***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 
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    Input: BACKGROUND Studies with pertuzumab , a novel anti-HER2 antibody , show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy . We investigated the combination of pertuzumab or trastuzumab , or both , with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting . METHODS In this multicentre , open-label , phase 2 study , treatment-naive women with HER2-positive breast cancer were r and omly assigned ( 1:1:1:1 ) central ly and stratified by operable , locally advanced , and inflammatory breast cancer , and by hormone receptor expression to receive four neoadjuvant cycles of : trastuzumab ( 8 mg/kg loading dose , followed by 6 mg/kg every 3 weeks ) plus docetaxel ( 75 mg/m(2 ) , escalating , if tolerated , to 100 mg/m(2 ) every 3 weeks ; group A ) or pertuzumab ( loading dose 840 mg , followed by 420 mg every 3 weeks ) and trastuzumab plus docetaxel ( group B ) or pertuzumab and trastuzumab ( group C ) or pertuzumab plus docetaxel ( group D ) . The primary endpoint , examined in the intention-to-treat population , was pathological complete response in the breast . Neither patients nor investigators were masked to treatment . This study is registered with Clinical Trials.gov , number NCT00545688 . FINDINGS Of 417 eligible patients , 107 were r and omly assigned to group A , 107 to group B , 107 to group C , and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate ( 49 of 107 patients ; 45·8 % [ 95 % CI 36·1 - 55·7 ] ) compared with those given trastuzumab plus docetaxel ( group A ; 31 of 107 ; 29·0 % [ 20·6 - 38·5 ] ; p=0·0141 ) . 23 of 96 ( 24·0 % [ 15·8 - 33·7 ] ) women given pertuzumab plus docetaxel ( group D ) had a pathological complete response , as did 18 of 107 ( 16·8 % [ 10·3 - 25·3 ] ) given pertuzumab and trastuzumab ( group C ) . The most common adverse events of grade 3 or higher were neutropenia ( 61 of 107 women in group A , 48 of 107 in group B , one of 108 in group C , and 52 of 94 in group D ) , febrile neutropenia ( eight , nine , none , and seven , respectively ) , and leucopenia ( 13 , five , none , and seven , respectively ) . The number of serious adverse events was similar in groups A , B , and D ( 15 - 20 serious adverse events per group in 10 - 17 % of patients ) but lower in group C ( four serious adverse events in 4 % of patients ) . INTERPRETATION Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel , without substantial differences in tolerability .  Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile . These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer . FUNDING F Hoffmann-La 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 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 BACKGROUND Subcutaneous trastuzumab has shown non-inferior efficacy and a similar pharmacokinetic and safety profile when compared with intravenous trastuzumab in patients with HER2-positive early breast cancer . We assessed patient preference for either  subcutaneous or intravenous trastuzumab in the international , r and omised PrefHer study . METHODS Eligible patients were women aged 18 years or older with HER2-positive , histologically confirmed primary invasive breast adenocarcinoma , no evidence of residual , locally recurrent , or metastatic disease after completion of surgery and chemotherapy ( neoadjuvant or adjuvant ) , an Eastern Cooperative Oncology Group performance status of 0 or 1 , and a baseline left-ventricular ejection fraction of 55 % or more before the first dose of trastuzumab . Radiotherapy or hormone therapy was allowed . Patients were r and omised ( r and omly permuted blocks of four ) to receive four cycles of 600 mg fixed-dose subcutaneous adjuvant trastuzumab via a single-use injection device or h and -held syringe followed by four cycles of st and ard intravenous trastuzumab , or the reverse sequence . R and omisation was stratified by de-novo versus non-de-novo use of intravenous trastuzumab . The primary endpoint was the proportion of patients indicating an overall preference for subcutaneous or intravenous trastuzumab  , assessed by patient interview in the evaluable intention-to-treat ( ITT ) population ( patients who completed both interviews and had at least one administration of both subcutaneous and intravenous trastuzumab ) . Data collection for PrefHer is ongoing . This study is registered with Clinical Trials.gov , number NCT01401166 . FINDINGS 124 patients were r and omly allocated to receive subcutaneous followed by intravenous trastuzumab , and 124 to receive the reverse sequence . 117 patients in the subcutaneous first group and 119 in the intravenous first group were included in the evaluable ITT population . Subcutaneous trastuzumab  via the single-use injection device was preferred by 216 patients ( 91·5 % , 95 % CI 87·2 - 94·7 ; p<0·0001 ) . Only 16 patients  preferred intravenous trastuzumab ( 6·8 % , 3·9 - 10·8 ) , and four had no preference ( 1·7 % , 0·5 - 4·3 ) . Clinician-reported adverse events occurred in 141 of 242 ( 58 % ) patients during the pooled subcutaneous periods and 105 of 241 ( 44 % ) patients during the pooled intravenous periods ; seven ( 3 % ) and five ( 2 % ) were grade 3 , no patients had a grade 4 or 5 event . The most common grade 3 adverse event was influenza ( two [ 0·8 
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Side effects were more common for patients treated with therapies other than trastuzumab or with dual-HER2 regimens and for patients with metastatic disease .
Conclusions This systematic review provides a detailed analysis of side effects of HER2 + therapies in a large number of patients included in trials , enabling an accurate estimate of prevalence and a complete underst and ing of the patients ' experience .