***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: Introduction To investigate the predictive value of clinical and biological markers for a pathological complete remission after a preoperative dose-dense regimen of doxorubicin and docetaxel , with or without tamoxifen , in primary operable breast cancer . Methods Patients with a histologically confirmed diagnosis of previously untreated , operable , and measurable primary breast cancer ( tumour ( T ) , nodes ( N ) and metastases ( M ) score : T2 - 3(≥ 3 cm ) N0 - 2 M0 ) were treated in a prospect ively r and omised trial with four cycles of dose-dense ( bi-weekly ) doxorubicin and docetaxel ( ddAT ) chemotherapy , with or without tamoxifen , prior to surgery . Clinical and pathological parameters ( menopausal status , clinical tumour size and nodal status , grade , and clinical response after two cycles ) and a panel of biomarkers ( oestrogen and progesterone receptors , Ki-67 , human epidermal growth factor receptor 2 ( HER2 ) , p53 , bcl-2 , all detected by immunohistochemistry ) were correlated with the detection of a pathological complete response ( pCR ) . Results A pCR was observed in 9.7 % in 248 patients r and omised in the study and in 8.6 % in the subset of 196 patients with available tumour tissue .  Clinical ly negative axillary lymph nodes , poor tumour differentiation , negative oestrogen receptor status , negative progesterone receptor status , and loss of bcl-2 were significantly predictive for a pCR in a univariate logistic regression model , whereas in a multivariate analysis only the clinical nodal status and hormonal receptor status provided significantly independent information . Backward stepwise logistic regression revealed a response after two cycles , with hormone receptor status and lymph-node status as significant predictors . Patients with a low percentage of cells stained positive for Ki-67 showed a better response when treated with tamoxifen , whereas patients with a high percentage of Ki-67 positive cells did not have an additional benefit when treated with tamoxifen . Tumours overexpressing HER2 showed a similar response to that in HER2-negative patients when treated without tamoxifen , but when HER2-positive tumours were treated with tamoxifen , no pCR was observed . Conclusion Reliable prediction of a pathological complete response after preoperative chemotherapy is not possible with clinical and biological factors routinely determined before start of treatment . The response after two cycles of chemotherapy is a strong but dependent predictor . The only independent factor in this subset of patients was bcl-2.Trial registration Our aim was to determine whether biological molecular markers can predict response to  neoadjuvant chemoendocrine therapy  in patients with early breast cancer . Ninety patients ( median age 56 years ; range , 28 - 69 years ) with primary operable breast carcinoma were studied . They were treated with four 3-weekly cycles of chemotherapy with mitozantrone , methotrexate ( + /- mitomycin C ) , and tamoxifen prior to surgery . Fine-needle aspiration was used to obtain sample s from patients prior to therapy , and the following parameters were assessed : estrogen receptor ( ER ) , progesterone receptor ( PgR ) , p53 , Ki67 , Bcl-2 , and c-erbB-2 measured by immunocytochemistry , and ploidy and S-phase fraction ( SPF ) by flow cytometry . The tumors of 78 % of the subjects responded ( complete response , 9 % ; partial response , 69 % ) and 22 % did not ( no change , 20 % ; progressive disease , 2 % ) . Response rates according to disease stage and patient age were as follows : T1 , 74 % ; T2 , 79 % ; T3/T4 , 78 % ; age < /=50 years , 76 % ; > 50 , 79 % ( P = not significant ) . Response rates for other parameters were as follows : ER-positive , 82 % , and -negative , 70 % ; PgR-positive , 86 % , and -negative , 71 % ; p53-positive , 74 % , and -negative , 81 % ; Bcl-2-positive , 85 % , and -negative 61 % ; c-erbB-2-positive , 57 % , and -negative , 93 % ; Ki67 high , 77 % , and low , 81 % ; SPF high , 77 % , and low , 77 % ; aneuploid , 71 % ; and diploid , 85 % . Only the difference for c-erbB-2 was statistically significant ( P = 0.007 ) . A trend for higher response rates to neoadjuvant chemoendocrine therapy for tumors that were positive for ER , PgR , and Bcl-2 was observed