***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: BACKGROUND The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor-positive tumors is poorly defined by clinical and histopathological measures . METHODS We tested whether the results of a reverse-transcriptase-polymerase-chain-reaction ( RT-PCR ) assay of 21 prospect ively selected genes in paraffin-embedded tumor tissue would correlate with the likelihood of distant recurrence in patients with node-negative , tamoxifen-treated breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trial B-14 . The levels of expression of 16 cancer-related genes and 5 reference genes were used in a prospect ively defined algorithm to calculate a recurrence score and to determine a risk group ( low , intermediate , or high ) for each patient . RESULTS Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks . The proportions of patients categorized as having a low , intermediate , or high risk by the RT-PCR assay were 51 , 22 , and 27 percent , respectively . The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-risk , intermediate-risk , and high-risk groups were 6.8 percent ( 95 percent confidence interval , 4.0 to 9.6 ) , 14.3 percent ( 95 percent confidence interval , 8.3 to 20.3 ) , and 30.5 percent ( 95 percent confidence interval , 23.6 to 37.4 ) . The rate in the low-risk group was significantly lower than that in the high-risk group ( P<0.001 ) . In a multivariate Cox model , the recurrence score provided significant predictive power that was independent of age and tumor size ( P<0.001 ) . The recurrence score was also predictive of overall survival ( P<0.001 ) and could be used as a continuous function to predict distant recurrence in individual patients . CONCLUSIONS The recurrence score has been vali date d as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative , estrogen-receptor-positive breast cancer PURPOSE Biomarkers can add substantial value to current medical practice by providing an integrated approach to prediction using the genetic makeup of the tumor and the genotype of the patient to guide patient-specific treatment selection . We discuss and evaluate various clinical trial design s for the validation of biomarker-guided therapy . METHODS Design s for predictive marker validation are broadly classified as retrospective ( ie , using data from previously well-conducted r and omized controlled trials [ RCTs ] ) versus prospect i ve ( enrichment , unselected , hybrid , or adaptive analysis ) . We discuss the salient features of each design in the context of real trials . RESULTS Well- design ed retrospective analysis from well-conducted prospect i ve RCTs can bring forward effective treatments to marker-defined subgroups of patients in a timely manner ( eg , KRAS and colorectal cancer ) . Enrichment design s are appropriate when preliminary evidence suggest that patients with or without that marker profile do not benefit from the treatments in question ; however , this may sometimes leave questions unanswered ( eg , trastuzumab and breast cancer ) . An unselected design is optimal where preliminary evidence regarding treatment benefit and assay reproducibility is uncertain ( eg , epidermal growth factor receptor and lung cancer ) . Hybrid design s are appropriate when preliminary evidence demonstrate the efficacy of certain treatments for a marker-defined subgroup , making it unethical to r and omly assign patients with that marker status to other treatments ( eg , multigene assay and breast cancer ) . Adaptive analysis design s allow for prespecified marker-defined subgroup analyses of data from an RCT . CONCLUSION The implementation of these design strategies will lead to a more rapid clinical validation of biomarker-guided therapy PURPOSE Development of a radiosensitivity predictive assay is a central goal of radiation oncology . We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients . METHODS AND MATERIAL S Radiosensitivity ( determined by survival fraction at 2 Gy ) was modeled as a function of gene expression , tissue of origin , ras status ( mut/wt ) , and p53 status ( mut/wt ) in 48 human cancer cell lines . Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index ( RSI , high index = radioresistance ) . This model was applied to three independent cohorts treated with concurrent chemoradiation : head- and -neck cancer ( HNC , n = 92 ) ; rectal cancer ( n = 14 ) ; and esophageal cancer ( n = 12 ) . RESULTS Predicted RSI was significantly different in responders ( R ) vs. nonresponders ( NR ) in the rectal ( RSI R vs. NR 0.32 vs. 0.46 , p = 0.03 ) , esophageal ( RSI R vs. NR 0.37 vs. 0.50 , p = 0.05 ) and combined rectal/esophageal ( RSI R vs. NR 0.34 vs. 0.48 , p = 0.001511 ) cohorts . Using a threshold RSI of 0.46 , the model has a sensitivity of 80 % , specificity of 82 % , and positive predictive value of 86 % . Finally , we evaluated the model as a prognostic marker in HNC . There was an improved 2-year locoregional control ( LRC ) in the predicted radiosensitive group ( 2-year LRC 86 % vs. 61 % , p = 0.05 ) . CONCLUSIONS We vali date a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients . To our knowledge , this is the first time that a systems biology-based radiosensitivity model is vali date d in multiple independent clinical data sets Predictive biomarkers to guide therapy for cancer patients are a cornerstone of precision medicine . Discussed herein are considerations regarding the design and interpretation of such predictive biomarker studies . These considerations are important for both planning and interpreting prospect i ve studies and for using specimens collected from completed r and omized clinical trials . Specific issues addressed are differentiation between qualitative and quantitative predictive effects , challenges due to sample size requirements for predictive biomarker assessment , and consideration of additional factors relevant to clinical utility assessment , such as toxicity and cost of new therapies as well as costs and potential morbidities associated with routine use of biomarker-based tests The 70-gene signature ( MammaPrint ™ ) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment . Given the strong association between locoregional and distant recurrence , we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence ( LRR ) . 