***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 Amplification of the human epidermal growth factor receptor type 2 ( HER2 , also called HER2/neu ) gene and overexpression of its product in breast-cancer cells may be associated with responsiveness to anthracycline-containing chemotherapy regimens . METHODS In the r and omized , controlled Mammary.5 trial , we studied 639 formalin-fixed paraffin-embedded specimens obtained from 710 premenopausal women with node-positive breast cancer who had received either cyclophosphamide , epirubicin , and fluorouracil ( CEF ) or cyclophosphamide , methotrexate , and fluorouracil ( CMF ) as adjuvant chemotherapy .  HER2 amplification or overexpression was evaluated with the use of fluorescence in situ hybridization , immunohistochemical analysis , and polymerase-chain-reaction analysis . RESULTS Amplification of HER2 was associated with a poor prognosis regardless of the type of treatment . In patients whose tumors showed amplification of HER2 , CEF was superior to CMF when assessed on the basis of relapse-free survival ( hazard ratio , 0.52 ; 95 percent confidence interval , 0.34 to 0.80 ; P=0.003 ) and overall survival ( hazard ratio , 0.65 ; 95 percent confidence interval , 0.42 to 1.02 ; P=0.06 ) . For women whose tumors lacked amplification of HER2 , CEF did not improve relapse-free survival ( hazard ratio for relapse , 0.91 ; 95 percent confidence interval , 0.71 to 1.18 ; P=0.49 ) or overall survival ( hazard ratio for death , 1.06 ; 95 percent confidence interval , 0.83 to 1.44 ; P=0.68 ) . The adjusted hazard ratio for the interaction between treatment and HER2 amplification was 1.96 for relapse-free survival ( 95 percent confidence interval , 1.15 to 3.36 ; P=0.01 ) and 2.04 for overall survival ( 95 percent confidence interval , 1.14 to 3.65 ; P=0.02 ) . CONCLUSIONS Amplification of HER2 in breast-cancer cells is associated with clinical responsiveness to anthracycline-containing chemotherapy . ( cancer.gov number , NCI-V90 - 0027 . ) Purpose : To critically assess the accuracy and reproducibility of  human epidermal growth factor receptor type 2 ( HER-2 ) testing in outside/local community-based hospitals versus two central ized reference laboratories and its effect on selection of women for  trastuzumab (Herceptin)–based clinical trials . Experimental Design : Breast cancer specimens from 2,600 women were prospect ively evaluated by fluorescence in situ hybridization ( FISH ) for entry into Breast Cancer International Research Group ( BCIRG ) clinical trials for HER-2-directed therapies . Results : HER-2 gene amplification by FISH was observed in 657 of the 2,502 ( 26 % ) breast cancers successfully analyzed . Among 2,243 breast cancers with central laboratory immunohistochemistry ( 10H8-IHC ) analysis , 504 ( 22.54 % ) showed overexpression ( 2 + or 3 + ) . Outside/local laboratories assessed HER-2 status by immunohistochemistry in 1,536 of these cases and by FISH in 131 cases . Overall , the HER-2 alteration status determined by outside/local immunohistochemistry showed a 79 % agreement rate [ κ statistic , 0.56 ; 95 % confidence interval ( 95 % CI ) , 0.52 - 0.60 ] , with FISH done by the central laboratories . The agreement rate comparing BCIRG central laboratory 10H8-IHC and outside/local laboratory immunohistochemistry was 77.5 % ( κ statistic , 0.51 ; 95 % CI , 0.46 - 0.55 ) . Finally , HER-2 status , determined by unspecified FISH assay methods at outside/local laboratories , showed a 92 % agreement rate ( κ statistic , 0.83 ; 95 % CI , 0.73 - 0.93 ) , with FISH done at the BCIRG central laboratories . Conclusions : Compared with the HER-2 status determined at central ized BCIRG reference laboratories , these results indicate superiority of FISH to accurately and reproducibly assess tumors for the HER-2 alteration at outside/local laboratories for entry to clinical trials BACKGROUND We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer . METHODS The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks ( group 1 ) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel ( group 2 ) . The North Central Cancer Treatment Group trial N9831 compared three regimens : doxorubicin and cyclophosphamide followed by weekly paclitaxel ( group A ) , the same regimen followed by 52 weeks of trastuzumab after paclitaxel ( group B ) , and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel ( group C ) . The studies were amended to include a joint analysis comparing groups 1 and A ( the control group ) with groups 2 and C ( the trastuzumab group ) . Group B was excluded because trastuzumab was not given concurrently with paclitaxel . RESULTS By March 15 , 2005 , 394 events ( recurrent , second primary cancer , or death before recurrence ) had been reported , triggering the first scheduled interim analysis . Of these , 133 were in the trastuzumab group and 261 in the control group ( hazard ratio , 0.48 ; P<0.0001 ) . This result crossed the early stopping boundary . The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years . Trastuzumab therapy was associated with a 33 percent reduction in the risk of death ( P=0.015 ) . The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831 . CONCLUSIONS Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer . ( Clinical Trials.gov numbers , NCT00004067 and NCT00005970 . BACKGROUND Women with HER2-overexpressing breast cancer have an unfavorable prognosis . Trastuzumab improves survival when combined with chemotherapy in the first-line treatment of patients with HER2-overexpressing metastatic breast cancer and decreases the