but did not reach statistical significance . Tumors negative for c-erbB-2 had a higher response rate , which was statistically significant . In contrast , Ki67 , ploidy , SPF , and p53 failed to predict for response INTRODUCTION Response to neoadjuvant chemotherapy for locally advanced breast cancer can be correlated with long-term outcomes . Surrogate end-point biomarkers may be used to assess response to the treatment . Most reported studies assessed the effects of combination chemotherapy . We assessed the feasibility of obtaining serial core breast biopsies , and correlated rates of apoptosis , proliferation , and expression of related proteins at baseline , during , and after neoadjuvant single agent chemotherapy for locally advanced breast cancer with response . EXPERIMENTAL DESIGN Women with a histologically confirmed unresected T(3 ) or T(4 ) infiltrating carcinoma of the breast were eligible . The first 20 patients received three cycles of doxorubicin 90 mg/m(2 ) followed by three cycles of paclitaxel 250 mg/m(2 ) , or the reverse . Nine women received four cycles of each ( doxorubicin 60 mg/m(2 ) and paclitaxel 175 mg/m(2 ) ) . Cycles were administered 14 days apart with filgastrim . End points included : ( a ) . clinical and pathological response ; ( b ) . serial apoptotic [ terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling ] and proliferation ( immunohistochemistry , IHC ) rates ; and ( c ) . expression ( IHC ) of estrogen receptor , HER2 , bcl2 , and p53 .  RESULTS From April 1997 to June 2001 , 29 women were r and omized . Twelve patients ( 42 % ) had a clinical complete response ( cCR ) , and 16 ( 55 % ) had a clinical partial response . Five women ( 17 % ) had a pathological complete response , 7 ( 24 % ) had microscopic residual disease , and 17 ( 58 % ) had macroscopic residual disease . Higher baseline apoptosis and proliferation were associated with an improved pathological response ( P = 0.006 and 0.003 , respectively ) . Among 14 evaluable patients , apoptosis increased in women who had a cCR to the first agent but not in women without a cCR . Estrogen receptor-positive patients had a worse pathological response ( P = 0.004 ) . CONCLUSIONS The selected regimen is efficacious . It is feasible to obtain serial core biopsies that are informative for studies of apoptosis and IHC . This clinical design can serve as a model for combining st and ard chemotherapy and novel agents BACKGROUND Biological considerations support the use of primary chemotherapy in operable breast cancer ; and despite wide variations of used regimens , clinical studies consistently show a significant tumor response allowing breast conservation in many patients otherwise c and i date s for mastectomy . We investigated the efficacy and the acceptance of a combination chemotherapy with vinorelbine , 5-fluorouracil and high-dose folinic acid in operable breast cancer with favorable prognostic factors and tested the relationship of hormone receptor status , Ki67,p53 , c-erbB2 and bcl-2 with treatment response . PATIENTS AND METHODS Thirty-nine patients ( median age 51 years , range 36 - 71 years ) , eight with T1 , twenty-eight with T2 and two with T3 lesions , were treated with 5-fluorouracil ( 350 mg/m2 , i.v . on day 1 to 3 ) preceded by folinic acid ( 100 mg/m2 i.v . on day 1 to 3 ) and vinorelbine , given on days 1 and 3 at the dose of 20 mg/m2 ( FLN regimen ) . Therapy was administered on an outpatient basis every three weeks . Non responders had surgery after three courses , while complete or partial responders underwent surgery after six courses . All but one were evaluable for response and toxicity . RESULTS Objective responses were observed in 23 of the 38 evaluable patients ( 61 % ; 95 % CI : 46%-76 % ) : three complete responses ( 8 % ) and 20 partial responses ( 53 % ) . Fifteen patients ( 39 % ) had stable disease , of whom nine ( 23 % ) had minor response . None of the patients had disease progression during treatment . Objective responses were significantly associated with no expression of estrogen and /or progesterone receptors and > 50 % decrease in Ki67 after induction chemotherapy . Tolerance was excellent and none of the patients experienced grade 2 alopecia . CONCLUSIONS The ' moderate ' efficacy of this regimen might be partially due to the selection of patients with high expression of steroid hormone receptors and low proliferation rate , which have an unfavorable impact on response to this chemotherapy Aim : To evaluate the relationship between apoptosis induced by chemotherapy and clinical response in breast cancer . Methods : Apoptosis index ( AI ) , mutant p53 and Bcl‐2 protein expression were evaluated in 44 breast tumour sample s from patients su bmi tted to neoadjuvant chemotherapy .  