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 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 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 We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment , and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients . METHODS For this open-label , r and omised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer . Each received four cycles of st and ard doxorubicin 60 mg/m(2 ) and cyclophosphamide 600 mg/m(2 ) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel ( 80 mg/m(2 ) ) intravenously on days 1 , 8 , and 15 , every 4 weeks . Concurrently with weekly paclitaxel , patients received either trastuzumab ( 4 mg/kg load , then 2 mg/kg intravenously ) weekly until surgery , lapatinib ( 1250 mg orally ) daily until surgery , or weekly trastuzumab plus lapatinib ( 750 mg orally ) daily until surgery . After surgery , all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy . R and omisation ( ratio 1:1:1 ) was done central ly with stratification by clinical tumour size , clinical nodal status , hormone-receptor status , and age . The primary endpoint was the pathological complete response in the breast , and analysis was performed on an intention-to-treat population . FINDINGS Patient accrual started on July 16 , 2007 , and was completed on June 30 , 2011 ; 529 women were enrolled in the trial . 519 patients had their pathological response determined .  Breast pathological complete response was noted in 93 ( 52·5 % , 95 % CI 44·9 - 59·5 ) of 177 patients in the trastuzumab group , 91 ( 53·2 % , 45·4 - 60·3 ) of 171 patients in the lapatinib group ( p=0·9852 ) ; and 106 ( 62·0 % , 54·3 - 68·8 ) of 171 patients in the combination group ( p=0·095 ) . The most common grade 3 and 4 toxic effects were neutropenia ( 29 [ 16 % ] patients in the trastuzumab group [ grade 4 in five patients ( 3 % ) , 28 [ 16 % ] in the lapatinib group [ grade 4 in eight patients ( 5 % ) ] , and 29 [ 17 % ] in the combination group [ grade 4 in nine patients ( 5 % ) ] ) and grade 3 diarrhoea ( four [ 2 % ] patients in the trastuzumab group , 35 [ 20 % ] in the lapatinib group , and 46 [ 27 % ] in the combination group ; p<0·0001 ) . Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven ( 4 % ) patients in the trastuzumab group , seven ( 4 % ) in the lapatinib group , and one ( < 1 % ) in the combination group ; p=0·185 ) . INTERPRETATION Substitution of lapatinib for trastuzumab in combination with chemotherapy result ed in similar high percentages of pathological complete response . Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy ; these findings are consistent with results from other studies . Trials are being undertaken to further assess these findings in the adjuvant setting BACKGROUND Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to  trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer . In this trial , we investigated whether pertuzumab , when added to adjuvant trastuzumab and chemotherapy , improves outcomes among patients with HER2‐positive early breast cancer . METHODS We r and omly assigned patients 
    Output:
    
agent
***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 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 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 We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment , and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients . METHODS For this open-label , r and omised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer . Each received four cycles of st and ard doxorubicin 60 mg/m(2 ) and cyclophosphamide 600 mg/m(2 ) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel ( 80 mg/m(2 ) ) intravenously on days 1 , 8 , and 15 , every 4 weeks . Concurrently with weekly paclitaxel , patients received either trastuzumab ( 4 mg/kg load , then 2 mg/kg intravenously ) weekly until surgery , lapatinib ( 1250 mg orally ) daily until surgery , or weekly trastuzumab plus lapatinib ( 750 mg orally ) daily until surgery . After surgery , all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy . R and omisation ( ratio 1:1:1 ) was done central ly with stratification by clinical tumour size , clinical nodal status , hormone-receptor status , and age . The primary endpoint was the pathological complete response in the breast , and analysis was performed on an intention-to-treat population . FINDINGS Patient accrual started on July 16 , 2007 , and was completed on June 30 , 2011 ; 529 women were enrolled in the trial . 519 patients had their pathological response determined .  Breast pathological complete response was noted in 93 ( 52·5 % , 95 % CI 44·9 - 59·5 ) of 177 patients in the trastuzumab group , 91 ( 53·2 % , 45·4 - 60·3 ) of 171 patients in the lapatinib group ( p=0·9852 ) ; and 106 ( 62·0 % , 54·3 - 68·8 ) of 171 patients in the combination group ( p=0·095 ) . The most common grade 3 and 4 toxic effects were neutropenia ( 29 [ 16 % ] patients in the trastuzumab group [ grade 4 in five patients ( 3 % ) , 28 [ 16 % ] in the lapatinib group [ grade 4 in eight patients ( 5 % ) ] , and 29 [ 17 % ] in the combination group [ grade 4 in nine patients ( 5 % ) ] ) and grade 3 diarrhoea ( four [ 2 % ] patients in the trastuzumab group , 35 [ 20 % ] in the lapatinib group , and 46 [ 27 % ] in the combination group ; p<0·0001 ) . Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven ( 4 % ) patients in the trastuzumab group , seven ( 4 % ) in the lapatinib group , and one ( < 1 % ) in the combination group ; p=0·185 ) . INTERPRETATION Substitution of lapatinib for trastuzumab in combination with chemotherapy result ed in similar high percentages of pathological complete response . Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy ; these findings are consistent with results from other studies . Trials are being undertaken to further assess these findings in the adjuvant setting BACKGROUND Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to  trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)–positive breast cancer . In this trial , we investigated whether pertuzumab , when added to adjuvant trastuzumab and chemotherapy , improves outcomes among patients with HER2‐positive early breast cancer . METHODS We r and omly assigned patients 
    Output:
    