Abstract
Background: KRAS exon 2 mutation is a validated biomarker of anti-EGFR antibodies for metastatic colorectal cancer (mCRC) patients. Recently, several reports confirmed that other KRAS (exon 3 or 4) and NRAS mutations are associated with the resistance to anti-EGFR antibodies for mCRC, while impact of BRAF or PIK3CA mutation on efficacy of treatment is still controversial.Methods: We have conducted a prospective, observational study to evaluate the frequencies and clinicopathological features of KRAS, BRAF, NRAS and PIK3CA mutations. These mutations were evaluated by novel research kit to detect 36 mutations in a single reaction. Among patients treated with anti-EGFR antibodies, objective response and progression-free survival (PFS) were also evaluated according to gene status.Results: A total of 265 patients were analyzed until from January 2013 to December 2013. 138 (52.1%) had tumors with no mutation (all wild type), 89 (33.6%) had tumors with mutation in KRAS exon 2, 10 (3.8%) with either KRAS exon 3 or 4, 10 (3.8%) with either NRAS exon 2, 3 or 4, 12 (4.5%) with BRAF codon 600, and 17 (6.4%) with PIK3CA mutations. All mutations except for PIK3CA were mutually exclusive. Rectal primary tumor tended to be more frequently observed in minor RAS mutated tumors rather than RAS wild type (65 vs 46%). BRAF mutated tumors more likely to develop on the right-sided colon (58 vs 20%), and to have the poorly differentiated adenocarcinoma or mucinous histology (33 vs 11%), and peritoneal metastasis (42 vs 17%) in comparison with BRAF wild tumors. Among the 53 patients treated with anti-EGFR therapies, the response rates (15.9 vs 0%) and PFS (5.6 vs 2.3 months) were significantly better in patients with all wild tumors (N = 44) than patients with any of the mutation (N = 9).Conclusions: Minor RAS mutations or BRAF mutations have been observed in KRAS wild type tumor, which associated with some clinicopathological features and resistance to anti-EGFR therapy in our patient cohort.
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