rate of disease relapse by 52 % and the rate of death by 33 % in women with HER2-overexpressing early-stage breast cancer . HER2 testing can be performed using immunohistochemistry ( IHC ) or fluorescence in situ hybridization ( FISH ) and can be performed at local pathology laboratories or at central /reference laboratories . Because of the significant benefit seen with trastuzumab , it is critical to accurately identify women most likely to benefit . The method and the location of HER2 testing contribute to the accuracy of test results . PATIENTS AND METHODS HER-First , a prospect i ve , community-based , phase IV study of first-line trastuzumab/taxane therapy , enrolled patients with HER2-overexpressing metastatic breast cancer . Retesting of all tumor specimens by HER2 IHC and FISH at a high-volume , experienced laboratory was required . RESULTS Concordance between local and central laboratory HER2 IHC testing was highest for local IHC 3 + sample s ( n = 377 ; 77 % ) and lowest for IHC 2 + sample s ( n = 184 ; 26 % ) . Thirty-three percent of sample s testing IHC 2 + at a local laboratory tested FISH-positive at the central laboratory . Concordance between HER2 IHC and FISH results was higher when both tests were performed at the central laboratory . CONCLUSION Accurate HER2 test results are critical to identify patients who are appropriate c and i date s for trastuzumab , a therapy with significant clinical benefits in HER2-overexpressing breast cancer . These data show that HER2 testing is most accurate when performed at a high-volume reference laboratory BACKGROUND We have previously reported that high expression of the erbB-2 gene ( also known as HER-2/neu and ERBB2 ) in breast cancer is associated with patient response to dose-intensive treatment with cyclophosphamide , doxorubicin ( Adriamycin ) , and 5-flurouracil ( CAF ) on the basis of short-term follow-up of 397 patients ( set A ) with axillary lymph node-positive tumors who were enrolled in Cancer and Leukemia Group B ( CALGB ) protocol 8541 . METHODS To vali date those findings , we conducted immunohistochemical analyses of erbB-2 and p53 protein expression in an additional cohort of 595 patients ( set B ) from CALGB 8541 , as well as a molecular analysis of erbB-2 gene amplification in tumors from all patients ( sets A and B ) . Marker data were compared with clinical , histologic , treatment , and outcome data . RESULTS Up date d analyses of data from set A ( median follow-up , 10.4 years ) showed an even stronger interaction between erbB-2 expression and CAF dose , by use of either immunohistochemical or molecular data . A similar interaction between erbB-2 expression and CAF dose was observed in all 992 patients , analyzed as a single group . However , for set B alone ( median follow-up , 8.2 years ) , results varied with the method of statistical analysis . By use of a proportional hazards model , the erbB-2 expression-CAF dose interaction was not significant for all patients . However , in the subgroups of patients r and omly assigned to the high- or the moderate-dose arms , significance was achieved . When patient data were adjusted for differences by use of a prognostic index ( to balance an apparent failure of r and omization in the low-dose arm ) , the erbB-2 expression-CAF dose interaction was significant in all patients from the validation set B as well . An interaction was also observed between p53 immunopositivity and CAF dose . CONCLUSIONS The hypothesis that patients whose breast tumors exhibit high erbB-2 expression benefit from dose-intensive CAF should be further vali date d before clinical implementation . Interactions between erbB-2 expression , p53 expression , and CAF dose underscore the complexities of predictive markers where multiple interactions may confound the outcome PURPOSE There is considerable interest in biologic markers able to predict the response of cancer patients to therapy . HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients . However , the significance of HER2 overexpression in responsiveness to cyclophosphamide , methotrexate , and fluorouracil ( CMF ) has remained unclear . In this study , we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up . PATIENTS AND METHODS Node-positive breast carcinoma patients were r and omly assigned to receive either no further treatment after radical mastectomy  ( 179 women ) or 12 monthly cycles of adjuvant CMF chemotherapy  ( 207 women ) . Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 ( 84 % ) of the 386 patients . Statistical analyses were performed to assess the efficacy of  CMF  treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach . The end points considered were relapse-free survival ( RFS ) and cause-specific survival ( CSS ) . RESULTS Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status . In particular regarding HER2 status , Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors , respectively . CONCLUSION CMF treatment showed a clinical benefit in the considered subgroups , defined according to HER2 and other tumor variables status . Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment , and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment 510 Background : CALGB 9344 showed 4 cycles of paclitaxel ( T ) after 4 cycles of doxorubicin/cyclophosphamide ( AC )  improved disease-free ( DFS ) 
    Output:
    
When carefully vali date d testing is performed , available data do not clearly demonstrate the superiority of either immunohistochemistry ( IHC ) or in situ hybridization ( ISH ) as a predictor of benefit from anti-HER2 therapy .