaluating FOLFOX (folinic acid, fluorouracil, oxaliplatin) + cetuximab. The results of these trials have induced the European Medicines Agency to apply restrictions to its approval of cetuximab and panitumumab for use in metastatic colorectal cancer patients with wild-type KRAS tumors. However, the absence of KRAS mutations is not sufficient to assure clinical response to cetuximab and panitumumab. We need to discover further molecular biomarkers of impairment in this or other signaling pathways to identify responders more specifically. Preclinical rationale is available for combined therapies, which simultaneously target EGFR and the RAS/RAF/MAPK signaling pathways for metastatic colorectal cancer.