***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: Purpose : Elevated levels or increases in circulating tumor cells ( CTC ) portend poor prognosis in patients with epithelial cancers . Less is known about CTCs as surrogate endpoints or their use for predictive biomarker evaluation . This study investigated the utility of CTC enumeration and characterization using the Cell Search platform , as well as mutation detection in circulating tumor DNA ( ctDNA ) , in patients with advanced non – small cell lung cancer ( NSCLC ) . Experimental Design : Forty-one patients were enrolled in a single-arm phase II clinical trial of erlotinib and pertuzumab .  Peripheral blood was analyzed for CTC enumeration , EGFR expression in CTCs , and detection of oncogenic mutations in CTCs and ctDNA . Changes in CTC levels were correlated with 2[18F]fluoro-2-deoxy-d-glucose – positron emission tomographic ( FDG-PET ) and computed tomographic ( CT ) imaging and survival endpoints . Results : CTCs were detected ( ≥1 CTC ) at baseline in 78 % of patients . Greater sensitivity for mutation detection was observed in ctDNA than in CTCs and detected mutations were strongly concordant with mutation status in matched tumor . Higher baseline CTC counts were associated with response to treatment by Response Evaluation Criteria in Solid Tumors ( RECIST , P = 0.009 ) and decreased CTC counts upon treatment were associated with FDG-PET and RECIST response ( P = 0.014 and P = 0.019 ) and longer progression-free survival ( P = 0.050 ) . Conclusion : These data provide evidence of a correlation between decreases in CTC counts and radiographic response by either FDG-PET or RECIST in patients with advanced NSCLC . These findings require prospect i ve validation but suggest a potential role for using CTC decreases as an early indication of response to therapy and ctDNA for real-time assessment of mutation status from blood . Clin Cancer Res ; 18(8 ) ; 2391–401 . © 2012 AACR Purpose : Activating mutations in the epidermal growth factor receptor ( EGFR ) are associated with enhanced response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer ( NSCLC ) , whereas KRAS mutations translate into poor patient outcomes . We hypothesized that analysis of plasma for EGFR and KRAS mutations from shed tumor DNA would have clinical utility . Methods : An allele-specific polymerase chain reaction assay using Scorpion-amplification refractory mutation system ( DxS , Ltd ) was used to detect mutations in plasma DNA from patients with advanced stage NSCLC treated as second- or third-line therapy on a phase I/II trial of docetaxel plus intercalated erlotinib .  Results : EGFR mutations were detected in 10 of 49 patients ( 20 % ) . Six ( 12 % ) had single activating mutations in EGFR , associated with improved progression-free survival ( median , 18.3 months ) , compared with all other patients ( median , 3.9 months ; p = 0.008 ) , or those with wild-type EGFR ( median , 4.0 months ; p = 0.012 ) . Four of 49 patients harbored a de novo T790 M resistance mutation ( median progression-free survival , 3.9 months ) . EGFR mutational status was associated with clinical response ( 45 assessable , p = 0.0001 ) ; in the six patients with activating mutations , all achieved complete ( 33 % ) or partial ( 67 % ) response . All CR patients had E19del detectable in both tumor and plasma . KRAS mutations were detected in two of 49 ( 4 % ) patients , both of whom had rapid progressive disease . Conclusions : Activating EGFR mutations detected in shed DNA in plasma are significantly associated with favorable outcomes in patients with advanced NSCLC receiving docetaxel plus intercalated erlotinib . The addition of docetaxel in this schedule did not diminish the efficacy of erlotinib against patients with EGFR activating mutations BACKGROUND Lung cancer is one of the most common malignant diseases worldwide and associated with considerable morbidity and mortality . New agents targeting the epidermal growth factor system are emerging , but only a subgroup of the patients will benefit from the therapy . Cell free DNA ( cfDNA ) in the blood allows for tumour specific analyses , including KRAS-mutations , and the aim of the study was to investigate the possible prognostic value of plasma mutated KRAS ( pmKRAS ) in patients with non-small cell lung cancer ( NSCLC ) . MATERIAL AND METHODS Patients with newly diagnosed , advanced NSCLC eligible for chemotherapy were enrolled in a prospect i ve biomarker trial . A pre-treatment blood sample was drawn and subsequently DNA was extracted and pmKRAS analysed . The patients received carboplatin ( AUC5 ) i.v . day 1 and vinorelbine ( 30mg/m(2 ) i.v . day 1 and 60mg/m(2 ) p.o . day 8) for a maximum of six cycles . Response to chemotherapy  was evaluated according to RECIST v.1.0 by CT scans of the chest and upper abdomen . The presence of pmKRAS at baseline was assessed by an in-house qPCR method . The primary endpoint was overall survival ( OS ) . Secondary end-points were progression free survival ( PFS ) and overall response rate . RESULTS The study included 246 patients receiving a minimum of 1 treatment cycle , and all but four were evaluable for response according to RECIST . Forty-three patients ( 17.5 % ) presented with a KRAS mutation . OS was 8.9 months and PFS by intention to treat 5.4 months . Patients with a detectable plasma-KRAS mutation had a significantly shorter OS and PFS compared to the wild type ( WT ) patients ( median OS 4.8 months versus 9.5 months , HR 1.87 , 95 % CI 1.23 - 2.84 , p=0.0002 and median PFS 3.0 months versus 5.6 months , HR 1.60 , 95 % CI 1.09 - 2.37 , p=0.0043 ) . A multivariate Cox regression analysis confirmed the independent prognostic value of pmKRAS in OS but not in PFS . The response rate to chemotherapy was significantly lower in the group of patients with a mutation compared to WT ( p<0.0001 ) . CONCLUSION The presence of KRAS mutations in plasma may be a marker of poor prognosis and may also hold predictive value . Further validation in an independent cohort is highly needed PURPOSE Mutations in the epidermal growth factor receptor ( EGFR ) kinase domain can predict tumor response to tyrosine kinase inhibitors ( TKIs ) in non-small-cell lung cancer ( NSCLC ) . However , obtaining tumor tissues for mutation analysis is challenging . We hypothesized that plasma-based EGFR mutation analysis is feasible and has value in predicting tumor response in patients with NSCLC . PATIENTS AND METHODS Plasma DNA sample s and matched tumors from 230 patients with stages IIIB to IV NSCLC were analyzed for EGFR mutations in exons 19 and 21 by using denaturing high-performance liquid chromatography . We compared the mutations in the plasma sample s and the matched tumors and determined an association between EGFR mutation status and the patients ' clinical outcomes prospect ively . RESULTS In 230 patients , we detected 81 EGFR mutations  in 79 ( 34.3 % ) of the patients ' plasma sample s. We detected the same mutations in 63 ( 79.7 % ) of the matched tumors . Sixteen plasma ( 7.0 % ) and fourteen tumor ( 6.1 % ) sample s showed unique mutations . The mutation frequencies were significantly higher in never-smokers and in patients with adenocarcinomas ( P = .012 and P = .009 , respectively ) . In the 102 patients who failed platinum-based treatment and who were treated with gefitinib  , 22 ( 59.5 % ) of the 37 with EGFR mutations in the plasma sample s , whereas only 15 ( 23.1 % ) of the 65 without EGFR mutations , achieved an objective response ( P = .002 ) . Patients with EGFR mutations had a significantly longer progression-free survival time than those without mutations ( P = .044 ) in plasma . CONCLUSION EGFR mutations can be reliably detected in plasma DNA of patients with stages IIIB to IV NSCLC and can be used as a biomarker to predict tumor response to TKIs 
    Output:
    
Sensitivity analyses and subgroup analyses demonstrated the stability of our conclusion .Our analysis showed that EGFR mutations in ctDNA predicted a better PFS , in particular in advanced NSCLC patients treated by EGFR-TKIs .
KRAS mutations in ctDNA indicated a worse PFS and OS in patients treated by chemotherapy