***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: The article presents final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab PURPOSE We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant ( HERA ) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy . PATIENTS AND METHODS The HERA trial is a three-group , r and omized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 ( HER2 ) -positive early breast cancer . Eligible patients had normal left ventricular ejection fraction ( LVEF ; > or= 55 % ) after completion of (neo)adjuvant chemotherapy with or without radiotherapy .  Cardiac function was monitored throughout the trial . This analysis considers patients r and omly assigned to 1 year of trastuzumab treatment or observation . RESULTS There were 1,698 patients r and omly assigned to observation and 1,703 r and omly assigned to 1 year of trastuzumab treatment ; 94.1 % of patients had been treated with anthracyclines . The incidence of discontinuation of trastuzumab because of cardiac disorders was low ( 5.1 % ) . At a median follow-up of 3.6 years , the incidence of cardiac end points remained low , though it was higher in the trastuzumab group than in the observation group ( severe CHF , 0.8 % v 0.0 % ; confirmed significant LVEF decreases , 3.6 % v 0.6 % ) In the trastuzumab group , 59 of 73 patients with a cardiac end point reached acute recovery ; of these 59 patients , 52 were considered by the cardiac advisory board ( CAB ) to have a favorable outcome from the cardiac end point . CONCLUSION The incidence of cardiac end points remains low even after longer-term follow-up . The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year , but it remains relatively constant thereafter PURPOSE This study sought to estimate cardiac dysfunction ( CD ) risk for patients receiving trastuzumab ;  to characterize observed CD by severity , treatment , and clinical outcome ; to assess effects of baseline clinical risk factors on CD ; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD . PATIENTS AND METHODS A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed . Predefined criteria were used for the diagnosis , and the New York Heart Association functional classification system was used to document CD severity . Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset . RESULTS Patients treated with trastuzumab  were found to be at an increased risk for CD . The incidence was greatest in patients receiving concomitant  trastuzumab and anthracycline plus cyclophosphamide ( 27 % ) . The risk was substantially lower in patients receiving paclitaxel and trastuzumab ( 13 % ) or trastuzumab alone ( 3 % to 7 % ) ; however , most of these patients had received prior anthracycline therapy . CD was noted in 8 % of patients receiving anthracycline plus cyclophosphamide and 1 % receiving paclitaxel alone . Most trastuzumab-treated patients developing CD were symptomatic ( 75 % ) , and most improved with st and ard treatment for congestive heart failure ( 79 % ) . CONCLUSION Trastuzumab is associated with an increased risk of CD , which is greatest in patients receiving concurrent anthracyclines . In most patients with metastatic breast cancer , the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab PURPOSE Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer . In the German Breast Group 26/Breast International Group 03 - 05 trial , we investigated if trastuzumab treatment should be continued beyond progression . METHODS Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were r and omly assigned to receive capecitabine ( 2,500 mg/m(2 ) body-surface area on days 1 through 14 [ 1,250 mg/m(2 ) semi-daily ] ) alone or with continuation of trastuzumab ( 6 mg/kg body weight ) in 3-week cycles . The primary end point was time to progression . RESULTS We r and omly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab .  Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up . Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 ( 95 % CI , 0.48 to 0.97 ; two-sided log-rank P = .0338 ) . Overall survival rates were 20.4 months ( 95 % CI , 17.8 to 24.7 ) in the capecitabine group and 25.5 months ( 95 % CI , 19.0 to 30.7 ) in the capecitabine-plus-trastuzumab group ( P = .257 ) . Overall response rates were 27.0 % with capecitabine and 48.1 % with capecitabine plus trastuzumab ( odds ratio , 2.50 ; P = .0115 ) . Continuation of trastuzumab beyond progression was not associated with increased toxicity . CONCLUSION Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment BACKGROUND mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss , by sensitising PTEN-deficient tumours to trastuzumab . The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer . METHODS In this phase 3 , r and omised , double-blind trial , patients were