***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 To evaluate the safety , efficacy and biomarkers of short-course proton beam radiation and capecitabine , followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma ( PDAC ) patients . METHODS AND MATERIAL S Patients with radiographically resectable , biopsy-proven PDAC were treated with neoadjuvant short-course ( 2-week ) proton-based radiation with capecitabine , followed by surgery and adjuvant gemcitabine . The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of < 20 % . Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood . RESULTS The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled , of whom 35 patients were treated in the phase 2 portion . There were no grade 4 or 5 toxicities , and only 2 of 35 patients ( 4.1 % ) experienced a grade 3 toxicity event ( chest wall pain grade 1 , colitis grade 1 ) . Of 48 patients eligible for analysis , 37 underwent pancreaticoduodenectomy . Thirty of 37 ( 81 % ) had positive nodes . Locoregional failure occurred in 6 of 37 resected patients ( 16.2 % ) , and distant recurrence occurred in 35 of 48 patients ( 72.9 % ) . With median follow-up of 38 months , the median progression-free survival for the entire group was 10 months , and overall survival was 17 months . Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12 , stromal CXCR7 expression , and circulating biomarkers CEA , CA19 - 9 , and HGF ( all , P<.05 ) . CONCLUSIONS This study met the primary endpoint by showing a rate of 4.1 % grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation . Treatment was associated with favorable local control . In exploratory analyses , KRAS(G12D ) status and high CXCR7 expression and circulating CEA , CA19 - 9 , and HGF levels were associated with poor survival BACKGROUND To investigate whether addition of cetuximab to st and ard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer , specifically whether the rate of disease-free survival ( DFS ) at 18 months ( primary end point ) exceeds the previously reported 35 % of gemcitabine alone . PATIENTS AND METHODS Prospect i ve , open-label , multicenter , nonr and omized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008 .  Gemcitabine and cetuximab were administered for 24 weeks . Secondary end points included overall survival ( OS ) and toxic effect . RESULTS Seventy-three patients received cetuximab .  Median DFS was 10.0 [ 95 % confidence interval ( CI ) 8.9 - 13.6 ] months and the DFS rate at month 18 of 27.1 % ( 16.7%-37.6 % ) was inferior to 35 % . Median OS was 22.4 ( 18.2 - 27.9 ) months . Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 ( median 14.7 versus 8.3 months , P = 0.073 ) and wild-type versus mutated K-Ras ( median 11.5 versus 9.3 months , P = 0.57 ) . Grade 3/4 toxic effects included neutropenia ( 11.0 % ) , thrombopenia ( 7 % ) , skin toxic effect ( 7 % ) and allergic reactions ( 7 % ) . CONCLUSION Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients . Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed Cure for ductal adenocarcinoma of the pancreas is restricted to resectable tumors , but survival after surgery is still poor . Despite apparently curative resection , these cancers rapidly recur . Thus , the present pathologic examination should be enriched by sensitive methods to detect minimal residual disease . In a prospect i ve setting we studied the frequency of minimal residual disease after curative resection by routine histopathology , immunohistology , and polymerase chain reaction ( PCR ) for mutated K-ras . Furthermore , the prognostic implication of detecting of MRD was determined . Prospect ively , tumor tissue and corresponding paraaortic lymph nodes were obtained from 78 patients , who underwent surgery for pancreatic head tumors between 1999 and 2001 . Sixty-nine of 78 cases were diagnosed for ductal adenocarcinoma ( study group ) , whereas nine cases were diagnosed for benign pancreatic tumors ( control group ) . Paraaortic lymph nodes were examined in step sections by routine histopathology ( hematoxylin and eosin ) and immunohistology using a pan-cytokeratin antibody . DNA of the primary tumor and corresponding paraaortic lymph nodes were analyzed by PCR-based assays with respect to mutated K-ras in codon 12 . The recurrence-free survival and overall survival were correlated with the results of the latter methods . In 3 of 69 patients tumor cells were detected in paraaortic lymph nodes by routine histopathology and in 5 of 69 patients by immunohistology . K-ras mutations were detected in 42 of 69 ductal adenocarcinomas ( 61 % ) , whereas 12 ( 17 % ) were positive in paraaortic lymph nodes . All of the latter patients had recurrence after surgery and a significant poorer survival than those without mutated K-ras . Furthermore , paraaortic lymph nodes diagnosed for K-ras mutation were independent prognostic markers in multivariate analysis . In the control group K-ras mutations were detected in one adenoma of Vater 's papilla but not in paraaortic lymph nodes . Tumor cell DNA can be detected more sensitively by the described PCR method than with hematoxylin and eosin or immunohistologic staining , leading