title: Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902 BCIRG 001 Molecular Analysis: Prognostic Factors in Node-Positive Breast Cancer Patients Receiving Adjuvant Chemotherapy Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. WSG ADAPT – adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Evaluation of microtubule-associated protein-Tau expression as a prognostic and predictive marker in the NSABP-B 28 randomized clinical trial. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study. NEAT: National Epirubicin Adjuvant Trial – toxicity, delivered dose intensity and quality of life Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer--results at the time of surgery. 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Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601). FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan Taxane-induced peripheral neuropathy and health-related quality of life in postoperative breast cancer patients undergoing adjuvant chemotherapy: N-SAS BC 02, a randomized clinical trial Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial Comparison of predictive and prognostic impact of molecular subtypes and central grade regarding taxane-based therapy in intermediate-risk breast cancer: Results from the EC-Doc trial. Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study. Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. Comparison of EQ-5D scores among anthracycline-containing regimens followed by taxane and taxane-only regimens for node-positive breast cancer patients after surgery: the N-SAS BC 02 trial. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Benefit from anthracyclines in relation to biological profiles in early breast cancer Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1–3 node-positive rapidly proliferating breast cancer Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. The SUCCESS-C trial: Interim analysis of toxicity evaluating the role of an anthracycline-free chemotherapy regimen in the adjuvant treatment of HER2/neu-negative breast cancer. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosi Prospective randomized trial of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus paclitaxel and FAC (TFAC) in patients with operable breast cancer: impact of taxane chemotherapy on locoregional control A phase III randomized trial of metformin versus placebo on recurrence and survival in early-stage breast cancer (BC) (NCIC Clinical Trials Group MA.32). Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high‐risk, premenopausal breast cancer Six cycles of doxorubicin and cyclophosphamide or Paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. Menstrual history and quality-of-life outcomes in women with node-positive breast cancer treated with adjuvant therapy on the NSABP B-30 trial. Randomized, phase III study of adjuvant doxorubicin plus cyclophosphamide (AC) → docetaxel (T) with or without capecitabine (X) in high-risk early breast cancer: Exploratory Ki-67 analyses. 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S0221: Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an anglo-celtic cooperative oncology group study. Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control of node-positive breast cancer: cancer and leukemia group B 9344. First analysis of SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early breast cancer. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Adjuvant chemotherapy in older women with early-stage breast cancer. A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant treatment of early breast cancer. Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000). A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study.
abstract: BACKGROUND A r and omized phase III trial in high-risk breast cancer patients was conducted , to further explore the impact of dose-density in the adjuvant treatment for breast cancer . The safety analysis is presented . PATIENTS AND METHODS From October 2000 until June 2005 , 1121 node-positive patients were r and omized to sequential dose-dense epirubicin 110 mg/m(2 ) and paclitaxel ( Taxol , Bristol Myers-Squibb , Princeton , New Jersey , USA ) 250 mg/m(2 ) ( group A ) , or concurrent epirubicin 83 mg/m(2 ) and paclitaxel 187 mg/m(2 ) ( group B ) , both followed by three cycles of ' intensified ' combination chemotherapy with cyclophosphamide , methotrexate and fluorouracil ( CMF ) . Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments . RESULTS Median dose intensity of epirubicin and paclitaxel was double in group A , as design ed , with significantly less cycles administered at full dose ( P < 0.001 ) . Median cumulative dose of all drugs and total treatment duration , however , were identical between groups . Severe taxane-related toxic effects were more frequent in group A , while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects , including febrile neutropenia . The rates of secondary malignancies were low . CONCLUSION Both regimens as used in the present study are well tolerated and safe . The rates of severe taxane-related toxic effects and thrombocytopenia , although low overall , are significantly increased with the dose-dense sequential regimen Introduction The Preoperative Chemotherapy in Primary Operable Breast Cancer ( POCOB ) study was design ed to compare preoperative with postoperative chemotherapy in patients with early breast cancer concerning breast conserving therapy ( BCT ) procedures ,  disease free survival ( DFS ) and overall survival ( OS ) . Methods Patients ( n = 698 ) with early breast cancer were enrolled between 1991 and 1999 and r and omized between  preoperative versus postoperative chemotherapy ( four cycles of fluorouracil , epirubicin , and cyclophosphamide ) . Endpoints were BCT procedures , DFS , OS , and tumor response to preoperative chemotherapy .  