***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 PURPOSE Pertuzumab , a recombinant humanized monoclonal antibody ( 2C4 ) , binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors . Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors . A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy . PATIENTS AND METHODS Patients with incurable , locally advanced , recurrent or metastatic solid tumors that had progressed during or after st and ard therapy were recruited to a dose-escalation study of pertuzumab ( 0.5 to 15 mg/kg ) given intravenously every 3 weeks . RESULTS Twenty-one patients received pertuzumab  and 19 completed at least two cycles . Pertuzumab was well tolerated . Overall , 365 adverse events were reported and 122 considered to be possibly drug related . Of these , 116 were of grade 1 to 2 intensity . The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies , supporting a 3-week dosing regimen . Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg . Two patients , one with ovarian cancer ( 5.0 mg/kg ) and one with pancreatic islet cell carcinoma ( 15.0 mg/kg ) , achieved a partial response . Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy , and lasted for 11 and 10 months , respectively . Stable disease lasting for more than 2.5 months ( range , 2.6 to 5.5 months ) was observed in six patients . CONCLUSION These results demonstrate that pertuzumab is well tolerated , has a pharmacokinetic profile which supports 3-week dosing , and is clinical ly active , suggesting that inhibition of dimerization may be an effective anticancer strategy Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors . We conducted a phase Ib study to determine the maximum-tolerated dose , the dose limiting toxicities ( DLT ) , and pharmacokinetic ( PK ) interaction of docetaxel when administered in combination with pertuzumab . Initially , two dose levels of docetaxel ( 60 and 75 mg m−2 ) were explored in combination with a fixed dose of 1050 mg of pertuzumab ; then two dose levels of docetaxel ( 75 and 100 mg m−2 ) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg . Both drugs were administered intravenously every 3 weeks . The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available . Two patients out of two treated at docetaxel 75 mg m−2 in combination with pertuzumab 1050 mg suffered DLT ( grade 3 diarrhoea and grade 4 febrile neutropaenia ) . Two out of five patients treated at docetaxel 100 mg m−2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT ( grade 3 fatigue and grade 4 febrile neutropaenia ) . Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a > 50 % decline in PSA in a patient with hormone refractory prostate cancer were observed . There were no pharmacokinetic drug – drug interactions . The recommended phase II dose of this combination was docetaxel 75 mg m−2 and 420 mg pertuzumab following a loading dose of 840 mg Objective rhuMAb 2C4 ( pertuzumab , RO4368451 ) , a human epidermal growth factor receptor-2 ( HER2 ) targeted antibody that binds to an epitope distinct from trastuzumab , blocks lig and -associated heterodimerization of HER2 with other HER receptor family members . This study evaluated the toxicity , pharmacokinetics and anti-tumor activities of pertuzumab in Japanese patients with solid tumors . Methods Patients with solid tumors refractory to st and ard therapy were administered pertuzumab 5 , 10 , 15 , 20 and 25 mg/kg intravenously once every 3 weeks . Grade 3 toxicities were considered as dose limiting . The maximum tolerated dose ( MTD ) was a dose at which two out of six patients had Grade 3 toxicities . Results Eighteen patients , aged 38–66 ( median 57 ) years , with solid tumors were enrolled and a total of 32 cycles of pertuzumab were administered . Toxicities were generally acceptable . Grade 3 elevation of gamma-glutamyl transpeptidase was observed in one patient at 25 mg/kg and was considered to be dose limiting . MTD was not reached up to a dose level of 25 mg/kg . The serum concentration of pertuzumab  declined slowly ( terminal half-life is approximately 3 weeks ) . The AUC proportionally increased over the dose range tested . There was limited evidence of activity ( stable disease 2 ; progressive disease 13 ; and not evaluable 3 ) ; however , tumor shrinkage and tumor marker decrease were observed in an ovarian cancer and a non-small-cell lung cancer patient , respectively . Conclusions Pertuzumab is well tolerated up to 25 mg/kg . Although objective tumor response was not observed , it is worth evaluating as a flat dose and in combination with other cytotoxics and molecular-targeted agents Purpose : To study the safety , pharmacokinetics , and recommended dose of the combination of pertuzumab , a humanized monoclonal antibody HER2-dimerization inhibitor , and capecitabine in patients with advanced malignancies . Experimental Design : Patients that had progressed to st and ard treatment were treated with pertuzumab at a fixed dose of 1,050 mg given i.v . on day 1 plus capecitabine at doses of 825 - 1,000 - 1,250 mg/m2 , twice daily orally on days 1 to 14 of each 21-day treatment cycle , in three sequential cohorts . The pharmacokinetics of capecitabine and pertuzumab were studied . Patients received a single dose of capecitabine in a pretreatment phase ( day −7 ) followed by serum sampling for capecitabine and its metabolites . Results : Nineteen patients were accrued and 18 were assessable . The combination of capecitabine and pertuzumab was well tolerated at all dose levels and no dose-limiting toxicities were observed . The most frequent adverse event was asthenia , which was grade 3 in two patients . One asymptomatic pulmonary embolism occurred . No other grade 3 or 4 adverse events or cardiac or left ventricular ejection fraction events were reported . There was no apparent change in the pharmacokinetics  of capecitabine  and its metabolites when combined with pertuzumab . The pharmacokinetics  of pertuzumab was apparently not modified when administered with capecitabine  . Disease stabilization was observed in 11 patients . Conclusions : Pertuzumab and capecitabine were well tolerated at all dose levels . Escalation beyond the highest dose level tested was not planned , as this included the recommended doses of monotherapy for both drugs . In conclusion , this combination is ready for phase II testing 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 ] ) 
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The antitumor activity with the significant reduction in the risk of progression or death , as reflected upon the increase of 6.1 months in median progression-free survival , indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2(+ ) .
Moreover , pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab .