human
***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 Adjuvant treatment decision-making based on conventional clinical /pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades . Response to therapy is currently not considered in the decision-making procedure . ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers , e.g. , Ki-67 , for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment . Methods / design The prospect i ve , multi-center , controlled , non-blinded , r and omized , investigator initiated phase II/III ADAPT trial has an innovative “ umbrella ” protocol design . The “ umbrella ” is common for all patients , consisting of dynamic testing of early therapy response .  ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany ; 4,000 patients with hormone receptor positive ( HR+ ) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial , where treatment decision is based on risk assessment and therapy response to induction therapy , and 380 patients will be included in ADAPT HER2+/HR+ . A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative . These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting . Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy , as reported by local/ central pathology for HR and HER2 status . Discussion Recent trials , such as the GeparTrio , have shown that response-guided therapy using clinical response may improve outcome . For chemotherapy or HER2-targeted treatment , pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome . For endocrine therapy , response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome . ADAPT now aims to combine static prognostic and dynamic predictive markers , focusing not just on single therapeutic targets , but also on general markers of proliferation and cell death . Biomarker analysis will help to optimize selection of subtype-specific treatment . Trial registration Clinical Trials.gov : ADAPT Umbrella : NCT01781338 ; ADAPT HR+/HER2- : NCT01779206 ; ADAPT HER2+/HR+ : NCT01745965 ; ADAPT HER2+/HR- : NCT01817452 ; ADAPT TN : NCT01815242 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 We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy . METHODS In the GeparQuinto r and omised phase 3 trial , patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7 , 2007 , and July 9 , 2010 . Patients were eligible if their tumours were classified as cT3/4a-d , or hormone receptor (HR)-negative , HR-positive with clinical ly node-positive and cT2 disease ( cT2 cN+ ) , or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease ( cT1 pN(SLN+ ) ) . Patients were r and omly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC ( epirubicin [ 90 mg/m(2 ) intravenously ] plus cyclophosphamide [ 600 mg/m(2 ) intravenously ] , every 3 weeks ) , and four cycles of docetaxel ( 100 mg/m(2 ) intravenously every 3 weeks ) with either trastuzumab ( 6 mg/kg intravenously , with a starting loading dose of 8 mg/kg , for eight cycles , every 3 weeks ) or lapatinib ( 1000 - 1250 mg per day orally ) throughout all cycles before surgery . R and omisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site , HR status , and extent of disease ( cT1 - 3 cN0 - 2 vs T4 or N3 ) . The primary endpoint was pathological complete response ( defined as ypT0 and ypN0 ) and was analysed in all patients who received at least one cycle of EC . Participants and investigators were not masked to treatment assignment . Pathologists in centres assessing surgery outcomes were masked to group assignment . This trial is registered with Clinical Trials.gov , number NCT00567554 . FINDINGS Of 620 eligible patients , 309 were r and omly assigned to chemotherapy with trastuzumab ( ECH-TH group ) and 311 to chemotherapy with lapatinib ( ECL-TL group ) . Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery . 93 ( 30·3 % ) of 307 patients in the ECH-TH group and 70 ( 22·7 % ) of 308 patients in the ECL-TL group had a pathological complete response ( odds ratio [ OR ] 0·68 [ 95%CI 0·47 - 0·97 ] ;  p=0·04 )  . Chemotherapy with trastuzumab was associated with more oedema ( 119 [ 39·1 % ] vs 88 [ 28·7 % ] ) and dyspnoea ( 90 [ 29·6 % ] vs 66 [ 21·4 % ] ) , and ECL-TL with more diarrhoea ( 231 [ 75·0 % ] vs 144 [ 47·4 % ] ) and skin rash ( 169 [ 54·9 % ] vs 97 [ 31·9 % ] ) . 43 ( 14·0 % ) patients discontinued in the ECH-TH group and 102 ( 33·1 % ) in the ECL-TL group . 