KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

摘要: RAS and RAF proteins play a key role in the control of cellular growth, proliferation differentiation (Bos, 1989; Wickenden et al, 2008) KRAS-activating mutations reduce or abolish intrinsic GTPase activity protein, leading to its constitutive activation (Conlin 2005) Similarly BRAF V600E mutation induces structural changes protein which increase kinase (Wan 2004) Activated are responsible for disregulation RAS/RAF/MAPKs signalling pathway. KRAS codons 12 13 activating widely recognised as predictors resistance treatment with anti-EGFR monoclonal antibodies (moAbs) metastatic colorectal cancer (mCRC) patients (Karapetis 2008; Amado 2008). Based on retrospectively collected data post hoc analyses large phase III studies, European Medicines Agency has restricted use cetuximab KRAS wild-type disease (about 60% overall population; EMEA, American Society Clinical Oncology similarly recommended recent provisional clinic opinion not administer moAbs mutated tumours (Allegra 2009). Nevertheless, systematic review meta-analysis, Linardou al reported very high specificity (0.93, (0.83–0.97)) much lower sensitivity (0.47, (0.43–0.52)) analysis predicting mCRC, thus underlining need additional predictive markers be combined evaluation, more accurate patients' selection (Linardou 2008). A recently published experience found correlation between V600E-activating mutation, mutually exclusive ones, panitumumab administered alone combination chemotherapy (Di Nicolantonio 2008). On basis above-mentioned evidences, around 50% candidate would excluded from receiving moAbs, significant improvement treatment's cost effectiveness. However, monotherapies determine response rate about 10% regardless line no than 23% respond irinotecan (Cunningham 2004; Van Cutsem 2007; Jonker 2007) it is plausible that receive an moAb might further slightly refined. Additional mutations, involving 61 146 (Edkins 2006) occur frequencies ranging 1 4% CRCs. These relatively rare well oncogenic (Buhrman Feig Cooper, 1988) pathway they account up resistant bearing tumours. To optimise who likely benefit we investigated cohort treated tumours, association clinical outcomes.