In addition , tumor tissue was collected for translational research and the following markers were examined : ER , PgR , HER2 , p21 , p53 , and bcl-2 expression . Results With a median follow-up of 10 years , there was no statistically significant difference between the two treatment arms for OS ( HR = 1.09 ; 95%CI 0.83–1.42 ; P = 0.54 ) , DFS ( HR = 1.12 ; 95%CI 0.90–1.39 ; P = 0.30 ) , or locoregional recurrences ( LRR , HR = 1.16 ; 95%CI 0.77–1.74 ) . Preoperative chemotherapy was associated with an increase in BCT rates . BCT in part feasible due to tumor downsizing after preoperative chemotherapy was not correlated with higher LRR or worse OS compared to BCT which was feasible without downsizing of the tumor . Using available tumor material , only tumor stage , nodal stage , and grade were independent prognostic factors for overall survival . Conclusions Preoperative chemotherapy does not result in a difference in OS or DFS compared to postoperative chemotherapy in patients with early breast cancer . Moreover , it increases BCT rates with no significant increase of LRR . This implies that preoperative chemotherapy is a safe procedure for patients with early breast cancer , even after a follow-up period of 10 years Purpose : There are currently no vali date d factors predictive of response to taxanes in patients with breast cancer . We analyzed specimens from patients included in the Breast Cancer International Research Group ( BCIRG ) 001 trial , a r and omized study which showed the superiority of docetaxel/doxorubicin/cyclophosphamide over fluorouracil/doxorubicin/cyclophosphamide as adjuvant therapy for node-positive operable breast cancer in terms of disease-free survival ( DFS ) and overall survival ( OS ) . Experimental Design : Immunohistochemical assessment of biological markers included histologic grade , tumor size , estrogen and progesterone receptors , lymph node status , HER2 , MUC1 , Ki-67/MIB-1 , p53 , Bcl-2 , Bax , Bcl-XL , BAG-1 , β-tubulin isotypes II , III and IV , τ protein , and detyrosinated α tubulin . Associations between selected parameters and survival were tested through univariate analyses , then completed with multivariate analyses and a bootstrap resampling technique . Results : In univariate analysis histologic grade , tumor size , number of involved nodes , estrogen and progesterone receptor status , p53 , Ki-67 , tubulin III , and τ protein were associated both with DFS and with OS . In multivariate analysis estrogen and progesterone receptors , tumor size , number of involved nodes , and Ki-67 protein were associated both with DFS and with OS , whereas τ protein levels were correlated with DFS and tubulin III and P53 were correlated with OS . No interaction was observed between Ki-67 and treatment allocation . Conclusions : We conclude that the expression in primary tumors of Ki-67 and p53 protein , as well as of the microtubule-related parameters τ protein and tubulin III , are independent prognostic factors in patients receiving adjuvant chemotherapy  for node-positive breast cancer but are not predictive of benefit from docetaxel-containing adjuvant chemotherapy . Clin Cancer Res ; 16(15 ) ; 3988–97 . © 2010 AACR PURPOSE Capecitabine is an active agent in the treatment of breast cancer . It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane , an anthracycline , and cyclophosphamide improves outcome in early breast cancer . PATIENTS AND METHODS Women with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive either three cycles of docetaxel and capecitabine ( TX ) followed by three cycles of cyclophosphamide , epirubicin , and capecitabine ( CEX ; n = 753 ) or three cycles of docetaxel ( T ) followed by three cycles of cyclophosphamide , epirubicin , and fluorouracil ( CEF ; n = 747 ) . The primary end point was recurrence-free survival ( RFS ) . RESULTS During a median follow-up time of 59 months , 214 RFS events occurred ( local or distant recurrences or deaths ; TX/CEX , n = 96 ; T/CEF , n = 118 ) . RFS was not significantly different between the groups ( hazard ratio [ HR ] , 0.79 ; 95 % CI , 0.60 to 1.04 ; P = .087 ; 5-year RFS , 86.6 % for TX/CEX v 84.1 % for T/CEF ) . Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF ( HR , 0.73 ; 95 % CI , 0.52 to 1.04 ; P = .080 ) . In exploratory analyses , TX/CEX improved breast cancer-specific survival ( HR , 0.64 ; 95 % CI , 0.44 to 0.95 ; P = .027 ) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis . We detected little severe late toxicity . CONCLUSION Integration of capecitabine into a regimen that contains docetaxel , epirubicin , and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine Background Adjuvant treatment decision-making based on conventional clinical /pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades . Response to therapy is currently not considered in the decision-making procedure . ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers , e.g. , Ki-67 , for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment . Methods / design The prospect i ve , multi-center , controlled , non-blinded , r and omized , investigator initiated phase II/III ADAPT trial has an innovative “ umbrella ” protocol design . The “ umbrella ” is common for all patients , consisting of dynamic testing of early therapy response .  ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany ; 4,000 patients with hormone receptor positive ( HR+ ) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial , where treatment decision is based on risk assessment and therapy response to induction therapy , and 380 patients will be included in ADAPT HER2+/HR+ . A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative . These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting . Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy , as reported by local/ central pathology for HR and HER2 status . Discussion Recent trials , such as the GeparTrio , have shown that response-guided therapy using clinical response may improve outcome . For chemotherapy or HER2-targeted treatment , pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome . For endocrine therapy , response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome . ADAPT now aims to combine static prognostic and dynamic predictive markers , focusing not just on single therapeutic targets , but also on general markers of proliferation and cell death . Biomarker analysis will help to optimize selection of subtype-specific treatment . Trial registration Clinical Trials.gov : ADAPT Umbrella : NCT01781338 ; ADAPT HR+/HER2- : NCT01779206 ; ADAPT HER2+/HR+ : NCT01745965 ; ADAPT HER2+/HR- : NCT01817452 ; ADAPT TN : NCT01815242 PURPOSE This study was design ed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a st and ard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival . PATIENTS AND METHODS After surgical treatment , 3,121 women with operable breast cancer and involved lymph nodes