***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 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 : To assess pathologic complete response ( pCR ) , clinical response , feasibility , safety , and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable , human epidermal growth factor receptor 2 (HER2)–positive breast cancer . Experimental Design : Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks . Single and multigene biomarker studies were done in an attempt to identify predictors of response . Results : Eight of 40 ( 20 % ) patients achieved pCR ( 95 % confidence interval , 9 - 36 % ) . Of 9 additional patients recruited for protocol -defined toxicity analysis , 8 were evaluable ; 42 of 48 ( 88 % ) patients had clinical response ( 16 patients , clinical complete response ; 26 patients , clinical partial response ) . T1 tumors more frequently exhibited clinical complete response ( P = 0.05 ) and showed a trend to exhibit pCR ( P = 0.07 ) . Five ( 13 % ) patients experienced grade 1 cardiac dysfunction during preoperative treatment . Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine . RNA profiling identified three top-level clusters by unsupervised analysis . Tumors with extremes of response [ pCR ( n = 3 ) versus nonresponse ( n = 3 ) ] fell into separate groups by hierarchical clustering . No predictive genes were identified in pCR tumors . Nonresponding tumors were more likely to be T4 stage ( P = 0.02 ) and express basal markers ( P < 0.00001 ) , growth factors , and growth factor receptors . Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate ( 50 % versus 97 % ; P = 0.001 ) . Conclusions : Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive , operable , stage II/III breast cancer . HER2-overexpressing tumors with a basal-like phenotype , or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways , are more likely to be resistant to this regimen BACKGROUND It is unknown how a very high tumor total HER2 ( human epidermal growth factor receptor-2 ) content ( H2 T ) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy .  PATIENTS AND METHODS H2 T was measured using a novel quantitative assay ( HERmark ( ® ) ) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial ( IS RCT N76560285 ) . In a chromogenic in situ hybridization ( CISH ) test , 197 ( 21.9 % ) patients had HER2-positive cancer and were r and omly assigned to receive trastuzumab or control .  RESULTS Cancer H2 T levels varied 1808-fold . High H2 T levels were correlated with a positive HER2 status by CISH ( P < 0.0001 ) . A nonlinear association was present between H2 T and the hazard of distant recurrence in a sub population treatment effect pattern plot analysis in CISH-positive disease . Patients with very high H2 T ( defined by ≥22-fold the median of HER2-negative cancers ; 13 % of CISH-positive cancers ) did not benefit from adjuvant trastuzumab [ hazard ratio ( HR ) 1.23 ; 95 % confidence interval ( CI ) 0.33 - 4.62 ; P = 0.75 ] , whereas the rest of the patients with HER2-positive disease by CISH ( 87 % ) did benefit ( HR 0.52 ; 95 % CI 0.28 - 1.00 ; P = 0.050 ) . CONCLUSION Patients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content PURPOSE To determine whether ( 1 ) immunohistochemical ( IHC ) HER2 status ( ie , 2 + or 3 + ) , ( 2 ) degree of fluorescence in situ hybridization ( FISH ) amplification according to ( 2a ) HER2/CEP17 ratio or ( 2b ) HER2 gene copy number , or ( 3 ) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 ( HER2 ) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy .  PATIENTS AND METHODS IHC and /or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry . FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival ( DFS ) after a median 2 years of follow-up . RESULTS Central FISH results were available for 2,071 ( 61 % ) of the 3,401 patients r and omized to the 2 arms . Among patients with FISH-positive disease , ( 1 ) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 ( 95 % CI , 0.32 to 0.99 ) for locally IHC2 + cases ( n = 340 ) and 0.80 ( 95 % CI , 0.40 to 1.61 ) for central ly IHC2 + cases ( n = 299 ) . There was no significant prognostic relationship between ( 2a ) HER2 FISH ratio , ( 2b ) HER2 copy number , or ( 3 ) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab . CONCLUSION There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases . The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy BACKGROUND Trastuzumab , a recombinant monoclonal antibody against HER2 , has clinical activity in advanced breast cancer that overexpresses HER2 . We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy . METHODS This international , multicenter , r and omized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy .  RESULTS Data were available for 1694 women r and omly assigned to two years of treatment with trastuzumab , 1694 women assigned to one year of trastuzumab , and 1693 women assigned to observation .  We report here the results only of treatment with trastuzumab for one year or observation . At the first planned interim analysis ( median follow-up of one year ) , 347 events ( recurrence of breast cancer , contralateral breast cancer , second nonbreast malignant disease , or death ) were observed : 127 events in the trastuzumab group and 220 in the observation group . The unadjusted hazard ratio for an event in the trastuzumab group , as compared with the observation group , was 0.54 ( 95 percent confidence interval , 0.43 to 0.67 ; P<0.0001 by the log-rank test , crossing the interim analysis boundary ) , representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points . Overall survival in the two groups was not significantly different ( 29 deaths with trastuzumab vs. 37 with observation ) . Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab . CONCLUSIONS One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer . ( Clinical Trials.gov number , NCT00045032 . 
    Output:
    
HER2 amplification level is not a prognostic factor for HER2-positive breast cancer with trastuzumab-based targeted therapy in the clinical adjuvant setting