***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 The proliferation marker Ki67 has been suggested as a promising cancer biomarker . As Ki67 needs an exact quantification , this marker is a prototype of a new generation of tissue-based biomarkers . In this study , we have systematic ally evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort . PATIENTS AND METHODS We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial . We used the st and ardized cutoff-finder algorithm for three end points [ response to neoadjuvant chemotherapy ( pCR ) , disease-free ( DFS ) and overall-survival ( OS ) ] . The analyses were stratified for hormone receptor ( HR ) and HER2 status by molecular subtype radar diagrams ( MSRDs ) . RESULTS A wide range of Ki67 cut points between 3%-94 % ( for pCR ) , 6%-46 % ( for DFS ) and 4%-58 % ( for OS ) were significant . The three groups of Ki67 ≤ 15 % versus 15.1%-35 % versus > 35 % had pCR-rates of 4.2 % , 12.8 % , and 29.0 % ( P < 0.0005 ) , this effect was also present in six of eight molecular subtypes . In MSRD , Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive , but not triple-negative tumors . CONCLUSIONS Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data -derived cut point optimization might not be possible . Ki67 could be used as a continuous marker ; in addition , the scientific community could define st and ardized cut points for Ki67 . Our analysis explains the variability observed for Ki67 cut points in previous studies ; however , this should not be seen as weakness , but as strength of this marker . MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer . The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers BACKGROUND The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy . METHODS Tumor sample s were obtained at baseline and at the end of treatment from 185 patients participating in a double blind r and omized Phase III study of neoadjuvant endocrine therapy .  These paired specimens were simultaneously analyzed for Ki67 , ER , progesterone receptor ( PgR ) , trefoil factor 1 ( PS2 ) , HER1 ( epidermal growth factor receptor ) , and HER2 ( ErbB2 or neu ) by semiquantitative immunohistochemistry . RESULTS The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole ( 87 % ) than tamoxifen ( 75 % ; analysis of covariance P = 0.0009 ) . Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and /or HER2 ( 88 versus 45 % , respectively ; P = 0.0018 ) . Twenty-three of 92 tumors ( 25 % ) on tamoxifen and 14 of 93 on letrozole ( 15 % ) showed a paradoxical increase in Ki67 with treatment , and the majority of these cases was HER1/2 negative . Letrozole , but not tamoxifen , significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1 , regardless of HER1/2 status ( P < 0.0001 ) . ER down-regulation occurred with both agents , although levels decreased more with tamoxifen ( P < 0.0001 ) . CONCLUSION Letrozole inhibited tumor proliferation to a greater extent than tamoxifen . The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2 + and HER1/2- tumors . A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented . This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells Background Expression of aromatase by malignant breast epithelial cells and /or the surrounding stroma implies local estrogen production that could influence the outcome of endocrine therapy for breast cancer . Methods A vali date d immunohistochemical assay for aromatase was applied to sample s from the P024 neoadjuvant endocrine therapy trial that compared tamoxifen and letrozole . The presence of aromatase expression by tumor or stromal cells was correlated with tumor response , treatment induced changes in proliferation index ( Ki67 ) , relapse-free survival ( RFS ) and breast cancer-specific survival ( BCSS ) . Results Tumor and stromal aromatase expression were highly correlated ( P = 0.0001 ) . Tumor cell aromatase , as a semi-continuous score , also correlated with smaller tumor size at presentation ( P = 0.01 ) higher baseline ER Allred score ( P = 0.006 ) and lower Ki67 levels ( P = 0.003 ) . There was no significant relationship with clinical response or treatment-induced changes in Ki67 . However , in a Cox multivariable model that incorporated a post-treatment tumor profile ( pathological T stage , N stage , Ki67 and ER status of the surgical specimen ) , the presence of tumor aromatase expression at baseline sample remained a favorable independent prognostic biomarker for both RFS ( P = 0.01 , HR 2.3 , 95 % CI 1.2–4.6 for absent expression ) and BCSS ( P = 0.008 , HR 3.76 , 95 % CI 1.4–10.0 ) . Conclusions Autocrine estrogen synthesis may be most characteristic of smaller , more indolent and ER-rich breast cancers with lower baseline growth rates . However , response to endocrine treatment may not depend on whether the estrogenic stimulus has a local versus systemic source Background : The National Epirubicin Adjuvant Trial ( NEAT ) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide , methotrexate and 5-fluorouracil ( E-CMF ) compared with st and ard CMF in adjuvant chemotherapy for women with early breast cancer . This report details longer follow-up with interesting additional time-dependent analyses . Methods : National Epirubicin Adjuvant Trial used epirubicin ( E ) 3-weekly for four cycles followed by classical ( c ) CMF for four cycles ( E-CMF ) compared with cCMF for six cycles . BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles , compared with CMF 3-weekly for eight cycles . Results : In all , 2391 eligible patients were r and omised and with a median 7.4-year follow-up , E-CMF confirmed a significant benefit over CMF in both relapse-free survival ( RFS ) ( 78 % vs 71 % 5 years RFS , respectively , hazard ratio (HR)=0.75 ( 95 % CI : 0.65–0.86 ) , P<0.0001 ) and overall survival ( OS ) ( 84 % vs 78 % 5 years OS , respectively , HR=0.76 ( 95 % CI : 0.65–0.89 ) , P=0.0007 ) . Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration ( Ch17CEP ) as previously reported . Poor prognostic factors at diagnosis ( ER and PR negative and HER2 positive ) showed time-dependent annual hazard rates for RFS and OS . In univariate analysis , these factors demonstrated more favourable HRs for RFS after 5 years . Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours . Conclusion : Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients . Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction . St and ard poor prognostic factors at diagnosis were time-dependent , and after 5 years disease-free , poor prognosis patients demonstrated favourable HRs for survival 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 : We have shown that DNA methylation of the PITX2 gene predicts risk of distant recurrence in steroid hormone receptor-positive , node-negative breast cancer . Here , we present results from a multicenter study investigating whether PITX2 and other c and i date DNA methylation markers predict outcome in node-positive , estrogen receptor-positive , HER-2-negative breast cancer patients who received adjuvant anthracycline-based chemotherapy .  Experimental Design : Using a microarray platform , we analyzed DNA methylation in regulatory regions of PITX2 and 60 additional c and i date genes in 241 breast cancer specimens . Using Cox regression analysis , we assessed the predictive power of the individual marker/marker panel c and i date s. Clinical endpoints were time to distant metastasis , disease-free survival , and overall survival . A nested bootstrap/cross-validation strategy was applied to identify and vali date marker panels . Results : DNA methylation of PITX2 and 14 other genes was correlated with clinical outcome . In multivariate models , each methylation marker added significant information to established clinical factors . A four-marker panel including PITX2 , BMP4 , FGF4 , and C20orf55 was identified that result ed in improvement of outcome prediction compared with PITX2 alone . Conclusions : This study provides further evidence for the PITX2 biomarker , which has now been successfully confirmed to predict outcome among different breast cancer patient population s. We further identify new DNA methylation biomarkers , three of which can be combined into a panel with PITX2 to increase the outcome prediction performance in our anthracycline-treated primary breast cancer population . Our results show that a well-defined panel of DNA methylation markers enables outcome prediction in lymph node-positive , HER-2-negative breast cancer patients treated with anthracycline-based chemotherapy Abstract This r and omized , multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide ( FEC ) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker . Patients were r and omized to 4 cycles of docetaxel/capecitabine ( docetaxel : 75 mg/m2 on day 1 ; capecitabine : 1,650 mg/m2 on days 1–14 every 3 weeks ) or docetaxel alone ( 75 mg/m2 on day 1 
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The use of these prognostic biomarkers should increase the options available for treatment algorithms