were r and omly assigned to receive a combination of cyclophosphamide ( C ) , 600 mg/m(2 ) , with one of three doses of doxorubicin ( A ) , 60 , 75 , or 90 mg/m(2 ) , for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2 ) . Tamoxifen was given to 94 % of patients with hormone receptor-positive tumors . RESULTS There was no evidence of a  doxorubicin dose effect . At 5 years , disease-free survival was 69 % , 66 % , and 67 % for patients r and omly assigned to 60 , 75 , and 90 mg/m(2 ) , respectively . The hazard reductions from adding paclitaxel to CA were 17 % for recurrence ( adjusted Wald chi(2 ) P = .0023 ; unadjusted Wilcoxon P = .0011 ) and 18 % for death ( adjusted P = .0064 ; unadjusted P = .0098 ) . At 5 years , the disease-free survival ( + /- SE ) was 65 % ( + /- 1 ) and 70 % ( + /- 1 ) , and overall survival was 77 % ( + /- 1 ) and 80 % ( + /- 1 ) after CA alone or CA plus paclitaxel , respectively . The effects of adding paclitaxel were not significantly different in subsets defined by the protocol , but in an unplanned subset analysis , the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 ( 95 % confidence interval , 0.59 to 0.86 ) for those with estrogen receptor-negative tumors and only 0.91 ( 95 % confidence interval , 0.78 to 1.07 ) for patients with estrogen receptor-positive tumors , almost all of whom received adjuvant tamoxifen . The additional toxicity from adding four cycles of paclitaxel was generally modest . CONCLUSION The addition of four cycles of paclitaxel after the completion of a st and ard course of CA improves the disease-free and overall survival of patients with early breast cancer PURPOSE We assessed Tau protein expression in primary breast cancer specimens of patients included in the National Surgical Breast and Bowel Project ( NSABP ) -B 28 clinical trial . Expression levels were correlated with disease-free survival ( DFS ) and overall survival ( OS ) . Interaction between this marker and paclitaxel efficacy was also examined . METHODS Tissue microarrays were available for 1,942 patients ( 63 % of all trial participants ) who were r and omly assigned to receive either four courses of doxorubicin and cyclophosphamide ( AC ) or AC followed by four courses of adjuvant paclitaxel chemotherapy . All patients who were hormone receptor positive received adjuvant  endocrine therapy . Immunohistochemistry was used to measure Tau expression at M. D. And erson Cancer Center blinded to clinical outcome . Correlation between Tau and OS and DFS was performed by the NSABP Biostatistical Center . RESULTS Forty-three percent of patients were Tau positive . Tau positivity correlated with estrogen receptor ( ER ) -positive status ( P < .0001 ) , lower histologic grade ( P < .001 ) , and lack of human epidermal growth factor receptor 2 ( HER2 ) expression ( P < .0001 ) . In univariate analyses , Tau- and ER-positive status were both associated with better DFS and OS ( P < .0001 ) whereas greater tumor size , high grade , lymph node- and HER2-positive status were each associated with worse DFS and OS ( P < .0001 ) . In multivariate analysis , the same variables except HER2 remained significant . There was no significant interaction between Tau expression and benefit from paclitaxel in the total population or among ER-positive or -negative patients . CONCLUSION High Tau protein expression is associated with better prognosis in patients treated with adjuvant anthracycline and paclitaxel chemotherapy and endocrine therapy  , but there was no significant interaction between Tau expression and paclitaxel benefit PURPOSE We previously reported that four cycles of docetaxel/cyclophosphamide ( TC ) produced superior disease-free survival ( DFS ) compared with four cycles of doxorubicin/cyclophosphamide ( AC ) in early breast cancer . Older women are under-represented in adjuvant chemotherapy trials . In our trial 16 % of patients were > or = 65 years . We now report 7-year results for DFS and overall survival ( OS ) as well as the impact of age , hormone receptor status , and HER2 status on outcome and toxicity . PATIENTS AND METHODS Patients were r and omly assigned to receive either four cycles of st and ard-dose AC ( 60/600 mg/m(2 ) ; n = 510 ) , or TC ( 75/600 mg/m(2 ) ; n = 506 ) , administered by intravenous infusion every 3 weeks . RESULTS The median age in women younger than 65 , was 50 years ( range , 27 to 64 ) and for women > or = 65 was 69 years ( range , 65 to 77 ) . Baseline characteristics in the two age subgroups were generally well matched , except that older women tended to have more lymph node involvement . At a median of 7 years follow-up , the difference in DFS between TC and AC was significant ( 81 % TC v 75 % AC ; P = .033 ; hazard ratio [ HR ] , 0.74 ; 95 % CI 0.56 to 0.98 ) as was OS ( 87 % TC v 82 % AC ; P = .032 ; HR , 0.69 ; 95 % CI , 0.50 to 0.97 ) . TC was superior in older patients as well as younger patients . There was no interaction of hormone-receptor status or HER-2 status and treatment . Older women experienced more febrile neutropenia with TC and more anemia with AC . CONCLUSION With longer follow-up , four cycles of TC was superior to st and ard AC ( DFS and OS ) and was a tolerable regimen in both older and younger patients BACKGROUND The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide ( EC ) with four cycles of docetaxel ( Taxotere , D ) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer . PATIENTS AND METHODS Patients were r and omly assigned to EC ( E 120 mg/m(2 ) , C 600 mg/m(2 ) , arm A ) for four cycles or four cycles of D ( 100 mg/m(2 ) ) followed by four cycles of EC ( arm B ) , both regimens every 21 days . Hormone receptor-positive patients were given hormonal therapy for 5 years . Primary end point was 5-year disease-free survival ( DFS ) . Secondary objectives were overall survival ( OS ) and safety . RESULTS There were 750 patients enrolled . With a median follow-up of 64 months , 5-year DFS was 73.4 % in both arms , and 5-year OS was 89.5 % versus 90.7 % in arm A and B [ hazard ratio was 0.99 ( 95 % confidence interval for DFS 0.75 - 1.31 ; P = 0.95 ) ] , respectively . Grade 3 - 4 toxicity was more common in arm B. CONCLUSIONS This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer . The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms The NEAT trial reported considerable benefit for ECMF ( epirubicin followed