to a higher sensitivity for detection of micrometastases . The described PCR method clearly determines subgroups of patients after curative resection with early recurrence and poor survival and could therefore enrich the pathologic examination Background : We aim ed to identify molecular epidermal growth factor receptor ( EGFR ) tissue biomarkers in pancreatic cancer ( PC ) patients treated with the anti-EGFR agent erlotinib within the phase 3 r and omised AIO-PK0104 study . Methods : AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC ; primary study end point was the time-to-treatment failure after first- and second-line therapy ( TTF2 ) . Translational analyses were performed for KRAS exon 2 mutations , EGFR expression , PTEN expression , the EGFR intron 1 and exon 13 R497 K polymorphism ( PM ) . Biomarker data were correlated with TTF , overall survival ( OS ) and skin rash . Results : Archival tumour tissue was available from 208 ( 74 % ) of the r and omised patients . The KRAS mutations were found in 70 % ( 121 out of 173 ) of patients and exclusively occurred in codon 12 . The EGFR overexpression was detected in 89 out of 181 patients ( 49 % ) by immunohistochemistry ( IHC ) , and 77 out of 166 patients ( 46 % ) had an EGFR gene amplification by fluorescence in-situ hybridisation ( FISH ) ; 30 out of 171 patients ( 18 % ) had a loss of PTEN expression , which was associated with an inferior TTF1 ( first-line therapy ; HR 0.61 , P=0.02 ) and TTF2 ( HR 0.66 , P=0.04 ) . The KRAS wild-type status was associated with improved OS ( HR 1.68 , P=0.005 ) ; no significant OS correlation was found for EGFR – IHC ( HR 0.96 ) , EGFR – FISH ( HR 1.22 ) , PTEN – IHC ( HR 0.77 ) , intron 1 ( HR 0.91 ) or exon 13 R497 K PM ( HR 0.83 ) . None of the six biomarkers correlated with the occurrence of skin rash . Conclusion : The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study ; it remains to be defined whether this association is prognostic or predictive Although erlotinib has become an important therapeutic option in addition to gemcitabine , the high frequency of KRAS mutations in pancreatic cancer probably limits the benefits . We retrospectively studied 136 pancreatic cancer patients with available formalin-fixed paraffin-embedded tumor blocks from 2003 to 2009 to underst and the clinical significance of KRAS mutations in pancreatic cancer patients treated with gemcitabine-based chemotherapy .  KRAS mutations were analyzed by sequencing codons 12 , 13 , and 61 . In this study , 71 ( 52.2 % ) of the 136 pancreatic adenocarcinomas examined harbored a point mutation in codons 12 ( n = 70 ) and 61 ( n = 1 ) of KRAS . KRAS mutation was not associated with clinicopathologic parameters . Patients with KRAS mutations showed a worse response ( 11.3 % ) than those with wild-type KRAS ( 26.2 % ) and poor survival ( mutant KRAS , 5.8 months vs. wild-type KRAS , 8.0 months ; P = 0.001 ) . Multivariate analysis revealed good prognostic factors for overall survival as well to moderately differentiated histology ( P < 0.001 ; HR = 0.437 , 95 % CI : 0.301–0.634 ) , locally advanced disease ( P < 0.001 ; HR = 0.417 , 95 % CI : 0.255–0.681 ) , response to first-line chemotherapy  ( P = 0.003 ; HR = 0.482 , 95 % CI : 0.297–0.780 ) , and wild-type KRAS ( P = 0.001 ; HR = 0.523 , 95 % CI : 0.355–0.770 ) . However , the observed survival advantage is derived from the subgroup of patients treated with gemcitabine/erlotinib ( 9.7 vs. 5.2 months ; P = 0.002 ) , whereas no survival difference based on KRAS mutation status is obvious in the other subgroup of patients treated without erlotinib ( 7.0 vs. 7.0 months ; P = 0.121 ) . These results need to be further explored in upcoming prospect i ve studies to provide a rationale for personalized medicine in pancreatic cancer . Mol Cancer Ther ; 10(10 ) ; 1993–9 . © 2011 AACR Background It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer ( PC ) . Methods AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine  in advanced PC . For this post hoc subgroup analysis , biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy ( OSc ) . Results KRAS codon 12 was mutated in 121 of 173 ( 70 % ) patients . The KRAS status showed no association with objective response ( p = 0.40 ) , but KRAS wildtype patients had an improved OS ( HR 1.68 , p = 0.005 ) . A trend for a survival benefit was also observed during ( non-erlotinib containing ) 2nd-line chemotherapy , with a HR of 1.47 ( p = 0.10 ) for the OSc . Conclusion This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC Pancreatic ductal adenocarcinoma ( PDAC ) remains one of the most lethal malignancies . The genomic l and scape of the PDAC genome features four frequently mutated genes ( KRAS , CDKN2A , TP53 , and SMAD4 ) and dozens of c and i date driver genes altered at low frequency , including potential clinical targets . Circulating cell-free DNA ( cfDNA ) is a promising re source to 
    Output:
    
In conclusion , this meta- analysis suggests that K-Ras mutations are associated with a worse overall survival  in pancreatic cancer patients , especially when mutations are detected in liquid biopsies or fresh frozen tumor tissue sample