Due to the retrospective nature of this study, these results should be interpreted carefully
Due to the retrospective nature of this study, these results should be interpreted carefully. compared to those with TT genotypes. Conclusions: These results are the first to indicate that this 3UTR polymorphism may predict for cetuximab responsiveness in mutation status has been demonstrated to be a predictive MMAD marker of clinical benefit to monoclonal antibodies targeting EGFR [8C11]. Although mutations, particularly those including codons 12 and 13 that are found in approximately 30%C40% of patients with metastatic colorectal malignancy (mCRC), strongly relate to resistance to monoclonal antibodies targeting EGFR, not all mCRC patients with derive benefit from these brokers, and there is a need to identify molecular markers that better identify which mCRC MMAD patients benefit from treatment. Previous studies had identified additional markers in patients that can better predict for cetuximab responsiveness. For example, Jacobs et al. found that gene expression levels of two EGFR ligands, epiregulin and amphiregulin (AREG) related to favorable end result in 220 chemorefractory mCRC patients treated with cetuximab and irinotecan [12]. Several studies have exhibited Rabbit polyclonal to Acinus that high EGFR gene copy number could be a predictive marker in CRC patients treated with cetuximab [13, 14]. Furthermore, Laurent-Puig et al. showed that status, cytoplasmic expression of and EGFR amplification were associated with clinical end result in patients treated with MMAD a cetuximab-based regimen [15]. Finally, Sartore-Bianchi et al. pointed out that mutations in CRC were associated with clinical resistance to EGFR-targeted monoclonal antibodies including cetuximab and panitumumab [16]. In addition to tumor characteristics playing an important role in determining responsiveness to cetuximab, the genetic makeup of patients may also contribute to determining cetuximab sensitivity. Several studies have found that FcRIIaCFcRIIIa polymorphisms, as well as COX-2 and EGFR germline polymorphisms, are associated with clinical end result in mCRC patients treated with single-agent cetuximab impartial of KRAS status [17C19]. MicroRNAs are small, noncoding RNAs that regulate gene expression by degrading and/or suppressing the translation of target messenger RNA (mRNA) by base pairing in the 3-untranslated region (UTR) of mRNA [20]. Very recently, microRNA polymorphisms were discovered and are becoming increasingly important in the fast growing field of personalized medicine. MicroRNA polymorphisms could present at or near a microRNA-binding site of functional genes. MicroRNA polymorphisms can affect gene expression by interfering with microRNA function. They have been shown to impact drug response and have the potential to confer drug resistance [21, 22]. The family of microRNAs were found to regulate KRAS activity by binding MMAD to the 3-UTR of human gene [23]. Previous study demonstrated that a microRNA polymorphism in the microRNA complementary-binding site (lcs6) of the 3UTR of gene was associated with increased expression in model [24]. Furthermore, this polymorphism was found to be associated with increased malignancy risk in non-small-cell lung malignancy (NSCLC) patients and reduced overall survival (OS) in oral cancers [24, 25], suggesting functional and clinical significance. Due to the important role of mutation status in predicting cetuximab efficacy in CRC, we hypothesized that this lcs6 polymorphism may predict efficacy of cetuximab in mCRC patients. We analyzed this polymorphism in 130 mCRC patients who were refractory to fluoropyrimidine, irinotecan, and oxaliplatin, and treated with cetuximab as monotherapy in a phase II study (IMCL-0144). patients and methods patient characteristics and statistical analysis One hundred and thirty (38%) of the 346 patients enrolled in IMCL-0144 experienced tumor tissues available and amenable for analysis of lcs6 polymorphism (Table 1). IMCL-0144 involved patients with histopathologically confirmed mCRC, who were treated with cetuximab monotherapy following failure of therapeutic regimens that included fluoropyrimidine, irinotecan and oxaliplatin [26]. All 130 patients who had available tumor tissue samples were included in the present pharmacogenetic study, irrespective of clinical end result and mutation status. This study was performed at the University or college of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) following approval by the Institutional Review Table of the University or college of Southern California for Medical Sciences. All patients provided their written informed consent for tissue collection to allow study of molecular correlates. Table 1. Pretreatment characteristics among patients whose specimens available for genotyping in IMCL-0144 = 130)Frequency%lcs6 polymorphism and tumor response in lcs6 polymorphism MMAD with tumor response was determined by contingency table and the Fishers exact test. The association between this.