by cyclophosphamide , methotrexate and 5-fluorouracil ) of 28 % for relapse-free survival ( RFS ) and 30 % for overall survival ( OS ) , when compared with classical CMF in early breast cancer . To assess tolerability , toxicity , dose intensity and quality of life ( QoL ) analyses were undertaken . All 2021 eligible patients had common toxicity criteria ( CTC ) , delivered chemotherapy and supportive treatments details and long-term morbidities recorded . The QoL sub study used multiple vali date d measures . ECMF produced low CTC scores , although higher than CMF  for nausea , vomiting , alopecia , constipation , stomatitis ( P<0.001 ) , infection ( P=0.001 ) and fatigue ( P=0.03 ) . Supportive treatments required , however , were similar across r and omised treatments . On-treatment deaths were more common with CMF ( 13 ) than ECMF(5 ) . Optimal course-delivered dose intensity ( CDDI ⩾85 % ) was received more often by ECMF patients ( 83 vs 76 % : P=0.0002 ) , and was associated with better RFS ( P=0.0006 ) . QoL over 2 years was equivalent across treatments , despite minimally worse side effects for ECMF during treatment . ECMF benefit spanned all levels of toxicity , CDDI and QoL. There are no reported acute myeloid leukaemias or cardiac dysfunctions . ECMF is tolerable , deliverable , and significantly more effective than CMF , with no serious long-term toxicity or QoL detriment Summary Background Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment . The UK TACT study ( CRUK01/001 ) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with st and ard chemotherapy of similar duration . Methods In this multicentre , open-label , phase III , r and omised controlled trial , 4162 women ( aged > 18 years ) with node-positive or high-risk node-negative operable early breast cancer were r and omly assigned by computer-generated permuted block r and omisation to receive FEC ( fluorouracil 600 mg/m2 , epirubicin 60 mg/m2 , cyclophosphamide 600 mg/m2 at 3-weekly intervals ) for four cycles followed by docetaxel ( 100 mg/m2 at 3-weekly intervals ) for four cycles ( n=2073 ) or control ( n=2089 ) . For the control regimen , centres chose either FEC for eight cycles ( n=1265 ) or epirubicin ( 100 mg/m2 at 3-weekly intervals ) for four cycles followed by CMF ( cyclophosphamide 600 mg/m2 , methotrexate 40 mg/m2 , and fluorouracil 600 mg/m2 at 4-weekly intervals ) for four cycles ( n=824 ) . The primary endpoint was disease-free survival . Analysis was by intention to treat ( ITT ) . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N79718493 . Findings All r and omised patients were included in the ITT population . With a median follow-up of 62 months , disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls ( hazard ratio [ HR ] 0·95 , 95 % CI 0·85–1·08 ; p=0·44 ) . 75·6 % ( 95 % CI 73·7–77·5 ) of patients in the experimental group and 74·3 % ( 72·3–76·2 ) of controls were alive and disease-free at 5 years . The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group ( p<0·0001 ) ; the most frequent events were neutropenia ( 937 events vs 797 events ) , leucopenia ( 507 vs 362 ) , and lethargy ( 456 vs 272 ) . Interpretation This study did not show any overall gain from the addition of docetaxel to st and ard anthracycline chemotherapy . Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy . Funding Cancer Research UK ( CRUK 01/001 ) , Sanofi-Aventis , Pfizer , and Roche Treatment with fluororacil , epirubicin , and cyclophosphamide followed by weekly paclitaxel ( FEC-P ) yielded superior disease-free survival than FEC in the adjuvant breast cancer trial GEICAM 9906 . We evaluate molecular subtypes predictive of prognosis and  paclitaxel response in this trial . Two molecular subtype classifications based on conventional immunohistochemical and fluorescent in situ hybridization determinations were used : # 1 : Four groups segregated according to the combination of hormone receptor ( HR ) and HER2 status ; # 2 : Intrinsic subtype classification ( Triple Negative ( TN ) , HER2 , Luminal B and Luminal A ) . Results : Both subtype classifications yielded prognostic and predictive information . HR + /HER2− patients ( and Luminal A patients ) had a significantly better outcome than the other subgroups of patients . The superiority of FEC-P over FEC  was clearly more marked in HR−/HER2− patients ( TN patients ) , particularly in the subset with basal phenotype ( TN and either EGFR+ or cytokeratins 5/6 + ) . The Luminal A subtype also achieved a significant benefit with FEC-P.  The molecular-defined subgroup of TN was clearly predictive of better response to treatment with FEC-P.  Luminal A patients had the best prognosis and also have a better outcome with weekly paclitaxel PURPOSE Adding taxanes to anthracycline-based adjuvant therapy improves survival outcomes of patients with node-positive breast cancer ( BC ) . Currently , however , most patients with BC are node negative at diagnosis . The only pure node-negative study ( Spanish Breast Cancer Research Group 9805 ) reported so far showed a docetaxel benefit but significant toxicity . Here we tested the efficacy and safety of weekly paclitaxel ( wP ) in node-negative patients , which is yet to be established . PATIENTS AND METHODS Patients with BC having T1-T3/N0 tumors and at least one high-risk factor for recurrence ( according to St. Gallen 1998 criteria ) were eligible . After primary surgery , 1,925 patients were r and omly assigned to receive fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) × 6 or FAC × 4 followed by wP × 8 ( FAC-wP ) . The primary end point was disease-free survival ( DFS ) after a median follow-up of 5 years . Secondary end points included toxicity and overall survival . RESULTS After a median follow-up of 63.3 months , 93 % and 90.3 % of patients receiving FAC-wP or FAC regimens , respectively , remained disease free ( hazard ratio [ HR ] , 0.73 ; 95 % CI , 0.54 to 0.99 ; log-rank P = .04 ) . Thirty-one patients receiving FAC-wP versus 40 patients receiving FAC died ( one and seven from cardiovascular diseases , respectively ; HR , 0.79 ; 95 % CI , 0.49 to 1.26 ; log-rank P = .31 ) . The most relevant grade 3 and 4 adverse events in the FAC-wP versus the FAC arm were febrile neutropenia ( 2.7 % v 3.6 % ) , fatigue ( 7.9 % v 3.4 % ) , and sensory neuropathy ( 5.5 % v 0 % ) . CONCLUSION For patients with high-risk node-negative