***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: Summary Purpose Pre clinical data has demonstrated the potential of simvastatin to overcome cetuximab resistance in KRAS mutant CRC patients . Therefore , we design ed a study using simvastatin/cetuximab/irinotecan for KRAS mutant CRC patients who are refractory to irinotecan and oxaliplatin-based chemotherapy . Patients and methods In this phase II study , patients received 500 mg/m2 cetuximab , 150–180 mg/m2 ( day 1 ) , and 80 mg simvastatin ( once daily , days 1–14 , every 2 weeks ) . The primary endpoint was the objective response rate ( ORR ) . Secondary endpoints were progression-free survival ( PFS ) , overall survival ( OS ) , the disease control rate ( DCR ) , and safety . We also analyzed the relationship between the RAS gene expression signature score and treatment response to simvastatin/cetuximab/irinotecan . Results Fifty-two KRAS mutant CRC patients were enrolled .  The ORR ( complete response [ CR ] , 0 ; partial response [ PR ] , 1 ) was 1.9 % ( 95 % confidence interval [ CI ] , −1.8–5.6 ) . The DCR ( CR , 0 ; PR , 1 ; stable disease , 33 ) was 65.4 % ( 95 % CI , 52.5–78.3 ) . The median PFS and OS from the time of study drug administration were 7·6 months ( 95 % CI , 4.4–10.8 ) and 12.8 months ( 95 % CI , 9.5–16.2 ) , respectively . The most common grade 3/4 adverse events were anemia ( 28.8 % ) , neutropenia ( 13.5 % ) , and diarrhea ( 7.7 % ) . The RAS signature score was significantly correlated with the maximal change in target lesions from baseline ( r = 0.57 , P = 0.014 ) . Conclusion The simvastatin/cetuximab/irinotecan regimen showed promising efficacy and safety in KRAS mutant CRC patients who failed irinotecan and oxaliplatin-based chemotherapy . The RAS signature may be a novel predictor of treatment response to cetuximab-combined chemotherapy in CRC patients BACKGROUND & AIMS Statin use has been associated with a reduced incidence of colorectal cancer and might also affect survival of patients diagnosed with colon cancer .  Statins are believed to inhibit Ras signaling and may also activate the bone morphogenetic protein ( BMP ) signaling pathway in colorectal cancer cells . We investigated the effects of statins on overall survival of patients with a diagnosis of colon cancer , and whether their effects were associated with changes in KRAS or the BMP signaling pathways . METHODS Data were derived from the PHARMO data base network ( Netherl and s ) and linked to patients diagnosed with colon cancer from 2002 through 2007 , listed in the Eindhoven Cancer Registry . We obtained information on causes of death from statistics Netherl and s. We constructed a tissue microarray  of 999 colon cancer specimens from patients who underwent surgical resection from 2002 through 2008 . Survival was analyzed with statin user status after diagnosis as a time-dependent covariate . Multivariable Poisson regression survival models and Cox analyses were used to study the effect of statins on survival . Tumor tissues were analyzed by immunohistochemistry for levels of SMAD4 , BMPR1A , BMPR1B , and BMPR2 proteins . Tumor tissues were considered to have intact BMP signaling if they contained SMAD4 plus BMPR1A , BMPR1B , or BMPR2 . DNA was isolated from tumor tissues and analyzed by quantitative polymerase chain reaction to detect mutations in KRAS . The primary outcome measures were overall mortality and cancer-specific mortality . RESULTS In this cohort , 21.0 % of the patients ( 210/999 ) were defined as statin users after diagnosis of colon cancer . Statin use after diagnosis was significantly associated with reduced risk of death from any cause ( adjusted relative risk [ RR ] , 0.67 ; 95 % confidence interval [ CI ] , 0.51 - 0.87 ; P = .003 ) and death from cancer ( adjusted RR , 0.66 ; 95 % CI , 0.49 - 0.89 ; P = .007 ) . Statin use after diagnosis was associated with reduced risk of death from any cause or from cancer for patients whose tumors had intact BMP signaling ( adjusted RR , 0.39 ; 95 % CI , 0.22 - 0.68 ; P = .001 ) , but not for patients whose tumors did not have BMP signaling ( adjusted RR , 0.81 ; 95 % CI , 0.55 - 1.21 ; P = .106 ; P < .0001 for the interaction ) . Statin use after diagnosis was not associated with reduced risk of death from any cause or from cancer for patients whose tumors did not contain KRAS mutations ( adjusted RR , 0.81 ; 95 % CI , 0.56 - 1.18 ; P = .273 ) or whose tumors did have KRAS mutations ( adjusted RR , 0.59 ; 95 % CI 0.35 - 1.03 ; P = .062 ; P = .90 for the interaction ) . CONCLUSIONS In an analysis of 999 patients with a diagnosis of colon cancer , we associated statin with reduced risk of death from any cause or from cancer . The benefit of statin use is greater for patients whose tumors have intact BMP signaling , independent of KRAS mutation status . R and omized controlled trials are required to confirm these results BACKGROUND Treatment with cetuximab , a monoclonal antibody directed against the epidermal growth factor receptor , improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy . The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value . METHODS We analyzed tumor sample s , obtained from 394 of 572 patients ( 68.9 % ) with colorectal cancer who were r and omly assigned to receive cetuximab plus best supportive care or best supportive care alone  , to look for activating mutations in exon 2 of the K-ras gene . We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups . RESULTS Of the tumors evaluated for K-ras mutations , 42.3 % had at least one mutation in exon 2 of the gene . The effectiveness of cetuximab was significantly