EGFR related mutational status and association to clinical outcome of third-line cetuximab-irinotecan in metastatic colorectal cancer

BACKGROUND: As supplement to KRAS mutational analysis, BRAF and PIK3CA mutations as well as expression of PTEN may account for additional non-responders to anti-EGFR-MoAbs treatment. The aim of the present study was to investigate the utility as biomarkers of these mutations in a uniform cohort of patients with metastatic colorectal cancer treated with third-line cetuximab/irinotecan. METHODS: One-hundred-and-seven patients were prospectively included in the study. Mutational analyses of KRAS, BRAF and PIK3CA were performed on DNA from confirmed malignant tissue using commercially available kits. Loss of PTEN and EGFR was assessed by immunohistochemistry. RESULTS: DNA was available in 94 patients. The frequency of KRAS, BRAF and PIK3CA mutations were 44%, 3% and 14%, respectively. All were non-responders. EGF receptor status by IHC and loss of PTEN failed to show any clinical importance. KRAS and BRAF were mutually exclusive. Supplementing KRAS analysis with BRAF and PIK3CA indentified additional 11% of non-responders. Patient with any mutation had a high risk of early progression, whereas triple-negative status implied a response rate (RR) of 41% (p < 0.001), a disease control (DC) rate of 73% (p < 001), and a significantly higher PFS of 7.7(5.1-8.6 95%CI) versus 2.3 months (2.1-3.695%CI) (p < 0.000). CONCLUSION: Triple-negative status implied a clear benefit from treatment, and we suggest that patient selection for third-line combination therapy with cetuximab/irinotecan could be based on triple mutational testing.