BC , the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS  compared with FAC therapy , in addition to manageable toxicity , especially regarding long-term cardiac effects 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 PURPOSE The initial report from the Programme Action Concertée Sein ( PACS ) PACS01 trial demonstrated a benefit at 5 years for disease-free survival ( DFS ) and overall survival ( OS ) rates with the sequential administration of docetaxel after FEC100 ( fluorouracil 500 mg/m(2 ) , epirubicin 100 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ) for patients with node-positive , operable breast cancer . We evaluate here the impact of this regimen at 8 years . PATIENTS AND METHODS Between June 1997 and March 2000 , a total of 1,999 patients ( age < 65 ) with localized , resectable , non-pretreated , unilateral breast cancer were r and omly assigned to receive either st and ard FEC100 for 6 cycles or 3 cycles of FEC100 followed by 3 cycles of 100 mg/m(2 ) docetaxel ( FEC-D ) , both given every 21 days . Radiotherapy was m and atory after conservative surgery and tamoxifen was given for 5 years to hormone receptor (HR)-positive patients . Five-year DFS was the trial 's main endpoint . Up date d 8-year survival data are presented . RESULTS With a median follow-up of 92.8 months , 639 patients experienced at least one event . A total number of 383 deaths were registered . Eight-year DFS rates were 65.8 % with FEC alone and 70.2 % with FEC-D.  OS rates at 8 years were 78 % with FEC alone and 83.2 % with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15 % reduction in the relative risk of relapse and a 25 % reduction in the relative risk of death in favor of FEC-D. Significant relative risk reductions were observed in the HR-positive , HER2-positive , and Ki67 ≥20 % sub population s. CONCLUSION Benefits for DFS and OS rates with the sequential FEC-D regimen are fully confirmed at 8 years Introduction Pre- clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity . However , dedicated clinical research has not defined a predictive role for TP53 gene mutations . The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02 - 98 r and omized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel . Methods The prognostic and predictive values of TP53 were analyzed in tumor sample s by gene sequencing within exons 5 to 8 . Patients were classified according to  p53 protein status predicted from TP53 gene sequence , as wild-type ( no TP53 variation or TP53 variations which are predicted not to modify p53 protein sequence ) or mutant ( p53 nonsynonymous mutations ) . Mutations were subcategorized according to missense or truncating mutations . Survival analyses were performed using the Kaplan-Meier method and log-rank test . Cox-regression analysis was used to identify independent predictors of outcome . Results TP53 gene status was determined for 18 % ( 520 of 2887 ) of the women enrolled in BIG 02 - 98 .  TP53 gene variations were found in 17 % ( 90 of 520 ) . Nonsynonymous p53 mutations , found in 16.3 % ( 85 of 520 ) , were associated with older age , ductal morphology , higher grade and hormone-receptor negativity . Of the nonsynonymous mutations , 12.3 % ( 64 of 520 ) were missense and 3.6 % were truncating ( 19 of 520 ) . Only truncating mutations showed significant independent prognostic value , with an increased recurrence risk compared to patients with non-modified p53 protein ( hazard ratio = 3.21 , 95 % confidence interval = 1.740 to 5.935 , P = 0.0002 ) . p53 status had no significant predictive value for response to docetaxel . Conclusions p53 truncating mutations were uncommon but associated with poor prognosis . No significant predictive role for p53 status was detected . Trial registration Clinical Trials.gov BACKGROUND Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer . Strategies to improve efficacy include the use of anthracyclines , taxanes , and intensified dose with bone marrow support . PATIENTS AND METHODS Patients received neoadjuvant epirubicin 90 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) followed by paclitaxel 175 mg/m(2 ) ( EC→T ) , each 3-weekly for four cycles ( n = 370 ) , or epirubicin 150 mg/m(2 ) followed by paclitaxel 225 mg/m(2 ) with pegfilgrastim followed by CMF ( cyclophosphamide 500 mg/m(2 ) , methotrexate 40 mg/m(2 ) , fluorouracil 600 mg/m(2 ) ) on days 1 and 8 ( E(dd)→T(dd)→CMF ) , each 2-weekly and for three cycles ( n = 363 ) . Patients were r and omly allocated to either simultaneous darbepoetin alfa ( DA ) ( n = 356 ) or none ( n = 377 ) . RESULTS Pathological complete response ( pCR ) rate ( breast ) was higher with E(dd)→T(dd)→CMF , 18.7 % versus 13.2 % with EC→T ; P = 0.043 , ypT0/Tis ; ypN0 was reported in 20.9 % versus 14.3 % respectively ; P = 0.019 . Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate . Mean hemoglobin values maintained higher with DA ( 13.6 versus 12.6 g/dl ) . E(dd)→T(dd)→CMF regimen showed more grade 3 - 4 mucositis , sensory neuropathy , and neurological complaints . Thromboembolic events were more frequent on DA ( 3 % versus 6 % ; P = 0.055 ) . CONCLUSION Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR . Primary use of DA did not affect pCR BACKGROUND Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival among women with operable lymph-node-positive breast cancer . The effectiveness of concurrent versus sequential regimens is not known . METHODS We r and omly assigned 5351 patients with operable , node-positive , early-stage breast cancer to receive four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel ( sequential ACT ) ; four cycles of doxorubicin and docetaxel ( doxorubicin-docetaxel ) ; or four cycles of doxorubicin , cyclophosphamide , and docetaxel ( concurrent ACT ) . The primary aims were to examine whether concurrent ACT was more effective than sequential ACT and whether the doxorubicin-docetaxel regimen would be as effective as the concurrent-ACT regimen . The secondary aims were to assess toxic effects and to correlate amenorrhea with outcomes in premenopausal women . RESULTS At a median follow-up of 73 months , overall survival was improved in the sequential-ACT group ( 8-year overall survival , 83 % ) as compared with the doxorubicin-docetaxel group ( overall survival , 79 % ; hazard ratio for death , 0.83 ; P=0.03 ) and the concurrent-ACT group ( overall survival , 79 % ; hazard ratio , 0.86 ; P=0.09 ) . Disease-free survival was improved in the sequential-ACT group ( 8-year disease-free survival , 74 % ) as compared with the doxorubicin-docetaxel group ( disease-free survival , 69 % ; hazard ratio for recurrence , a second malignant condition , or death , 0.80 ; P=0.001 ) and the concurrent-ACT group ( disease-free survival , 69 % ; hazard ratio , 0.83 ; P=0.01 ) . The doxorubicin-docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival ( hazard ratio , 0.96 ; 95 % confidence interval , 0.82 to 1.14 ) . Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups , independently of estrogen-receptor status . CONCLUSIONS Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT , and it improved overall survival as compared with doxorubicin-docetaxel .  Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status . ( Clinical Trials.gov number , NCT00003782 . PURPOSE We investigated whether capecitabine and docetaxel followed by fluorouracil , epirubicin , and cyclophosphamide ( FEC ) or weekly paclitaxel ( WP ) followed by FEC would improve relapse-free survival ( RFS ) in operable breast cancer . PATIENTS AND METHODS In this single-institution study , patients with clinical stages I to IIIC breast cancer were r and omly assigned on a 1:1 basis to WP 80 mg/m(2 ) for 12 weeks followed by fluorouracil 500 mg/m(2 ) , epirubicin 100 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ( FEC-100 ) every 3 weeks for four cycles or docetaxel 75 mg/m(2 ) on day 1 and capecitabine ( XT ) 1,500 mg/m(2 ) on days 1 through 14 every 3 weeks for four cycles followed by FEC for four cycles and stratified by timing of chemotherapy ( preoperative v adjuvant ) . Accrual was stopped short of 930 patients on the basis of a Bayesian predictive calculation that additional accrual would be unlikely to change the qualitative comparison of the two regimens . RESULTS After enrollment of 601 patients and a median follow-up of 50 months , we observed no improvement in RFS between XT ( 87.5 % ; 95 % CI , 82.7 % to 91.1 % ) and WP ( 90.7 % ; 95 % CI , 86.4 % to 93.7 % ; P = .51 ) . In the preoperative group , the pathologic complete response rate was 19.8 % and 16.4 % in the XT and WP arms , respectively ( P = .45 ) . Rates of breast-conserving surgery were similar between the two groups ( P = .48 ) . The XT arm had a significantly higher incidence of stomatitis ( P < .001 ) , h and -foot syndrome ( P < .001 ) , and neutropenic infection ( P < .001 ) . CONCLUSION There was no difference in efficacy between WP and XT as used in this r and omized phase III trial . XT was associated with higher GI , skin , and neutropenic-related toxicities PURPOSE Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional  adjuvant therapy .  We compared intense dose-dense ( IDD ) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer . PATIENTS AND METHODS In this r and omized , phase III trial , a total of 1,284 eligible patients with four or more involved axillary lymph nodes were r and omly assigned to receive IDD sequential epirubicin , paclitaxel , and cyclophosphamide ( IDD-ETC ) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks . The primary end point was event-free survival ( EFS ) . RESULTS At a median follow-up of 62 months , 5-year event-free survival rates were 62 % in the conventional arm and 70 % in the IDD-ETC arm , representing a 28 % reduction of the relative risk of relapse ( P < .001 ) . This benefit was independent of menopausal , hormone receptor , or human epidermal growth factor receptor 2 status . The 5-year overall survival rates were 77 % versus 82 % , representing a 24 % reduction of the relative risk of death ( P = .0285 ) . IDD therapy was associated with significantly more nonhematologic and hematologic toxicities , but no treatment-related death occurred . Four occurrences of acute myeloid leukemia or myelodysplastic syndrome ( MDS ) were observed in the IDD-ETC arm . No severe congestive heart failure was reported . CONCLUSION IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes BACKGROUND Anthracyclines and taxanes have been the st and ard neoadjuvant chemotherapies for breast cancer in the past decade . We aim ed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide , and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel ( with or without gemcitabine ) . METHODS In our r and omised , open-label , 2 × 2 factorial phase 3 trial ( Neo-tAnGo ) , we enrolled women ( aged > 18 years ) with newly diagnosed breast cancer ( tumour size > 20 mm ) at 57 centres in the UK . Patients were r and omly assigned via a central r and omisation procedure to epirubicin and cyclophosphamide then paclitaxel ( with or without gemcitabine ) or paclitaxel ( with or without gemcitabine ) then epirubicin and cyclophosphamide . Four cycles of each component were given . The primary endpoint was pathological complete response ( pCR ) , defined as absence of invasive cancer in the breast and axillary lymph nodes . This study is registered with EudraCT ( 2004 - 002356 - 34 ) , IS RCT N ( 78234870 ) , and Clinical Trials.gov ( NCT00070278 ) . FINDINGS Between Jan 18 , 2005 , and Sept 28 , 2007 , we r and omly allocated 831 participants ; 207 received epirubicin and cyclophosphamide then paclitaxel ; 208 were given paclitaxel then epirubicin and cyclophosphamide ; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine ; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide .  828 patients were eligible for analysis . Median follow-up was 47 months ( IQR 37 - 51 ) . 207 ( 25 % ) patients had inflammatory or locally advanced disease , 169 ( 20 % ) patients had tumours larger than 50 mm , 413 ( 50 % ) patients had clinical involvement of axillary nodes , 276 ( 33 % ) patients had oestrogen receptor (ER)-negative disease , and 191 ( 27 % ) patients had HER2-positive disease . Addition of gemcitabine did not increase pCR : 70 ( 17 % , 95 % CI 14 - 21 ) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 ( 17 % , 14 - 21 ) of 408 patients who received additional gemcitabine ( p=0·98 ) . Receipt of a taxane before anthracycline was associated with improved pCR : 82 ( 20 % , 95 % CI 16 - 24 ) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 ( 15 % , 11 - 18 ) of 406 patients who received epirubicin and cyclophosphamide first ( p=0·03 ) . Grade 3 toxicities were reported at expected levels : 173 ( 21 % ) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia , 66 ( 8 % ) had infection , 41 ( 5 % ) had fatigue , 41 ( 5 % ) had muscle and joint pains , 37 ( 5 % ) had nausea , 36 ( 4 % ) had vomiting , 34 ( 4 % ) had neuropathy , 23 ( 3 % ) had transaminitis , 16 ( 2 % ) had acute hypersensitivity , and 20 ( 2 % ) had a rash . 