***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: SIR,-In his article on the treatment of early breast cancer Mr. J. I. Burn ( 23 May , p. 467 ) comments on the administrative disadvantages of " multicentre " clinical trials , quotes H and ley ' as saying that a controlled trial should be carried out in a single unit by a single team , and suggests that if Deeley 's system2 of paired r and omization is adopted " large numbers of patients may not be necessary . " We feel that these remarks , with their implied discouragement of multicentre participation in clinical trials , are unfortunate at a time when the idea of widespread collaboration is at last gaining ground . It may also mislead people into embarking again on trials where the likely rate of patient intake will make the effort of very doubtful value . Too few patients in a trial are a disadvantage for two reasons . Firstly , the r and omization procedure , although eliminating obvious bias , may not result in the final treatment groups consisting of closely comparable clinical material . It may not therefore be possible to draw any valid conclusions from the trial . This is the problem dealt with by Deeley,2 and his system of paired r and omization is design ed to give comparable groups even with small numbers in a trial . The second disadvantage of small numbers , which is not overcome by Deeley 's procedure , arises from the fact that if the difference we are looking for between two treatments is small ( and it seems likely that this will be so in the cancer field ) , then it is not possible to demonstrate such a difference convincingly with small numbers . To give a simple example : if 100 patients are -treated in each of two treatment groups and 60 survive in one compared with 50 surviving in the other then this difference is not statistically significant at the usually accepted 5 % ° , level , however carefully we may have design ed our trial . But if there are 1,000 patients in each group , and 600 are cured by one treatment while only 500 are cured by the other , then a highly significant difference between the two treatments will have been demonstrated , although the percentages cured are still the same as in the smaller trial . Collaboration between a number of centres therefore appears to us to be the only way of obtaining in a reasonably short time the numbers of patients required to make useful comparisons of cancer treatments possible . We have found great enthusiasm for this collaboration among surgeons working away from the major centres , and this enthusiasm , the surgeons ' skill , and the numbers that they treat must not be lightly ab and oned . The administrative difficulties of a multicentre trial are not insurmountable , and Burn 's apparent preference for the small trial in a single centre is , in our view , misguided . To be fair to the authors he quotes in his support it shoulc & also be noted that Deeley2 makes no cl aim that pairing will reduce the numbers required for statistical significance , and H and ley ' advocated a trial " in the same unit by the same team " as being preferable to uncontrolled comparisons between different series each treated in different centres . He did not discuss at all the relative merits of single centre as compared with multicentre trials.-We are , etc . BACKGROUND Clinical trials have shown that trastuzumab , a recombinant monoclonal antibody against HER2 receptor , significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer , but long-term follow-up data are needed . We report the results of comparing observation with two duration s of trastuzumab treatment at a median follow-up of 11 years , for patients enrolled in the HERA ( HERceptin Adjuvant ) trial . METHODS HERA ( BIG 1 - 01 ) is an international , multicentre , open-label , phase 3 r and omised trial of 5102 women with HER2-positive early breast cancer , who were enrolled from hospitals in 39 countries between Dec 7 , 2001 , and June 20 , 2005 . After completion of all primary therapy ( including , surgery , chemotherapy , and radiotherapy as indicated ) , patients were r and omly assigned ( 1:1:1 ) to receive trastuzumab for 1 year ( once at 8 mg/kg of bodyweight intravenously , then 6 mg/kg once every 3 weeks ) or for 2 years ( with the same dose schedule ) , or to the observation group . Primary endpoint is disease-free survival , and analyses are in the intention-to-treat population . Hazard ratios ( HRs ) were estimated from Cox models , and survival curves were estimated by the Kaplan-Meier method . Comparison of 2 years versus 1 year of trastuzumab is based on 366-day l and mark analyses . This study is registered with Clinical Trials.gov ( NCT00045032 ) . FINDINGS Of the 5102 women r and omly assigned in the HERA trial , three patients had no evidence of having provided written informed consent to participate . We followed up the intention-to-treat population of 5099 patients ( 1697 in observation , 1702 in 1-year trastuzumab , and 1700 in 2-years trastuzumab groups ) . After a median follow-up of 11 years ( IQR 10·09 - 11·53 ) , r and om assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event ( HR 0·76 , 95 % CI 0·68 - 0·86 ) and death ( 0·74 , 0·64 - 0·86 ) compared with observation . 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug ( HR 1·02 , 95 % CI 0·89 - 1·17 ) . Estimates of 10-year disease-free survival were 63 % for observation , 69 % for 1 year of trastuzumab , and 69 % for 2 years of trastuzumab . 884 ( 52 % ) patients assigned to the observation group selectively crossed over to receive trastuzumab . Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase . The incidence of secondary cardiac endpoints was 122 ( 7·3 % ) in the 2-years trastuzumab group , 74 ( 4·4 % ) in the 1-year trastuzumab group , and 15 ( 0·9 % ) in the observation group . INTERPRETATION 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival , compared with observation . 