Objective response ( OR ) to primary chemotherapy was observed in 37 patients ( 84 % ) and no response ( NR ) in seven . AI was measured by the rate of apoptotic cells identified using morphological criteria . p53 and Bcl‐2 protein expression were evaluated using an immunoperoxidase staining technique . Results : The median AI change observed between pre‐chemotherapy AI and post‐chemotherapy AI was 0.84 in the OR group and 0.01 in the NR group , ( rho = 0.4 ; p = 0.006 ) . There was no change in Bcl‐2 protein expression  following chemotherapy . In the OR group , p53 protein expression was positive in 41.6 % of patients before and in 22.2 % after chemotherapy ( difference = 16.6 % ; p = 0.03 ) . No change was detected in the NR group . Conclusion : A positive correlation was found between the increase in AI and clinical response to neoadjuvant chemotherapy in locally advanced breast cancer Abstract Purpose . Primary chemotherapy is commonly used in patients with breast cancer to downstage the primary tumour prior to surgery . There is a need to establish , prior to commencement of chemotherapy , predictors of clinical and pathological response , which may then be surrogate markers for patient survival and thus allow identification of patients who are most likely to benefit from such treatment . Patients and methods . A total of 104 patients with large and locally advanced breast cancers received an anthracycline/docetaxel-based regimen  prior to surgery . Immunohistochemistry was carried out on pre-treatment core biopsies of the tumour to detect hormone receptors ( oestrogen-ER ; progesterone-PR ) , a proliferation marker ( MIB-1 ) , the oncoprotein Bcl-2 , an extracellular matrix degradation enzyme ( cathepsin D ) , p53 , and an oestrogen associated protein ( pS2 ) . Both clinical and pathological response were assessed following completion of chemotherapy . Results . Patients whose tumours did not express oestrogen receptor ( p= 0.02 ) or did not express Bcl-2 ( p < 0.01 ) had a better pathological response in a univariate analysis . However , in a multivariate model , it was only the absence of detectable Bcl-2 protein that predicted a better pathological response ( p= 0.001 ) . Conclusions . This study has identified that patients whose breast cancers are most likely to experience the greatest degree of tumour destruction by primary chemotherapy do not express either oestrogen receptors or Bcl-2 . This may have important implication s in the selection of patients with breast cancer for primary chemotherapy who are most likely to gain a survival benefit TP53 status [ mutations , immunostaining , and loss of heterozygosity ( LOH ) ] , expression of c-erbB-2 , bcl-2 , and histological grading were correlated to the response to doxorubicin monotherapy ( 14 mg/m2 ) administered weekly to 90 patients with locally advanced breast cancer . Mutations in the TP53 gene , in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein , were associated with lack of response to chemotherapy ( P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3 , respectively ) . Similarly , expression of c-erbB-2 ( P = 0.041 ) , a high histological grade ( P = 0.023 ) , and lack of expression of bcl-2 ( P = 0.018 ) all predicted chemoresistance . No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded , 
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Besides , negative Bcl-2 expression was significantly associated with good OR and pathological CR in anthracycline-based chemotherapy subgroup .
Furthermore , there were significant links between negative Bcl-2 expression and  taxane-based chemotherapy with pathological CR , but not OR .
Conclusion The results of the present meta- analysis suggest that Bcl-2 expression is a predictive factor for chemotherapy sensitivity in breast cancer patients .
They could also potentially benefit further clinical treatment for breast cancers