On the contrary, other studies have reported that K-ras mutation is not a prognostic factor for patient outcome.24,3639Masi et al claimed that patients with K-ras mutations derive similar clinical benefit from bevacizumab compared with patients who have WT K-ras.36This variability in results could be a result of several factors, including the number of patients included in different trials, the proportions of patients tested for K-ras mutation status and technology used, the chemotherapy regime under investigation, and subsequent second- and third-line therapies.39 == Table 2. both for patients with wild-type (WT) K-ras and mutated (MT) K-ras (hazard ratio [HR] 0.94,P=0.75); neither difference in median OS was significant (27 months WT K-ras versus 26 months MT K-ras, HR 0.92;P=0.70). A further analysis was carried out in the two groups according to metastatic sites. No statistically significant difference in terms of PFS and OS was demonstrated between WT K-ras and MT K-ras with liver metastases only and in those with extrahepatic disease. == Conclusion == Although further study is required, our results seem to confirm that K-ras mutation does not have a prognostic role in mCRC patients receiving first-line treatment with bevacizumab. Keywords:K-ras, bevacizumab, prognostic factor, metastatic colorectal cancer, liver metastases, extrahepatic disease == Introduction == Predictive and prognostic tumor markers are playing an increasingly important role in personalized metastatic colorectal cancer (mCRC) care.1,2These tags range Rhein (Monorhein) from conventional single protein-, ribonucleic acid- or deoxyribonucleic acid Rhein (Monorhein) (DNA)-based markers to molecular signatures based on multiplex assays, and they are used to guide clinical management of patients.3Currently, biomolecular factors with ascertained predictive and prognostic value in mCRC are the K-ras andBRAFoncogenes, respectively.410K-ras, the human homologue of the Kirsten rat sarcoma 2 virus oncogene, encodes a small guanosine triphosphate-binding protein that acts as a self-inactivating signal transducer by cycling from guanosine diphosphate- to guanosine triphosphate-bound states in response to stimulation of a cell-surface receptor.11,12K-ras can harbor oncogenic mutation that yields a constitutively active protein. Mutations (mainly at exons 2 and 3) occur early in the progression of colorectal adenoma to carcinoma and they are found in approximately 30%50% of CRC.5,11,13,14The identification of a biologic and a clinical role for K-ras mutation marked a turning point in the scenario Rhein (Monorhein) of mCRC treatment. As a matter of a fact, the importance of K-ras and its downstream signaling pathways in tumor development is well established. In the last few years, K-ras mutation has acquired an essential clinical significance as a negative predictive factor in mCRC patients treated with anti-epidermal growth factor receptor (EGFR) agents, such as cetuximab and panitumumab.1,2In addition, the prognostic value of tumor K-ras status has been extensively evaluated, but results have been conflicting. Some studies have demonstrated a prognostic effect,1,5while others have failed.6 The interaction of EGFR and vascular endothelial growth factor (VEGF) is well known.15,16Bevacizumab, a humanized monoclonal antibody that binds to and neutralizes VEGF-A, has been widely used in various mCRC treatment lines, improving response rates, progression-free survival (PFS), and overall survival (OS).1724At the time, anti-VEGF predictive and prognostic factors were not found, and the role of K-ras-mutation status in patients undergoing treatment with bevacizumab remains of great interest. Furthermore, it has been ascertained that K-ras mutation is also associated with specific clinical signatures of tumor as an increased risk of metastasis in lung and brain, even if does not modify the risk of metastasis in the liver.25 In a previous study, we examined the role of K-ras status as a predictive factor of response on antiangiogenic therapy, affirming that bevacizumab provides clinical benefit and objective response rate in mCRC patients independently of K-ras expression and metastatic sites.26 Moving from such Rhein (Monorhein) an appealing biological and clinical background, we planned an additional retrospective analysis aimed at the identification of a possible prognostic role of K-ras in mCRC patients treated with first-line chemotherapy plus bevacizumab. Correlations between K-ras status and PFS and OS were analyzed. Furthermore, we evaluated whether K-ras mutation could influence the outcome of patients with liver metastases only, in comparison to patients with extra-hepatic disease. == Materials and methods == == Patients and study design == The design of Rabbit polyclonal to ZNF238 this study has been reported previously.26In brief, this was a retrospective study enrolling consecutive 108 unresectable mCRC patients, treated in clinical practice in three Italian oncology centers (Rome, Latina, Gaeta) between September 2008 and March 2011. Patients with histologically confirmed mCRC, Eastern Cooperative Oncology Group performance status 2, assessment of K-ras mutation status, no previous chemotherapy for advanced disease, treated with first-line chemotherapy with either the FOLFOX (oxaliplatin, leucovorin, and fluorouracil) or FOLFIRI (folic acid, fluorouracil, and irinotecan) regimen combined with bevacizumab, not a candidate for liver metastasis resection after chemotherapy, with adequate hepatic and renal function, and no contraindications to bevacizumab therapy were included. The primary end point of this study Rhein (Monorhein) was to assess the prognostic.