***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The development of tumor biomarkers ready for clinical use is complex . We propose a refined system for biomarker study design , conduct , analysis , and evaluation that incorporates a hierarchal level of evidence scale for tumor marker studies , including those using archived specimens . Although fully prospect i ve r and omized clinical trials to evaluate the medical utility of a prognostic or predictive biomarker are the gold st and ard , such trials are costly , so we discuss more efficient indirect " prospect ive-retrospective " design s using archived specimens . In particular , we propose new guidelines that stipulate that 1 ) adequate amounts of archived tissue must be available from enough patients from a prospect i ve trial ( which for predictive factors should generally be a r and omized design ) for analyses to have adequate statistical power and for the patients included in the evaluation to be clearly representative of the patients in the trial ; 2 ) the test should be analytically and preanalytically vali date d for use with archived tissue ; 3 ) the plan for biomarker evaluation should be completely specified in writing before the performance of biomarker assays on archived tissue and should be focused on evaluation of a single completely defined classifier ; and 4 ) the results from archived specimens should be vali date d using specimens from one or more similar , but separate , studies Purpose : Plasma proteins [ vascular endothelial growth factor ( VEGF ) , soluble VEGF receptor 2 ( sVEGFR-2 ) , carbonic anhydrase IX ( CAIX ) , tissue inhibitor of metalloproteinase 1 ( TIMP-1 ) , and Ras p21 ] and one tumor gene ( VHL ) were analyzed to identify prognostic biomarkers or indicators of response to sorafenib in a subset of patients enrolled in the Treatment Approaches in Renal Cancer Global Evaluation Trial . Experimental Design : Nine hundred three patients with advanced renal cell carcinoma ( RCC ) were r and omized to 400 mg sorafenib twice a day or placebo . Sample s collected at baseline and after 3 and 12 weeks were subjected to enzyme-linked immunosorbent assays . VHL exons were sequenced from tumor biopsies . Results : Baseline biomarker data were available for VEGF ( n = 712 ) , sVEGFR-2 ( n = 713 ) , CAIX ( n = 128 ) , TIMP-1 ( n = 123 ) , Ras p21 ( n = 125 ) , and VHL mutational status ( n = 134 ) . Higher Eastern Cooperative Oncology Group performance status ( ECOG PS ) score correlated with elevated baseline VEGF ( P < 0.0001 ) and a higher incidence of VHL mutations ( P = 0.008 ) , whereas higher Memorial Sloan-Kettering Cancer Center ( MSKCC ) score correlated with elevated VEGF ( P < 0.0001 ) , CAIX ( P = 0.027 ) , and TIMP-1 ( P = 0.0001 ) . Univariable analyses of baseline levels in the placebo cohort identified VEGF ( P = 0.0024 ) , CAIX ( P = 0.034 ) , TIMP-1 ( P = 0.001 ) , and Ras p21 ( P = 0.016 ) as prognostic biomarkers for survival . TIMP-1 remained prognostic for survival in a multivariable analysis model ( P = 0.002 ) that also included ECOG PS , MSKCC score , and the other biomarkers assayed . In the placebo cohort , TIMP-1 ( P < 0.001 ) and Ras p21 ( P = 0.048 ) levels increased at 12 weeks . In the sorafenib cohort , VEGF levels increased at 3 and 12 weeks of treatment ( both weeks P < 0.0001 ) , whereas sVEGFR-2 ( both weeks P < 0.0001 ) and TIMP-1 levels ( P = 0.002 , week 3 ; P = 0.006 , week 12 ) decreased . Conclusions : VEGF , CAIX , TIMP-1 , and Ras p21 levels were prognostic for survival in RCC patients . Of these , TIMP-1 has emerged as being independently prognostic . Clin Cancer Res ; 16(19 ) ; 4853–63 . © 2010 AACR BACKGROUND Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs . Thus , we aim ed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma ( ccRCC ) . PATIENTS AND METHODS The expression of eight key proteins related to hypoxia ( CAIX , HIF1A , HIF2A , VEGFA , VEGFR1 , VEGFR2 , VEGFR3 and PDGFRB ) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC sample s from prospect ively recruited patients treated with first-line sunitinib .  The proteins expression , VHL inactivation and EGLN3 mRNA content were compared with the patients ' response to sunitinib . RESULTS High expression of HIF2A and PDGFRB was associated with better  sunitinib RECIST objective response ( P = 0.024 and P = 0.026 ; respectively ) and increased VEGFR3 expression was associated with longer progression-free survival ( P = 0.012 ) . VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 ( P = 0.002 ) , a sunitinib resistance predictor . With respect to overall survival ( OS ) , high VEGFA was associated with short ( P = 0.009 ) and HIF2A with long ( P = 0.048 ) survival times . High EGLN3 mRNA content was associated with shorter OS ( P = 0.023 ) . CONCLUSIONS We found an association between several proteins involved in hypoxia and sunitinib efficacy . In addition , low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele , reinforcing VEGFR3 as a marker of sunitinib resistance BACKGROUND Metastatic renal cell carcinoma ( mRCC ) patients treated with anti-vascular endothelial growth factor ( VEGF ) therapies  demonstrate promising outcomes but not all patients benefit . Factors that predict response remain to be eluci date d. PATIENTS AND METHODS Nephrectomy material from 37 patients with mRCC receiving bevacizumab + /- erlotinib  was used for protein and gene expression assessment . Protein lysates were subjected to reverse-phase protein array profiling . RNA extracts were used to carry out gene expression microarray-based profiling . Normalized protein and gene expression data were correlated with overall survival ( OS ) and progression-free survival ( PFS ) using univariate Cox hazard model and linear regression . Immunoblotting was carried out to vali date the results . RESULTS High protein levels of AMP-activated protein kinase and low levels of cyclin B1 ( CCNB1 ) were associated with longer OS and PFS . Further validation revealed reduced expression and activation of phosphoinositide 3-kinase ( PI3 K ) pathway components and cell cycle factors in patients with prolonged survival after therapy . Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS . CONCLUSIONS The OS and PFS of bevacizumab + /- erlotinib-treated  patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3 K pathway and cell cycle signaling BACKGROUND We conducted a phase 3 , r and omized , double-blind , placebo-controlled trial of sorafenib , a multikinase inhibitor of tumor-cell proliferation and angiogenesis , in patients with advanced clear-cell renal-cell carcinoma . METHODS From November 2003 to March 2005 , we r and omly assigned 903 patients with renal-cell carcinoma that was resistant to st and ard therapy to receive either continuous treatment with oral sorafenib ( at a dose of 400 mg twice daily ) or placebo ;  451 patients received sorafenib and 452 received placebo .  The primary end point was overall survival . A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo . Consequently , crossover was permitted from placebo to sorafenib , beginning in May 2005 . RESULTS At the January 2005 cutoff , the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group ( hazard ratio for disease progression in the sorafenib group , 0.44 ; 95 % confidence interval [ CI ] , 0.35 to 0.55 ; P<0.01 ) . The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death , as compared with placebo ( hazard ratio , 0.72 ; 95 % CI , 0.54 to 0.94 ; P=0.02 ) , although this benefit was not statistically significant according to the O'Brien-Fleming threshold . Partial responses were reported as the best response in 10 % of patients receiving sorafenib and in 2 % of those receiving placebo ( P<0.001 ) . Diarrhea , rash , fatigue , and h and -foot skin reactions were the most common adverse events associated with sorafenib . Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo . CONCLUSIONS As compared with placebo , treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed ; however , treatment is associated with increased toxic effects . ( Clinical Trials.gov number , NCT00073307 [ Clinical Trials.gov ] . ) BACKGROUND No biomarkers that could guide patient selection for treatment with the anti-VEGF monoclonal antibody bevacizumab have been identified . We assessed whether genetic variants in the VEGF pathway could act as biomarkers for bevacizumab treatment outcome . METHODS We investigated DNA from white patients from two phase 3 r and omised studies . In AViTA , patients with metastatic pancreatic adenocarcinoma were r and omly assigned to receive gemcitabine and erlotinib plus either bevacizumab or placebo . In AVOREN , patients with metastatic renal-cell carcinoma were r and omly assigned to receive interferon alfa-2a plus either bevacizumab or placebo . We assessed the correlation of 138 SNPs in the VEGF pathway with progression-free survival and overall survival in a sub population of patients from AViTA . Significant findings were confirmed in a sub population of patients from AVOREN and functionally studied at the molecular level . FINDINGS We investigated DNA of 154 patients from AViTA , of whom 77 received bevacizumab , and 110 patients from AVOREN , of whom 59 received bevacizumab .  Only rs9582036 , a SNP in VEGF receptor 1 ( VEGFR1 or FLT1 ) , was significantly associated with overall survival in the bevacizumab group of AViTA after correction for multiplicity ( per-allele hazard ratio [ HR ] 2·1 , 95 % CI 1·45 - 3·06 , p=0·00014 ) . This SNP was also associated with progression-free survival ( per-allele HR 1·89 , 1·31 - 2·71 , p=0·00081 ) in bevacizumab-treated patients from AViTA . AC and CC carriers of this SNP exhibited HRs for overall survival of 2·0 ( 1·19 - 3·36 ; p=0·0091 ) and 4·72 ( 2·08 - 10·68 ; p=0·0002 ) relative to AA carriers . No effects were seen in placebo-treated patients and a significant genotype by treatment interaction ( p=0·041 ) was recorded , indicating that the VEGFR1 locus containing this SNP serves as a predictive marker for bevacizumab treatment outcome in AViTA . Fine-mapping experiments of this locus identified rs7993418 , a synonymous SNP affecting tyrosine 1213 in the VEGFR1 tyrosine-kinase domain , as the functional variant underlying the association . This SNP causes a shift in codon usage , leading to increased VEGFR1 expression and downstream VEGFR1 signalling . This VEGFR1 locus correlated significantly with progression-free survival ( HR 1·81 , 1·08 - 3·05 ; p=0·033 ) but not overall survival ( HR 0·91 , 0·45 - 1·82 , p=0·78 ) in the bevacizumab group in AVOREN . INTERPRETATION A locus in VEGFR1 correlates with increased VEGFR1 expression and poor outcome of bevacizumab treatment . Prospect i ve assessment is underway to vali date the predictive value of this novel biomarker . FUNDING F Hoffmann-La Roche Anti-angiogenic therapy benefits many patients with advanced renal cell carcinoma ( 
    Output:
    
IL-6 is the most corroborated predictive biomarker based on its consistent predictive value in two different trials .