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group . INTERPRETATION This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate  with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab . Unless long-term outcome data show different results , lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy . FUNDING GlaxoSmithKline , Roche , and Sanofi-Aventis BACKGROUND Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30 - 65 % of patients . We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy . METHODS This r and omised trial was done at 36 centres in the USA and Puerto Rico . Women with operable HER2-positive invasive breast cancer were r and omly assigned ( 1:1 ) with a biased coin minimisation algorithm , stratified for age , tumour size , and hormone receptor status . Neither patients nor investigators ( except for a cardiac safety review panel ) were masked to treatment assignment . Patients r and omly assigned to sequential treatment received fluorouracil 500 mg/m(2 ) , epirubicin 75 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ( FEC-75 ) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2 ) and trastuzumab 2 mg/kg ( after a 4 mg/kg loading dose ) once per week for 12 weeks , while those r and omly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 ( on day 1 of each 21-day cycle ) and once-weekly trastuzumab , in the same doses as the sequential group . Surgery , including evaluation of the axilla , was done within 6 weeks of completion of neoadjuvant treatment . The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT00513292 . FINDINGS From Sept 15 , 2007 , to Dec 15 , 2011 , 282 women were enrolled ( 140 in the sequential group , 142 in the concurrent group ) . Two patients in the sequential group withdrew consent before starting treatment . 78 of 138 ( 56·5 % , 95 % CI 47·8 - 64·9 ) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 ( 54·2 % , 95 % CI 45·7 - 62·6 ) who received concurrent treatment ( difference 2·3 % , 95 % CI -9·3 to 13·9 ) . No treatment-related deaths occurred . The most common severe toxic effects were neutropenia ( 35 [ 25·3 % ] of 138 patients in the sequ 
    Output:
    
agent
Longer trastuzumab duration ( hera : 2 years vs. 1 year ) showed no improvement in dfs or os and a higher rate of cardiac events .
In the neoadjuvant setting ( neoaltto , GeparQuinto , Neosphere ) , trastuzumab alone or in combination with another anti-her2 agent ( lapatinib , pertuzumab ) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response .
In the adjuvant setting , lapatinib alone or in combination with trastuzumab , compared with trastuzumab alone ( altto ) or with placebo ( teach ) , was not superior in dfs .
***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 Adjuvant treatment decision-making based on conventional clinical /pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades . Response to therapy is currently not considered in the decision-making procedure . ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers , e.g. , Ki-67 , for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment . Methods / design The prospect i ve , multi-center , controlled , non-blinded , r and omized , investigator initiated phase II/III ADAPT trial has an innovative “ umbrella ” protocol design . The “ umbrella ” is common for all patients , consisting of dynamic testing of early therapy response .  ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany ; 4,000 patients with hormone receptor positive ( HR+ ) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial , where treatment decision is based on risk assessment and therapy response to induction therapy , and 380 patients will be included in ADAPT HER2+/HR+ . A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative . These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting . Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy , as reported by local/ central pathology for HR and HER2 status . Discussion Recent trials , such as the GeparTrio , have shown that response-guided therapy using clinical response may improve outcome . For chemotherapy or HER2-targeted treatment , pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome . For endocrine therapy , response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome . ADAPT now aims to combine static prognostic and dynamic predictive markers , focusing not just on single therapeutic targets , but also on general markers of proliferation and cell death . Biomarker analysis will help to optimize selection of subtype-specific treatment . Trial registration Clinical Trials.gov : ADAPT Umbrella : NCT01781338 ; ADAPT HR+/HER2- : NCT01779206 ; ADAPT HER2+/HR+ : NCT01745965 ; ADAPT HER2+/HR- : NCT01817452 ; ADAPT TN : NCT01815242 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 We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy . METHODS In the GeparQuinto r and omised phase 3 trial , patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7 , 2007 , and July 9 , 2010 . Patients were eligible if their tumours were classified as cT3/4a-d , or hormone receptor (HR)-negative , HR-positive with clinical ly node-positive and cT2 disease ( cT2 cN+ ) , or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease ( cT1 pN(SLN+ ) ) . Patients were r and omly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC ( epirubicin [ 90 mg/m(2 ) intravenously ] plus cyclophosphamide [ 600 mg/m(2 ) intravenously ] , every 3 weeks ) , and four cycles of docetaxel ( 100 mg/m(2 ) intravenously every 3 weeks ) with either trastuzumab ( 6 mg/kg intravenously , with a starting loading dose of 8 mg/kg , for eight cycles , every 3 weeks ) or lapatinib ( 1000 - 1250 mg per day orally ) throughout all cycles before surgery . R and omisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site , HR status , and extent of disease ( cT1 - 3 cN0 - 2 vs T4 or N3 ) . The primary endpoint was pathological complete response ( defined as ypT0 and ypN0 ) and was analysed in all patients who received at least one cycle of EC . Participants and investigators were not masked to treatment assignment . Pathologists in centres assessing surgery outcomes were masked to group assignment . This trial is registered with Clinical Trials.gov , number NCT00567554 . FINDINGS Of 620 eligible patients , 309 were r and omly assigned to chemotherapy with trastuzumab ( ECH-TH group ) and 311 to chemotherapy with lapatinib ( ECL-TL group ) . Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery . 93 ( 30·3 % ) of 307 patients in the ECH-TH group and 70 ( 22·7 % ) of 308 patients in the ECL-TL group had a pathological complete response ( odds ratio [ OR ] 0·68 [ 95%CI 0·47 - 0·97 ] ;  p=0·04 )  . Chemotherapy with trastuzumab was associated with more oedema ( 119 [ 39·1 % ] vs 88 [ 28·7 % ] ) and dyspnoea ( 90 [ 29·6 % ] vs 66 [ 21·4 % ] ) , and ECL-TL with more diarrhoea ( 231 [ 75·0 % ] vs 144 [ 47·4 % ] ) and skin rash ( 169 [ 54·9 % ] vs 97 [ 31·9 % ] ) . 43 ( 14·0 % ) patients discontinued in the ECH-TH group and 102 ( 33·1 % ) in the ECL-TL group . 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group . INTERPRETATION This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate  with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab . Unless long-term outcome data show different results , lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy . FUNDING GlaxoSmithKline , Roche , and Sanofi-Aventis BACKGROUND Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30 - 65 % of patients . We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy . METHODS This r and omised trial was done at 36 centres in the USA and Puerto Rico . Women with operable HER2-positive invasive breast cancer were r and omly assigned ( 1:1 ) with a biased coin minimisation algorithm , stratified for age , tumour size , and hormone receptor status . Neither patients nor investigators ( except for a cardiac safety review panel ) were masked to treatment assignment . Patients r and omly assigned to sequential treatment received fluorouracil 500 mg/m(2 ) , epirubicin 75 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ( FEC-75 ) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2 ) and trastuzumab 2 mg/kg ( after a 4 mg/kg loading dose ) once per week for 12 weeks , while those r and omly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 ( on day 1 of each 21-day cycle ) and once-weekly trastuzumab , in the same doses as the sequential group . Surgery , including evaluation of the axilla , was done within 6 weeks of completion of neoadjuvant treatment . The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT00513292 . FINDINGS From Sept 15 , 2007 , to Dec 15 , 2011 , 282 women were enrolled ( 140 in the sequential group , 142 in the concurrent group ) . Two patients in the sequential group withdrew consent before starting treatment . 78 of 138 ( 56·5 % , 95 % CI 47·8 - 64·9 ) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 ( 54·2 % , 95 % CI 45·7 - 62·6 ) who received concurrent treatment ( difference 2·3 % , 95 % CI -9·3 to 13·9 ) . No treatment-related deaths occurred . The most common severe toxic effects were neutropenia ( 35 [ 25·3 % ] of 138 patients in the sequ 
    Output:
    