Accordingly, the prognostic associations inhibitor Brefeldin A of KRAS mutations in colorectal cancer may vary by specific mutation. Considered in con junction with evidence that KRAS codon 61 and 146 mutations possess weaker transforming potential than codon 12 mutations, it may be the case that KRAS codon 61 or 146 mutation is not associated with patient prognosis. However, considering the limited case and event numbers for KRAS codon 61 and 146 mutations, our sur vival analyses should be considered exploratory. Additional larger studies, perhaps necessitating pooling of data, are re quired to definitively assess the prognostic roles codon 61 and 146 mutations in colorectal cancer. Several studies have examined the predictive value of KRAS mutation in codon 61 and or 146 in metastatic colorectal cancer treated with anti EGFR therapy.

Pentheroudakis et al. did not observe any association between KRAS codon 61 or 146 mutation and Inhibitors,Modulators,Libraries survival. De Roock et al. showed that KRAS mutation in codon 61, but not that in codon 146, was signifi cantly associated with lack of response to cetuximab. Seymour et al. reported that KRAS codon Inhibitors,Modulators,Libraries 146 mu tations were not associated with overall or progression free survival. In contrast, Loupakis et al. reported that, among BRAF wild type cancers, KRAS codon 61 or 146 mutant cases experienced a significantly lower response rate and progression free survival. Indeed, a few experimental studies also re ported that tumors harboring KRAS mutations in co dons 61 and 146 were resistant to anti EGFR therapy. In addition, a recent published study reported by Douillard et al.

showed that RAS mutants with any mutation in KRAS codons 61, 117 and 146, or NRAS codons 12, 13, 61, 117 and 146, did not benefit from combined panitumumab plus FOLFOX4 chemo therapy. In our dataset, due to scarcity of data on cancer treatment, we were unable to examine the im portant question of the predictive value of KRAS muta tions in relation to anti EGFR therapy. Further clinical studies Inhibitors,Modulators,Libraries in this area are clearly required. The question arises as to whether it is worth investi gating these relatively rare mutations in the clinical set ting. Given that over 250,000 individuals each year die of colorectal cancer in Europe and the U. S.and most of these unfavorable outcomes are due to distant metasta ses, we estimate that every year approximately 10,000 cases have KRAS mutations in codon 61 or 146, and would be regarded as KRAS wild type through current KRAS codon 12 and 13 testing protocols.

Considering that KRAS codon 61 and 146 mutations may also confer resistance to EGFR inhibitors, patients who have metastatic Inhibitors,Modulators,Libraries colorectal cancer with KRAS Inhibitors,Modulators,Libraries mutation in codon 61 or 146 could receive more tailored manage ment through clinical testing of these additional KRAS codons. A limitation of this study is the absence of data on KRAS selleck inhibitor codon 117 mutation and NRAS mutations.