MUTATIONS IN NRAS CODON 61 AND KRAS CODON 146 ARE POOR PROGNOSTIC FACTORS IN PATIENTS WHO RECEIVED ANTI-EGFR MONOCLONAL ANTIBODY FOR METASTATIC COLORECTAL CANCER

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Abstract

Background

Previous studies showed that gene mutations (NRAS, BRAF, PIK3CA) are associated with a poor prognosis or resistance of anti-EGFR antibody in metastatic colorectal cancer (mCRC) patients with wild-type (WT) of KRAS codon 12/13 (KRAS-WT). However, the significance of these biomarkers has not been clarified. In addition, EGFR immunohistochemistry (IHC) and EGFR gene amplification to evaluate the efficacy of anti-EGFR antibody treatment have not been reported for mCRC.

Method

We evaluated tumor response and survival in patients who received anti-EGFR antibody by mutation analysis of KRAS, NRAS, BRAF, and PIK3CA in KRAS-WT patients with mCRC. Tumor DNA samples are obtained from patients treated in our hospital with anti-EGFR antibody between August 2008 and August 2011.

Results

A total of 117 patients were enrolled in this analysis, including 100 KRAS-WT patients. Seventy-one patients (60.7%) were all WT for KRAS, NRAS, BRAF, and PIK3CA, and 46 patients (39.3%) had at least one mutation or had insufficient DNA samples to analyze. Mutations of KRAS codon 61 (2 patients), KRAS codon 146 (5), BRAF V600E (2), PIK3CA exon9 (8), NRAS codon 12/13 (2), and NRAS codon 61 (5) were detected. No patients had a mutation of PIK3CA exon 20. Patients with at least one mutation had no response. Mutations of KRAS codon 146, NRAS codon 61, and BRAF V600E were associated with a shorter progression-free survival (PFS) compared with all WT patients (P = 0.049, P = 0.004, P = 0.036, respectively). Twelve patients (12% of KRAS-WT patients) with a mutation of KRAS codon 146, BRAF V600E, NRAS codon 61 had poor prognosis compared with the other KRAS-WT patients (PFS, 6.4 versus 2.0 months, P < 0.001; overall survival (OS), 13.7 versus 7.9 months, P = 0.012). In all WT patients, moderate to strong EGFR IHC was associated with a better response rate than negative and weak IHC (P = 0.046).

Conclusion

Mutations of KRAS codon 146, NRAS codon 61, and BRAF V600E could be a strong prognostic factor of anti-EGFR antibody in patients with mCRC. Combination of IHC and DISH of EGFR could identify patients with a tumor response to anti-EGFR antibody in patients that are all wild type for KRAS, NRAS, BRAF, and PIK3CA.

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