***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: PURPOSE Dose-dense doxorubicin and cyclophosphamide ( AC ) followed by paclitaxel and trastuzumab ( PT ) is feasible . Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 ( HER2 ) -positive metastatic breast cancer . We conducted a pilot study of dose-dense AC followed by PT plus lapatinib ( PTL ) followed by trastuzumab plus lapatinib ( TL ) . PATIENTS AND METHODS Patients with stages I to III , HER2-positive breast cancer and left ventricular ejection fraction ( LVEF ) of > or = 50 % were enrolled . Treatment consisted of AC ( 60 mg/m(2 ) and 600 mg/m(2 ) ) for 4 cycles every 2 weeks ( with pegfilgrastim 6 mg on day 2 ) followed by paclitaxel ( 80 mg/m(2 ) ) for 12 doses weekly plus trastuzumab and lapatinib . Trastuzumab ( 4 mg/kg loading dose , then 2 mg/kg weekly during paclitaxel then 6 mg/kg every 3 weeks after paclitaxel ) and lapatinib ( 1,000 mg daily ) were given for 1 year . The primary end points were feasibility defined as > or = 80 % patients completing the PTL phase without a dose delay/reduction and a cardiac event rate of < or = 4 % . RESULTS From March 2007 to April 2008 , we enrolled 95 patients . Median age was 46 years ( range , 28 to 73 years ) . At a median follow-up of 22 months , 92 were evaluable . Of the 92 patients , 41 patients ( 45 % ) withdrew for PTL-specific toxicities . Overall , 40 ( 43 % ) of 92 patients had lapatinib dose reductions , and 27 ( 29 % ) of 92 patients had grade 3 diarrhea . Three patients ( 3 % ) had congestive heart failure ; three patients dropped out because of significant asymptomatic LVEF decline during PTL followed by TL . CONCLUSION Dose-dense AC followed by PTL and then followed by TL was not feasible because of a high rate of lapatinib dose reduction , mostly caused by unacceptable grade 3 diarrhea . Lapatinib ( 1,000 mg/d ) was not feasible combined with weekly PT 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 Lapatinib adds to the efficacy of trastuzumab in pre clinical models and also in the neo-adjuvant setting . This study assesses the safety and feasibility of adding lapatinib to paclitaxel and trastuzumab ( THL ) as part of the adjuvant therapy for HER2-positive breast cancer ( HER2 + BC ) . In this single-arm phase II study , patients with stages I – III HER2 + BC received st and ard anthracycline-based chemotherapy followed by weekly taxane , with concurrent st and ard trastuzumab , plus daily lapatinib for a total of 12 months . The primary endpoint was symptomatic congestive heart failure , secondary endpoints included overall safety .  A total of 109 eligible patients were enrolled . Median follow-up is 4.3 years . No patients experienced congestive heart failure while on treatment . Mean left ventricular ejection fraction at baseline and at the end of THL were 63.6 % ( N = 109 , SD = 5.7 ) and 59.8 % ( N = 98 , SD = 8.1 ) , respectively [ mean change −3.95 % ( N = 98 , SD = 8.3 ) , p < 0.001 ] . One hundred and two patients initiated post-AC treatment ; of them , 31 % experienced grade 3 ( no G4 ) diarrhea with lapatinib at 750 mg/day . The addition of lapatinib to paclitaxel and trastuzumab following AC does not add cardiac toxicity . Lapatinib dose of 750 mg/day in combination with st and ard chemotherapy plus trastuzumab has acceptable overall tolerability BACKGROUND The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer . We argue that the two anti-HER2 agents given together would be better than single-agent therapy . METHODS In this parallel groups , r and omised , open-label , phase 3 study undertaken between Jan 5 , 2008 , and May 27 , 2010 , women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were r and omly assigned to oral lapatinib ( 1500 mg ) , intravenous trastuzumab ( loading dose 4 mg/kg [ DOSAGE ERROR CORRECTED ] , subsequent doses 2 mg/kg ) , or lapatinib ( 1000 mg ) plus trastuzumab . Treatment allocation was by stratified , permuted blocks r and omisation , with four stratification factors . Anti-HER2 therapy alone was given for the first 6 weeks ; weekly paclitaxel ( 80 mg/m(2 ) ) was then added to the regimen for a further 12 weeks , before definitive surgery was undertaken . After surgery , patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks . The primary endpoint was the rate of pathological complete response ( pCR ) , analysed by intention to treat . This trial is registered with Clinical Trials.gov , NCT00553358 . FINDINGS 154 patients received lapatinib , 149 trastuzumab , and 152 the combination . pCR rate was significantly higher in the group given lapatinib and trastuzumab ( 78 of 152 patients [ 51·3 % ; 95 % CI 43·1 - 59·5 ] ) than in the group given trastuzumab alone ( 44 of 149 patients [ 29·5 % ; 22·4 - 37·5 ] ; difference 21·1 % , 9·1 - 34·2 , p=0·0001 ) . We recorded no significant difference in pCR between the lapatinib ( 38 of 154 patients [ 24·7 % , 18·1 - 32·3 ] ) and the trastuzumab ( difference -4·8 % , -17·6 to 8·2 , p=0·34 ) groups . No major cardiac dysfunctions occurred . Frequency of grade 3 diarrhoea was higher with lapatinib ( 36 patients [ 23·4 % ] ) and lapatinib plus trastuzumab ( 32 [ 21·1 % ] ) than with trastuzumab ( three [ 2·0 % ] ) . Similarly , grade 3 liver-enzyme alterations were more frequent with lapatinib ( 27 [ 17·5 % ] ) and lapatinib plus trastuzumab ( 15 [ 9·9 % ] ) than with trastuzumab ( 11 [ 7·4 % ] ) . INTERPRETATION Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting . FUNDING GlaxoSmithKline PURPOSE We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)- amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor ( ER ) when expressed . In this clinical trial , we sought to translate these findings to patients using targeted therapy without chemotherapy . PATIENTS AND METHOD Women with stages II to III HER2-positive breast cancers were eligible . They received trastuzumab once per week ( 4 mg/kg loading , then 2 mg/kg ) and lapatinib 1000 mg once per day for 12 weeks . Women with ER-positive tumors also received letrozole ( plus a luteinizing hormone-releasing hormone [ LHRH ] agonist if premenopausal ) .  Pathologic response was assessed by ER status . Biopsies were obtained at baseline , weeks 2 and 8 , and time of surgery . RESULTS Sixty-six patients were enrolled , and 64 were eligible and evaluable for response .  Median tumor size was 6 cm ( range , 1.5 to 30 cm ) . Adverse events were mainly grade s 1 to 2 ( GI , 63 % ; skin , 46 % ) . Grade 3 metabolic , GI , and liver ( 18 % ; 12 patients ) and grade 4 liver toxicities ( one patient ) were also observed . Overall , in-breast pathologic complete response ( pCR ; ypT0-is ) was 27 % ( ER positive , 21 % ; ER negative , 36 % ) . The rate of low-volume residual disease ( ypT1a-b ) was 22 % ( ER positive , 33 % ; ER negative , 4 % ) . CONCLUSION In patients with locally advanced HER2-positive breast cancer , our approach of targeted therapy only result ed in a high pCR rate without chemotherapy . Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy , and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study PURPOSE The exact definition of pathologic complete response ( pCR ) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain . MET 
    Output:
    
Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer .