***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 Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response ( pCR ) after neoadjuvant chemotherapy differ among breast cancer subtypes . Methods Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy ( four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks ) between 2006 and 2011 were retrospectively analyzed .  Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer . Expression of estrogen receptor ( ER ) , progesterone receptor ( PgR ) , HER2 , and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens . Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype . Results Of 64 patients , 30 ( 47 % ) were ER-positive ( ER+ ) HER2-negative ( HER2− ) , including eight as luminal A ( Ki67 labeling index ( LI ) < 14 % ) and 22 as luminal B ( Ki67 LI ≥ 14 % ) subtypes , 11 ( 17 % ) were ER+ HER2-positive ( HER2 + ) , 12 ( 19 % ) were ER-negative ( ER− ) HER2 + , and 11 ( 17 % ) were ER− HER2−. The clinical response rates were significantly higher in luminal B , ER+ HER2 + , and ER− HER2 + subtypes compared with luminal A subtype . Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy  . Ki67 LI was a predictive marker for pCR , and all patients whose tumors achieved pCR are currently disease-free . Furthermore , high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype . Conclusions It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy PURPOSE This is one of the first reports of weekly docetaxel ( Taxotere ) in the neoadjuvant treatment of stage II and III breast cancer . We evaluated docetaxel 's  efficacy and safety and analyzed correlations between response and the expression of c-erbB2 , ER status , and Ki-67 labeling index . EXPERIMENTAL DESIGN Patients with previously untreated , stage II and III breast cancer were entered into the study .  Docetaxel ( 40 mg/m(2 ) ) was given i.v . once weekly for the first 6 weeks of an 8-week cycle for 2 cycles . RESULTS A total of 56 patients were evaluated by intention-to-treat analysis for efficacy and safety . The overall clinical response rate was 68 % ( complete and partial response , 29 and 39 % , respectively ) . Nine patients ( 16 % ) achieved a pathological complete response . There was no correlation between response to docetaxel and the expression of molecular markers , however , the majority of the pathological complete responses were observed in patients with c-erbB2-negative tumors .  Nonhematological toxicity was more common than hematological toxicity , with alopecia and asthenia the most frequently reported adverse events ( 89 and 77 % of patients , respectively ) . Severe hematological toxicity was rare . CONCLUSIONS Weekly docetaxel appears to be very effective in the neoadjuvant setting . A high pathological response rate was achieved with tolerable toxicity 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 every 3 weeks ) after completion of 4 cycles of FEC ( 5-fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks ) . The primary endpoint was the pathological complete response ( pCR ) rate . Predictive factor analysis was conducted using clinicopathological markers , including hormone receptors and Ki67 labeling index ( Ki67LI ) . A total of 477 patients were r and omized ; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 % , respectively . There were no significant differences in the pCR rate  ( docetaxel/capecitabine : 23 % ; docetaxel : 24 % ; p = 0.748 ) , disease-free survival , or overall survival . However , patients with mid-range Ki67LI ( 10–20 % ) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone . Furthermore , multivariate logistic regression analysis showed pre-treatment Ki67LI ( odds ratio 1.031 ; 95 % CI 1.014–1.048 ; p = 0.0004 ) to be a significant predictor of pCR in this neoadjuvant treatment setting . Docetaxel/capecitabine ( after 4 cycles of FEC ) did not generate significant improvement in pCR compared to docetaxel alone . However , exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer BACKGROUND Combinations of anthracyclines , taxanes and gemcitabine have shown high activity in breast cancer . This trial was design ed to evaluate a modified combination regimen as primary chemotherapy . Non-pegylated liposomal doxorubicin ( NPLD ) was used instead of conventional doxorubicin to improve cardiac safety .  Gemcitabine was given 72 h after NPLD and docetaxel as a prolonged infusion over 4 h in order to optimize synergistic effects and accumulation of active metabolites . PATIENTS AND METHODS Forty-four patients with histologically confirmed stage II or III breast cancer were treated with NPLD ( 60 mg/m(2 ) ) and docetaxel ( 75 mg/m(2 ) ) on day 1 and gemcitabine as 4-h infusion ( 350 mg/m(2 ) ) on day 4 . Treatment was repeated every 3 weeks for a maximum of six cycles . All patients received prophylactically recombinant granulocyte colony-stimulating factor .  Patients with axillary lymph node involvement after primary chemotherapy received adjuvant treatment with cyclophosphamide , methotrexate and fluorouracil . RESULTS The clinical response rate was 80 % , and complete remissions of the primary tumor occurred in 10 patients ( 25 % ) . Breast conservation surgery was performed in 19 out of 20 patients ( 95 % ) with an initial tumor size of less than 3 cm and in 14 patients ( 70 % ) with a tumor size < or=3 cm . Seven patients had histologically confirmed complete responses accounting for a pCR rate of 17.5 % . Expression of Ki--67 was the most important predictive parameter for response with high 38.9 % breast pCR rate in patients with elevated Ki--67 expression . Although the predominant toxicity was myelosuppression with grade 3/4 neutropenia in 61 % of patients few neutropenic complications result ed . Non-hematological toxicity was generally moderate with grade 3 or 4 toxicity in 10.0 % of cycles . Most common non-hematologic toxicities were nausea , vomiting , alopecia , mucositis , asthenia and elevation of liver enzymes . CONCLUSION The evaluated schedule provides a safe and highly effective combination treatment for patients with early breast cancer , which is suitable for phase III studies PURPOSE OF THE STUDY Trastuzumab combined with sequential chemotherapy with taxanes and anthracyclines as primary systemic therapy achieved high rates of pathologic complete response ( pCR ) .  Non-pegylated liposome-encapsulated doxorubicin ( NPLD ) has shown equal efficacy but minor cardiotoxicity compared to doxorubicin . This phase II study aim ed to evaluate the activity and safety of trastuzumab with sequential chemotherapy for early or locally advanced HER2 positive BC . METHODS Preoperative treatment included NPLD ( 60 mg/mq iv ) plus cyclophosphamide ( 600 mg/mq iv ) every 3 weeks for 4 cycles followed by docetaxel ( 35 mg/mq iv ) plus trastuzumab ( 4 mg/mq loading dose iv , then 2 mg/mq iv ) weekly for 16 weeks . Primary endpoint was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes . Clinical staging was exploratory evaluated by CT-PET . RESULTS 43 pts were treated from december 2005 to September 2011 , 39 of them were evaluable for the purpose of study . Median age was 53 years ( range : 31 - 78 ) , the majority of pts had tumour stage cT2 ( 63 % ) , tumour grade 3 ( 86 % ) , clinical nodes involvement N+ ( 77 % ) , ER positive ( 56 % ) and Ki-67 ≥20 % ( 77 % ) . pCR was reported in 19 ( 49 % ) of 39 pts . There was an association between Ki-67 ≥20 % at baseline and pCR ( p = 0.018 ) . No cardiac toxicity or discontinuation of trastuzumab was reported . CT-PET modified the clinical stage for 10 patients showing new loco-regional lymph nodes . CONCLUSIONS This study confirms that integrating anti-HER2 therapy in primary treatment for HER2 positive breast cancer is active . NPLD is a safe option to minimize cardiotoxicity Oestrogen receptor ( ER ) negative breast cancers are more likely to achieve a pathological complete response ( pCR ) to neoadjuvant chemotherapy compared to those with ER positive tumours . ER positive tumours exhibit low proliferation and ER negative cancers high proliferation . The aim of this study was to determine to what extent the better response of ER negative cancers correlates with proliferation rate . A retrospective analysis of a prospect ively maintained data base identified 175 neoadjuvant chemotherapy patients with tissue available for Ki67 analysis . On univariate analysis , pre-therapy Ki67 ( P = 0.04 ) , ER status ( P = 0.002 ) , HER2 status ( P = 0.004 ) and grade ( P = 0.0009 ) were associated with a pCR . In a multivariate model , HER2 was the only significant predictor of pCR . No significant relationship between pre-therapy Ki67 and relapse-free and overall survival was demonstrated . Ki67 is not an independent predictor of clinical CR or pCR . Aspects of 
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Ki-67 could predict pCR in those who received anthracyclines plus taxanes , and anthracyclines only , and those from Asia and Europe .
High Ki-67 before NAC was a predictor for pCR in neoadjuvant setting for breast cancer patients