Background: The mutation in KRAS exon 2 is a validated biomarker of resistance to anti-epidermal growth factor\nreceptor (EGFR) therapy in metastatic colorectal cancer (mCRC). Several reports have confirmed associations of\nother RAS mutations with resistance to anti-EGFR therapy. However, the impact of BRAF and PIK3CA mutations on\nthe efficacy of anti-EGFR therapy remains controversial. Little is known about the frequencies and clinicopathological\nfeatures of these mutations, as well as the therapeutic effects of anti-EGFR therapy in mCRC patients with these\nmutations, especially in the Asian population.\nMethods: In this retrospective observational study, frequencies and clinicopathological features of KRAS, NRAS,\nBRAF and PIK3CA mutations were evaluated in patients with mCRC. Among patients treated with anti-EGFR therapy,\nobjective response, progression-free survival (PFS), and overall survival (OS) were evaluated according to gene status.\nResults: Among 264 patients, mutations in KRAS exon 2, KRAS exons 3 or 4, NRAS, BRAF and PIK3CA were detected in\n34.1%, 3.8%, 4.2%, 5.4% and 6.4%, respectively. Thus, a total of 12.1% of patients without KRAS exon 2 mutations had\nother RAS mutations. Primary rectal tumors tended to be more frequently observed in RAS mutant tumors. BRAF\nmutations were more frequently observed with right-sided colon, poorly differentiated or mucinous adenocarcinoma,\nand peritoneal metastasis. Among the 66 patients with KRAS exon 2 wild-type tumors treated with anti-EGFR agents,\nPFS (5.8 vs. 2.2 months) and OS (17.7 vs. 5.2 months) were significantly better in patients with all wild-type tumors (n = 56)\nthan in those with any of the mutations (n = 10). The response rate also tended to be better with all wild-type tumors\n(26.8 vs. 0%).\nConclusion: Other RAS and BRAF mutations were observed in KRAS exon 2 wild-type tumors, which were associated with\nsome clinicopathological features and resistance to anti-EGFR therapy in our patient cohort.
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