***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 In the primary analysis of the NeoSphere trial , patients given neoadjuvant pertuzumab , trastuzumab , and docetaxel showed a significantly improved pathological complete response compared with those given trastuzumab and docetaxel after surgery . Here , we report 5-year progression-free survival , disease-free survival , and safety . METHODS In this multicentre , open-label , phase 2 r and omised trial in hospitals and medical clinics , treatment-naive adults with locally advanced , inflammatory , or early-stage HER2-positive breast cancer were r and omly assigned ( 1:1:1:1 ) 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 ) every 3 weeks , increasing to 100 mg/m(2 ) from cycle 2 if tolerated ; group A ) , pertuzumab ( 840 mg loading dose , followed by 420 mg every 3 weeks ) and trastuzumab plus docetaxel ( group B ) , pertuzumab and trastuzumab ( group C ) , or pertuzumab and docetaxel ( group D ) . After surgery , patients received three cycles of FEC ( fluorouracil 600 mg/m(2 ) , epirubicin 90 mg/m(2 ) , and cyclophosphamide 600 mg/m(2 ) ) every 3 weeks ( patients in group C received four cycles of docetaxel prior to FEC ) , and trastuzumab 6 mg/kg every 3 weeks to complete 1 year 's treatment ( 17 cycles in total ) . R and omisation was done by a central centre using dynamic allocation , stratified by operable , locally advanced , and inflammatory breast cancer , and by oestrogen and /or progesterone receptor positivity . Safety analyses were done according to treatment received . The primary endpoint ( pathological complete response ) was previously reported ; secondary endpoints reported here are 5-year progression-free survival ( analysed in the intention-to-treat population ) and disease-free survival ( analysed in patients who had surgery ) . Secondary and exploratory analyses were not powered for formal statistical hypothesis testing , and therefore results are for descriptive purpose s only . The study ended on Sept 22 , 2014 ( last patient , last visit ) . This study is registered with Clinical Trials.gov , number NCT00545688 . FINDINGS Between Dec 17 , 2007 , and Dec 22 , 2009 , 417 eligible patients were r and omly assigned to group A ( 107 patients ) , group B ( 107 patients ) , group C ( 107 patients ) , or group D ( 96 patients ) . One patient in group A withdrew before treatment . One patient assigned to group D received group A treatment , one patient assigned to group D received group B treatment , and one patient assigned to group B received group C treatment . At clinical cutoff , 87 patients had progressed or died . 5-year progression-free survival rates were 81 % ( 95 % CI 71 - 87 ) for group A , 86 % ( 77 - 91 ) for group B , 73 % ( 64 - 81 ) for group C , and 73 % ( 63 - 81 ) for group D ( hazard ratios 0·69 [ 95 % CI 0·34 - 1·40 ] group B vs group A , 1·25 [ 0·68 - 2·30 ] group C vs group A , and 2·05 [ 1·07 - 3·93 ] group D vs group B ) . Disease-free survival results were consistent with progression-free survival results and were 81 % ( 95 % CI 72 - 88 ) for group A , 84 % ( 72 - 91 ) for group B , 80 % ( 70 - 86 ) for group C , and 75 % ( 64 - 83 ) for group D. Patients who achieved total pathological complete response ( all groups combined ) had longer progression-free survival compared with patients who did not ( 85 % [ 76 - 91 ] in patients who achieved total pathological response vs 76 % [ 71 - 81 ] in patients who did not achieve total pathological response ; hazard ratio 0·54 [ 95 % CI 0·29 - 1·00 ] ) . There were no new or long-term safety concerns and tolerability was similar across groups ( neoadjuvant and adjuvant treatment periods combined ) . The most common grade 3 or worse adverse events were neutropenia ( group A : 71 [ 66 % ] of 107 patients ; group B : 59 [ 55 % ] of 107 ; group C : 40 [ 37 % ] of 108 ; group D : 60 [ 64 % ] of 94 ) , febrile neutropenia ( group A : 10 [ 9 % ] ; group B : 12 [ 11 % ] ; group C : 5 [ 5 % ] ; group D : 15 [ 16 % ] ) , and leucopenia ( group A : 13 [ 12 % ] ; group B : 6 [ 6 % ] ; group C : 4 [ 4 % ] ; group D : 8 [ 9 % ] ) . The number of patients with one or more serious adverse event was similar across groups ( 19 - 22 serious adverse events per group in 18 - 22 % of patients ) . INTERPRETATION Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs , but support the primary endpoint ( pathological complete response ) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel . Additionally , they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer . FUNDING F Hoffmann-La Roche 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 . Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 ( HER2 ) –targeted monoclonal antibodies , and trastuzumab emtansine ( T-DM1 ) is an antibody – drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1 . T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer .  Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study . Methods In the MARIANNE study , 1,095 patients with central ly assessed , HER2-positive , advanced breast cancer and no prior therapy for advanced disease were r and omly assigned 1:1:1 to control ( trastuzumab plus taxane ) , T-DM1 plus placebo , hereafter T-DM1 , or T-DM1 plus pertuzumab at st and ard doses . Primary end point was progression-free survival ( PFS ) , as assessed by independent review . Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane ( median PFS : 13.7 months with trastuzumab plus taxane , 14.1 months with T-DM1 , and 15.2 months with T-DM1 plus pertuzumab ) . Neither experimental arm showed PFS superiority to trastuzumab plus taxane . Response rate was 67.9 % in patients who were treated with trastuzumab plus taxane , 59.7 % with T-DM1 , and 64.2 % with T-DM1 plus pertuzumab ; median response duration was 12.5 months , 20.7 months , and 21.2 months , respectively . The incidence of grade ≥ 3 adverse events was numerically higher in the control arm ( 54.1 % ) versus the T-DM1 arm ( 45.4 % ) and T-DM1 plus pertuzumab arm ( 46.2 % ) . Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms , and health-related quality of life was maintained for longer in the T-DM1 arms . Conclusion T-DM1 showed noninferior , but not superior , efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive , advanced breast cancer Maytansine , a new ansa macrolide antitumor antibiotic , was administered to 60 patients as part of a phase I study . The doses given ranged from 0.01 ( starting level ) to 0.9 mg/m2 for 3 days . The toxic effects encountered consisted principally of nausea , vomiting , diarrhea , and occasionally , stomatitis and alopecia . Superficial phlebitis was also encountered and occurred when the drug was diluted in a volume of less than 250 ml . Myelosuppression occurred infrequently ; it was almost regularly associated with abnormal liver function tests . Antitumor activity was detected in one patient each with melanoma , breast carcinoma ; and head and neck clear cell carcinoma . Further studies are indicated with this compound since it has shown evidence of activity with little or no myelosuppression Maytansine has significant antitumor activity in animal model systems . The initial clinical trial of maytansine was carried out in 38 adult solid tumor patients . Five daily bolus injections were repeated at 21-day intervals . A total of 78 courses were administered over a dose range of 0.1 - -0.8 mg/m2/day X 5 days . Gastrointestinal toxicity was dose-related and dose-limiting at doses of greater than or equal to 0.5 mg/m2 . Dose-related neurotoxicity was also observed . No drug-related myelosuppression or change in serum creatinine level was seen . Hepatic toxicity was sub clinical and reversible . Of 16 patients evaluable for response , two with breast cancer had therapeutic benefit . Phase II studies of maytansine are recommended at a starting dose of 2.0 - -2.5 mg/m2/course repeated at 21-day intervals BACKGROUND HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant , adjuvant , and metastatic setting s ; however , some patients remain at risk of relapse or death for many years after treatment of early-stage disease . Therefore , new strategies are needed . We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment . METHODS We did a r and omised , open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres ( hospitals and specialty cancer centres in Asia , Europe , USA , and Canada ) . Eligible participants were aged 18 years or older with central ly confirmed HER2-positive stage II-III operable breast cancer ( > 2 cm tumour size ) , an Eastern Cooperative Oncology Group performance status of 0 - 1 , and a baseline left ventricular ejection fraction of at least 55 % ( by echocardiogram or multiple-gated acquisition scan ) . We r and omly assigned participants ( 1:1 ) to receive either tr 
    Output:
    
Conclusions : Our meta- analysis demonstrates that T-DM1-based therapy is associated with an increased risk of AST and ALT elevations