enrolled across 141 sites in 28 countries . Eligible patients were aged 18 years or older , with locally assessed HER2-positive advanced breast cancer , with Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 1 , who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of r and omisation , had measurable disease as per Response Evaluation Criteria in Solid Tumors ( RECIST ) or bone lesions in the absence of measurable disease , without previous systemic treatment for advanced disease except endocrine therapy . Patients were r and omly assigned ( 2:1 ) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m(2 ) on days 1 , 8 , and 15 of each 4 week cycle . R and omisation was stratified according to previous use of trastuzumab and visceral metastasis . Patients and investigators were masked to the assigned treatments . Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging , labelling , appearance , and administration schedule . The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline ; the latter was added during the course of the study , before unmasking based on new clinical and biological findings from other studies . All efficacy analyses were based on the intention-to-treat population . Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here . This trial is registered with Clinical Trials.gov , number NCT00876395 . FINDINGS Between Sept 10 , 2009 , and Dec 16 , 2012 , 719 patients were r and omly assigned to receive everolimus ( n=480 ) or placebo ( n=239 ) . Median follow-up was 41·3 months ( IQR 35·4 - 46·6 ) . In the full population , median progression-free survival was 14·95 months ( 95 % CI 14·55 - 17·91 ) with everolimus versus 14·49 months ( 12·29 - 17·08 ) with placebo ( hazard ratio 0·89 , 95 % CI 0·73 - 1·08 ; p=0·1166 ) . In the HR-negative sub population ( n=311 ) , median progression-free survival with everolimus was 20·27 months ( 95 % CI 14·95 - 24·08 ) versus 13·08 months ( 10·05 - 16·56 ) with placebo ( hazard ratio 0·66 , 95 % CI 0·48 - 0·91 ; p=0·0049 ) ; however , the protocol -specified significance threshold ( p=0·0044 ) was not crossed . The most common adverse events with everolimus were stomatitis ( 314 [ 67 % ] of 472 patients in the everolimus group vs 77 [ 32 % ] of 238 patients in the placebo group ) , diarrhoea ( 267 [ 57 % ] vs 111 [ 47 % ] patients ) , and alopecia ( 221 [ 47 % ] vs 125 [ 53 % ] ) . The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia ( 117 [ 25 % ] vs 35 [ 15 % ] ) , stomatitis ( 59 [ 13 % ] vs three [ 1 % ] ) , anaemia ( 46 [ 10 % ] vs six [ 3 % ] ) and diarrhoea ( 43 [ 9 % ] vs 10 [ 4 % ] ) On-treatment adverse event-related deaths were reported in 17 ( 4 % ) patients in the everolimus group and none in the placebo group . INTERPRETATION Although progression-free survival was not significantly different between groups in the full analysis population , the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative , HER2-positive population warrants further investigation , even if it did not meet prespecified criteria for significance . The safety profile was generally consistent with what was previously reported in BOLERO-3 . Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial . FUNDING Novartis Pharmaceuticals PURPOSE The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 ( HER2 ) -positive metastatic breast cancer ( BC ) is unknown . PATIENTS AND METHODS The MA.31 trial compared a combination of first-line anti-HER2 therapy ( lapatinib or trastuzumab ) and taxane therapy for 24 weeks , followed by the same anti-HER2 monotherapy until progression . Stratification was by prior (neo)adjuvant anti-HER2 therapy , prior (neo)adjuvant taxane , planned taxane , and liver metastases . The primary end point was intention-to-treat ( ITT ) progression-free survival ( PFS ) , defined as time from r and om assignment to progression by RECIST ( version 1.0 ) criteria , or death for patients with locally assessed HER2-positive tumors . The primary test statistic was a stratified log-rank test for noninferiority . PFS was also assessed for patients with central ly confirmed HER2-positive tumors . RESULTS From July 17 , 2008 , to December 1 , 2011 , 652 patients were accrued from 21 countries , result ing in 537 patients with central ly confirmed HER2-positive tumors . Median follow-up was 21.5 months . Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab . By ITT analysis , PFS was inferior for lapatinib compared with trastuzumab , with a stratified hazard ratio ( HR ) of 1.37 ( 95 % CI , 1.13 to 1.65 ; P = .001 ) . In patients with central ly confirmed HER2-positive tumors , median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab ( HR , 1.4 
    Output:
    
Conclusions HER2-directed therapies had an undeniable beneficial impact on the OS of patients with HER2 + mBC .