2 years of trastuzumab had no additional benefit . FUNDING F Hoffmann-La Roche ( Roche ) BACKGROUND Findings from the r and omised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone . Here , we report data for the prespecified secondary endpoints of event-free and overall survival , and assess the association between these outcomes and pathological complete response . METHODS We enrolled women with HER2-positive early breast cancer and r and omly assigned them to receive oral lapatinib ( 1500 mg ) , intravenous trastuzumab ( 4 mg/kg loading dose followed by 2 mg/kg ) , or lapatinib ( 1000 mg ) plus trastuzumab ( same dose as for single agent ) in combination for 6 weeks , followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel ( 80 mg/m(2 ) ) . Definitive surgery was done 4 weeks after the last dose of paclitaxel . After surgery , women received three cycles of FEC ( fluorouracil 500 mg/m(2 ) plus epirubicin 100 mg/m(2 ) plus cyclophosphamide 500 mg/m(2 ) ) given intravenously every 3 weeks , followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy . The primary endpoint was pathological complete response . Secondary endpoints included event-free and overall survival ( intention-to-treat analysis ) , and the association between pathological complete response and event-free or overall survival ( analysed by l and mark analysis at 30 weeks after r and omisation ) . Follow-up is ongoing , and the trial is registered with Clinical Trials.gov , number NCT00553358 . FINDINGS 455 patients were enrolled : 154 ( 34 % ) were assigned to the lapatinib group , 149 ( 33 % ) to the trastuzumab group , and 152 ( 33 % ) to the lapatinib plus trastuzumab group . At an event follow-up of 3·77 years ( IQR 3·50 - 4·22 ) , 3-year event-free survival was 78 % ( 95 % CI 70 - 84 ) in the lapatinib group , 76 % ( 68 - 82 ) in the trastuzumab group , and 84 % ( 77 - 89 ) in the combination group . Event-free survival did not differ between the lapatinib and trastuzumab groups ( HR 1·06 , 95 % CI 0·66 - 1·69 , p=0·81 ) , nor between the combination and trastuzumab groups ( 0·78 , 0·47 - 1·28 , p=0·33 ) . Median survival follow-up was 3·84 years ( IQR 3·60 - 4·24 ) , and 3-year overall survival was 93 % ( 95 % CI 87 - 96 ) for lapatinib , 90 % ( 84 - 94 ) for trastuzumab , and 95 % ( 90 - 98 ) for combination therapy . Overall survival did not significantly differ between the lapatinib and trastuzumab groups ( HR 0·86 , 95 % CI 0·45 - 1·63 , p=0·65 ) , nor between the combination and trastuzumab groups ( 0·62 , 0·30 - 1·25 , p=0·19 ) . L and mark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not ( HR 0·38 , 95 % CI 0·22 - 0·63 , p=0·0003 ) , as was 3-year overall survival ( 0·35 , 0·15 - 0·70 , p=0·005 ) . Adverse events occurred in 149 ( 99 % ) patients receiving lapatinib , 142 ( 96 % ) patients receiving trastuzumab , and 147 ( 99 % ) patients receiving combination therapy . The most common adverse events were diarrhoea , rash or erythema , hepatic adverse events , and neutropenia ( not related to FEC administration ) , and were consistent with known safety profiles of lapatinib and trastuzumab . Three primary and eight secondary cardiac events occurred , with no significant difference in incidence between treatment groups for primary or any cardiac events . INTERPRETATION Although event-free survival or overall survival did not differ between treatment groups , findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response . FUNDING GlaxoSmithKline No data are available on the role of HER2 overexpression in predicting the efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients . We retrospectively evaluated this role in patients enrolled in a phase III study comparing st and ard FEC21 ( 5-fluorouracil , epirubicin , and cyclophosphamide , administered every 3 weeks ) vs dose-dense FEC14 ( the same regimen repeated every 2 weeks )  . HER2 status was determined for 731 of 1214 patients . Statistical analyses were performed to test for interaction between treatment and HER2 status with respect to event-free survival ( EFS ) and overall survival ( OS ) ; EFS and OS were compared within each HER2 subgroup and within each treatment arm . Median follow-up was 6.7 years . Among FEC21-treated patients , both EFS ( HR=2.07 ; 95 % CI 1.27–3.38 ) and OS ( HR=2.47 ; 95 % CI 1.34–4.57 ) were significantly worse in HER2 + patients than in HER2 − patients . Among FEC14-treated patients , differences in either EFS ( HR=1.21 ; 95 % CI 0.65–2.24 ) or OS ( HR=1.85 ; 95 % CI 0.88–3.89 ) between HER2 + and HER2 − patients were not statistically significant . Interaction analysis suggested that the use of dose-dense FEC14 might remove the negative prognostic effect of HER2 overexpression on EFS and OS . Our data suggest a potential role of HER-2 overexpression in predicting the efficacy of dose-dense epirubicin-containing chemotherapy and the need to confirm this hypothesis in future prospect i ve studies BACKGROUND We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment , and of the addition of lapatinib and trastuzumab combined after doxorubic 
    Output:
    
In the reference case cNMA ( RCTs alone ) , initial evidence demonstrated an OS advantage  for H/chemotherapy compared with chemotherapy alone in HER2 + EBC patients .
As additional OS data were published , the precision around this survival benefit strengthened over time .
Both H/anthracycline-containing chemotherapy and H/non-anthracycline-containing chemotherapy regimens provided similar OS advantages for HER2 + EBC patients .
These findings demonstrate why H/chemotherapy is now the established st and ard of care in HER2 + EBC .
In the case of H , the benefits of early patient access far outweighed the risk of waiting for more precise information .