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherl and s Cancer Institute between 1984 and 2006 were included .  Adjuvant treatment consisted of radiotherapy , chemotherapy , and /or endocrine therapy as indicated by guidelines used at the time . All patients were included in various 70-gene signature validation studies . After a median follow-up of 8.96 years with 87 LRRs , patients with a high-risk 70-gene signature ( n = 492 ) had an LRR risk of 12.6 % ( 95 % CI 9.7–15.8 ) at 10 years , compared to 6.1 % ( 95 % CI 4.1–8.5 ) for low-risk patients ( n = 561 ; P < 0.001 ) . Adjusting the 70-gene signature in a competing risk model for the clinicopathological factors such as age , tumour size , grade , hormone receptor status , LVI , axillary lymph node involvement , surgical treatment , endocrine treatment , and chemotherapy result ed in a multivariable HR of 1.73 ( 95 % CI 1.02–2.93 ; P = 0.042 ) . Adding the signature to the model based on clinicopathological factors improved the discrimination , albeit non-significantly [ C-index through 10 years changed from 0.731 ( 95 % CI 0.682–0.782 ) to 0.741 ( 95 % CI 0.693–0.790 ) ] . Calibration of the prognostic models was excellent . The 70-gene signature is an independent prognostic factor for LRR . A significantly lower local recurrence risk was seen in patients with a low-risk 70-gene signature compared to those with high-risk 70-gene signature Radical radiotherapy and surgery achieve similar cure rates in muscle-invasive bladder cancer , but the choice of which treatment would be most beneficial can not currently be predicted for individual patients . The primary aim of this study was to assess whether expression of any of a panel of DNA damage signaling proteins in tumor sample s taken before irradiation could be used as a predictive marker of radiotherapy response , or rather was prognostic . Protein expression of MRE11 , RAD50 , NBS1 , ATM , and H2AX was studied by immunohistochemistry in pretreatment tumor specimens from two cohorts of bladder cancer patients ( validation cohort prospect ively acquired ) treated with radical radiotherapy and one cohort of cystectomy patients .  In the radiotherapy test cohort ( n = 86 ) , low tumor MRE11 expression was associated with worse cancer-specific survival compared with high expression [ 43.1 % versus 68.7 % 3-year cause-specific survival ( CSS ) , P = 0.012 ] by Kaplan-Meier analysis . This was confirmed in the radiotherapy validation cohort ( n = 93 ; 43.0 % versus 71.2 % , P = 0.020 ) . However , in the cystectomy cohort ( n = 88 ) , MRE11 expression was not associated with cancer-specific survival , commensurate with MRE11 being a predictive marker . High MRE11 expression in the combined radiotherapy cohort had a significantly better cancer-specific survival compared with the high-expression cystectomy cohort ( 69.9 % versus 53.8 % 3-year CSS , P = 0.021 ) . In this vali date d immunohistochemistry study , MRE11 protein expression was shown and confirmed as a predictive factor associated with survival following bladder cancer radiotherapy , justifying its inclusion in subsequent trial design s. MRE11 expression may ultimately allow patient selection for radiotherapy or cystectomy , thus improving overall cure rates BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with st and ard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer ( NSCLC ) is unknown . METHODS We conducted an open-label , phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease . Patients were r and omly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy ( pemetrexed , 500 mg per square meter of body-surface area , plus either cisplatin , 75 mg per square meter , or carboplatin , target area under the curve of 5 to 6 mg per milliliter per minute ) every 3 weeks for up to six cycles . Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy . The primary end point was progression-free survival as assessed by independent radiologic review . RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy ( median , 10.9 months vs. 7.0 months ; hazard ratio for progression or death with crizotinib , 0.45 ; 95 % confidence interval [ CI ] , 0.35 to 0.60 ; P<0.001 ) . Objective response rates were 74 % and 45 % , respectively ( P<0.001 ) . Median overall survival was not reached in either group ( hazard ratio for death with crizotinib , 0.82 ; 95 % CI , 0.54 to 1.26 ; P=0.36 ) ; the probability of 1-year survival was 84 % with crizotinib and 79 % with chemotherapy . The most common adverse events with crizotinib were vision disorders , diarrhea , nausea , and edema , and the most common events with chemotherapy were nausea , fatigue , vomiting , and decreased appetite . As compared with chemotherapy , crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life . CONCLUSIONS Crizotinib was superior to st and ard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC . ( Funded by Pfizer ; PROFILE 1014 Clinical Trials.gov number , NCT01154140 . ) PURPOSE To investigate the expression and predictive role of the Mre11/Rad50/Nbs1 ( MRN ) complex and the ataxia-telangiectasia mutated protein ( ATM ) for the outcome of radiotherapy in breast cancer patients . METHODS AND MATERIAL S The protein expression of ATM and the DNA repair proteins in the MRN complex were investigated using immunoh 
    Output:
    
Although these biomarkers show promise , there is not enough evidence to justify their use in routine practice .