associated with K-ras mutation status ( P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival , respectively ) . In patients with wild-type K-ras tumors , treatment with cetuximab as compared with supportive care alone significantly improved overall survival ( median , 9.5 vs. 4.8 months ; hazard ratio for death , 0.55 ; 95 % confidence interval [ CI ] , 0.41 to 0.74 ; P<0.001 ) and progression-free survival ( median , 3.7 months vs. 1.9 months ; hazard ratio for progression or death , 0.40 ; 95 % CI , 0.30 to 0.54 ; P<0.001 ) . Among patients with mutated K-ras tumors , there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival ( hazard ratio , 0.98 ; P=0.89 ) or progression-free survival ( hazard ratio , 0.99 ; P=0.96 ) . In the group of patients receiving best supportive care alone , the mutation status of the K-ras gene was not significantly associated with overall survival ( hazard ratio for death , 1.01 ; P=0.97 ) . CONCLUSIONS Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab , whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab . The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone . ( Clinical Trials.gov number , NCT00079066 . BACKGROUND Although pre clinical and epidemiological data suggest that statins may have antineoplastic properties , the impact of statin use on patient survival after a curative resection of stage III colon cancer is unknown . METHODS We conducted a prospect i ve observational study of 842 patients with stage III colon cancer enrolled in a r and omized adjuvant chemotherapy trial from April 1999 to May 2001 to investigate the relationship between statin use and survival . Disease-free survival ( DFS ) , recurrence-free survival ( RFS ) , and overall survival ( OS ) were investigated by Kaplan-Meier curves and log-rank tests in the overall study population and in a subset of patients stratified by KRAS mutation status ( n = 394 ) , and Cox proportional hazards regression was used to assess the simultaneous impact of confounding variables . All statistical tests were two-sided . RESULTS Among 842 patients , 134 ( 15.9 % ) reported statin use after completing adjuvant chemotherapy .  DFS among statin users and nonusers was similar ( hazard ratio [ HR ] of cancer recurrence or death = 1.04 , 95 % confidence interval [ CI ] = 0.73 to 1.49 ) . RFS and OS were also similar between statin users and nonusers ( adjusted HR of cancer recurrence = 1.14 , 95 % CI = 0.77 to 1.69 ; adjusted HR of death = 1.15 , 95 % CI = 0.77 to 1.71 ) . Survival outcomes were similar regardless of increasing duration of statin use before cancer diagnosis ( P(trend ) = .63 , .63 , and .59 for DFS , RFS , and OS , respectively ) . The impact of  statin  use did not differ by tumor KRAS mutation status , with similar DFS , RFS , and OS for statin use among mutant and wild-type subgroups ( P(interaction ) = .84 , .67 , and .98 for DFS , RFS , and OS , respectively ) . CONCLUSION Statin use during and after adjuvant chemotherapy was not associated with improved DFS , RFS , or OS  in patients with stage III colon cancer , regardless of KRAS mutation status BACKGROUND : Achieving a pathologic complete response to neoadjuvant chemoradiation improves prognosis in rectal cancer .  Statin therapy has been shown to enhance the impact of treatment in several malignancies , but little is known regarding the impact on rectal cancer response to neoadjuvant chemoradiation . OBJECTIVE : The purpose of this study was to determine whether statin use during neoadjuvant chemoradiation improves pathologic response in rectal cancer . DESIGN : This was a retrospective cohort study based on data from a prospect ively maintained colorectal cancer data base . The 2 cohorts were defined by statin use during neoadjuvant chemoradiation . SETTING : This study was performed at a single tertiary referral center . PATIENTS : Four hundred seven patients with primary rectal adenocarcinoma who underwent neoadjuvant therapy then proctectomy between 2000 and 2012 were included . Ninety-nine patients ( 24.3 % ) took a statin throughout the entire course of neoadjuvant therapy . MAIN OUTCOME MEASURES : The primary outcome measure was pathologic response to neoadjuvant chemoradiotherapy as defined by the American Joint Committee on Cancer tumor regression grading system , grade s 0 to 3 . RESULTS : Patients in the statin cohort had a lower median regression grade ( 1 vs 2 , p = 0.01 ) and were more likely to have a better response ( grade s 0–1 vs 2–3 ) than those not taking a statin ( 65.7 % vs 48.7 % , p = 0.004 ) . Statin use remained a significant predictor of an American Joint Committee on Cancer grade 0 to 1 ( OR , 2.25 ; 95 % CI , 1.33–3.82 ) in multivariate analyses . Although statin use itself did not significantly improve oncologic outcomes , an American Joint Committee on Cancer grade 0 to 1 response was associated with statistically significant improvements in overall survival , disease-free survival , cancer-specific mortality , and local recurrence . LIMITATIONS : This was a retrospective study and subject to nonr and omization of patients and incorporated patients on variable statin agents and doses . CONCLUSIONS : Statin therapy is associated with an improved response of rectal cancer to neoadjuvant chemoradiation . These data provide the foundation for a prospect i ve clinical trial 
    Output:
    
For post-diagnosis statin uses , there is no difference in ACM when stratified by KRAS gene ( KRAS ) mutation status .
Our meta- analysis demonstrates that both pre-diagnosis and post-diagnosis statin uses are associated with reduced ACM and CSM for CRC patients