86 ( 11 % ) patients had grade 4 neutropenia and 3 ( < 1 % ) had grade 4 infection . INTERPRETATION Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR , sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in st and ard neoadjuvant chemotherapy for breast cancer . FUNDING Cancer Research UK , Eli Lilly , Bristol-Myers Squibb tAnGo is a large r and omised trial assessing the addition of gemcitabine(G ) to paclitaxel(T ) , following epirubicin(E ) and cyclophosphamide(C ) in women with invasive higher risk early breast cancer . To assess the safety and tolerability of adding G , a detailed safety sub study was undertaken . A total of 135 patients had cardiac , pulmonary and hepatic function assessed at ( i ) r and omisation , ( ii ) mid-chemotherapy , ( iii ) immediately post-chemotherapy and ( iv ) 6 months post-chemotherapy .  Skin toxicity was assessed during radiotherapy . No differences were detected in FEV1 or FVC levels between treatment arms or time points . Diffusion capacity ( TLCO ) reduced during treatment ( P<0.0001 ) , with a significantly lower drop in EC-GT patients ( P=0.02 ) . Most of the reduction occurred during EC and recovered by 6-months post treatment . There was no difference in cardiac function between treatment arms . Only 11 patients had echocardiography/MUGA results  change from normal to abnormal during treatment , with only five having LVEF<50 % . Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy ( AST P=0.03 , ALT P=0.003 ) , although the majority was low grade . There was no correlation between transaminitis and other toxicities . Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels . Despite these being greater with EC-GT , both regimens appear well tolerated To compare the long-term outcome of women with primary or locally advanced breast cancer r and omised to receive either doxorubicin and cyclophosphamide ( AC ) or doxorubicin and docetaxel ( AD ) as primary chemotherapy . Eligible patients with histologic-proven breast cancer with primary tumours ≥3 cm , inflammatory or locally advanced disease , and no evidence of distant metastases , were r and omised to receive a maximum of 6 cycles of either doxorubicin ( 60 mg/m2 ) plus cyclophosphamide ( 600 mg/m2 ) i/v or doxorubicin ( 50 mg/m2 ) plus docetaxel ( 75 mg/m2 ) i/v every 3 weeks , followed by surgery on completion of chemotherapy . Clinical and pathologic responses have previously been reported . Time to relapse , site of relapse , and all-cause mortality were recorded . This up date d analysis compares long-term disease-free ( DFS ) and overall survival ( OS ) using stratified log rank methods . A total of 363 patients were r and omised to AC ( n = 181 ) or AD ( n = 182 ) .  A complete pathologic response was observed in 16 % for AC and 12 % for AD ( P = 0.43 ) . The number of patients with positive axillary nodes at surgery with AC was 61 % and AD 66 % ( P = 0.36 ) . At a median follow-up of 99 months there is no significant difference between the two groups for DFS ( P = 0.20 ) and OS ( P = 0.24 ) . Deaths were due to metastatic breast cancer in 96 % of patients . Our data do not support a clinical benefit for simultaneous administration of AD compared with AC . However , the data do not exclude a smaller benefit than the study was powered to detect and are consistent with an increase in both disease-free and overall survival of about 5 % for AD compared with AC . Outcome is consistent with the pathologic complete response following surgery The r and omized multicenter study on rapidly proliferating breast cancer , assessed according to thymidine labelling index ( TLI ) , was activated at the end of the 1980s . The present work investigated whether and to what degree the short-term advantages observed from adjuvant CMF ( cyclophosphamide , methotrexate , 5-fluorouracil ) were maintained at a longer follow-up . Two hundred and eighty-one patients with node-negative and high TLI tumors were r and omized to receive six cycles of CMF or no further treatment . At a median follow-up of 12 years , CMF produced a 25 % and 20 % relative reduction in relapse and death cumulative incidence , respectively . A breakdown analysis identified a subgroup of patients with intermediate proliferating tumors for whom a 70 % and 73 % reduction in relapse and death was observed in the intention-to-treat population . An even higher reduction of 80 % and 84 % in relapse and death was seen for the patients who had received the full CMF dose . We identified a subgroup of patients with intermediate proliferating tumors in whom the high benefit obtained from adjuvant CMF was maintained at a long-term follow up PURPOSE We investigated disease-free survival ( DFS ) and overall survival ( OS ) after response-guided neoadjuvant chemotherapy in patients with early breast cancer . PATIENTS AND METHODS We treated 2,072 patients with two cycles of docetaxel , doxorubicin , and cyclophosphamide ( TAC )  and r and omly assigned early responders to four ( n = 704 ) or six ( n = 686 ) additional TAC cycles , and early nonresponders to four cycles of TAC ( n = 321 ) or vinorelbine and capecitabine ( NX ; n = 301 ) before surgery . RESULTS DFS was longer in early responders receiving TAC × 8 than in those receiving TAC × 6 ( hazard ratio [ HR ] , 0.78 ; 95 % CI , 0.62 to 0.97 ; P = .026 ) , and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 ( HR , 0.59 ; 95 % CI , 0.49 to 0.82 ; P = .001 ) . Exploratory analysis showed that DFS  after response-guided chemotherapy ( TAC × 8 or TAC-NX ) was significantly longer ( HR , 0.71 ; 95 % CI , 0.60 to 0.85 ; P < .003 ) , as was OS ( HR , 0.79 ; 95 % CI , 0.63 to 0.99 ; P = .048 ) , than on conventional chemotherapy ( TAC × 6 ) . DFS was longer after response-guided chemotherapy in all hormone receptor-positive tumors ( luminal A HR = 0.55 , luminal B [ human epidermal growth factor receptor 2 ( HER2 ) negative ] HR = 0.40 , and luminal B [ HER2 positive ] HR = 0.56 ) , but not in hormone receptor-negative tumors ( HER2 positive [ nonluminal ] HR = 1.01 and triple negative HR = 0.87 ) . Pathologic complete response did not predict these survival effects . pCR predicted an improved DFS in triple-negative ( HR = 6.67 ) , HER2-positive ( nonluminal ; HR 5.24 ) , or luminal B ( HER2-negative ) tumors ( HR = 3.74 ) . CONCLUSION This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor-positive tumors . If confirmed , the response-guided approach could provide a clinical ly meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer BACKGROUND A regimen of docetaxel , doxorubicin , and cyclophosphamide ( TAC ) is superior to a regimen of fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) when used as adjuvant therapy in women with node-positive breast cancer . The value of taxanes in the treatment of node-negative disease has not been determined . METHODS We r and omly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence ( according to the 1998 St. Gallen criteria ) to treatment with TAC or FAC every 3 weeks for six cycles after surgery . The primary end point was disease-free survival after at least 5 years of follow-up . Secondary end points included overall survival and toxicity . RESULTS At a median follow-up of 77 months , the proportion of patients alive and disease-free was higher among the 539 women in the TAC group ( 87.8 % ) than among the 521 women in the FAC group ( 81.8 % ) , representing a 32 % reduction in the risk of recurrence with TAC ( hazard ratio , 0.68 ; 95 % confidence interval [ CI ] , 0.49 to 0.93 ; P=0.01 by the log-rank test ) . This benefit was consistent , regardless of hormone-receptor status , menopausal status , or number of high-risk factors . The difference in survival rates  ( TAC , 95.2 % ; FAC , 93.5 % ) was not significant ( hazard ratio , 0.76 ; 95 % CI , 0.45 to 1.26 ) ; however , the number of events was small ( TAC , 26 ; FAC , 34 ) . Rates of grade 3 or 4 adverse events were 28.2 % with TAC and 17.0 % with FAC ( P<0.001 ) . Toxicity associated with TAC was diminished when primary prophylaxis with granulocyte colony-stimulating factor was provided . CONCLUSIONS As compared with adjuvant FAC , adjuvant TAC improved the rate of disease-free survival among women with high-risk , node-negative breast cancer . ( Funded by GEICAM and Sanofi-Aventis ; Clinical Trials.gov number , NCT00121992 . ) PURPOSE Using a 2 x 2 factorial design , we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin ( A ) , paclitaxel ( T ) , and cyclophosphamide ( C ) with concurrent doxorubicin and cyclophosphamide ( AC ) followed by paclitaxel ( T ) for disease-free ( DFS ) and overall survival ( OS ) ; to determine whether the dose density of the agents improves DFS and OS ; and to compare toxicities . PATIENTS AND METHODS A total of 2,005 female patients were r and omly assigned to receive one of the following regimens : ( I ) sequential A x 4 ( doses ) -- > T x 4 -- > C x 4 with doses every 3 weeks , ( II ) sequential A x 4 -- > T x 4 -- > C x 4 every 2 weeks with filgrastim , ( III ) concurrent AC x 4 -- > T x 4 every 3 weeks , or ( IV ) concurrent AC x 4 -- > T x 4 every 2 weeks with filgrastim . RESULTS A protocol -specified analysis was performed at a median follow-up of 36 months : 315 patients had experienced relapse or died , compared with 515 expected treatment failures . Dose-dense treatment improved the primary end point , DFS ( risk ratio [ RR ] = 0.74 ; P = .010 ) , and OS ( RR = 0.69 ; P = .013 ) . Four-year DFS was 82 % for the dose-dense regimens and 75 % for the others . There was no difference in either DFS or OS between the concurrent and sequential schedules . There was no interaction between density and sequence . Severe neutropenia was less frequent in patients who received the dose-dense regimens . CONCLUSION Dose density improves clinical outcomes significantly , despite the lower than expected number of events at this time . Sequential chemotherapy is as effective as concurrent chemotherapy BACKGROUND E75 ( nelipepimut-S ) is a human leukocyte antigen (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein . We have conducted phase I/II clinical trials vaccinating breast cancer patients with nelipepimut-S and granulocyte-macrophage colony-stimulating factor ( GM-CSF ) in the adjuvant setting to prevent disease recurrence . All patients have completed 60 months follow-up , and here , we report the final analyses . PATIENTS AND METHODS The studies were conducted as dose escalation/schedule optimization trials enrolling node-positive and high-risk node-negative patients with tumors expressing any degree of HER2 ( immunohistochemistry 1 - 3 + ) . HLA-A2/3 + patients were vaccinated ; others were followed prospect ively as controls .  Local and systemic toxicity was monitored . Clinical recurrences were documented , and disease-free survival ( DFS ) was analyzed by Kaplan-Meier curves ; groups were compared using log-rank tests . RESULTS Of 195 enrolled patients , 187 were assessable : 108 ( 57.8 % ) in the vaccinated group ( VG ) and 79 ( 42.2 % ) in the control group ( CG ) . The groups were well matched for clinicopathologic characteristics . Toxicities were minimal . Five-year DFS was 89.7 % in the VG versus 80.2 % in the CG ( P = 0.08 ) . Due to trial design , 65 % of patients received less than the optimal vaccine dose . Five-year DFS was 94.6 % in optimally dosed patients ( P = 0.05 versus the CG ) and 87.1 % in suboptimally dosed patients . A voluntary booster program was initiated , and among the 21 patients that were optimally boosted , there was only one recurrence ( DFS = 95.2 % ) . CONCLUSION The E75 vaccine is safe and appears to have clinical efficacy . A phase III trial evaluating the optimal dose and including booster inoculations has been initiated . CLINICAL TRIALS NCT00841399 , NCT00584789 Purpose : p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results . We studied p53 protein expression , by immunohistochemistry , in a r and omized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [ Cancer and Leukemia Group B ( CALGB ) 9344 , INT0148 ] . Patients and Methods : Epithelial p53 expression was evaluated using two immunohistochemical antibodies ( DO7 and 1801 ) in formalin-fixed , paraffin-embedded tissue from patients with node-positive breast cancer who were r and omized to four cycles of cyclophosphamide and one of three doses of doxorubicin  ( 60 , 75 , or 90 mg/m2 ; AC ) and to receive four subsequent cycles of paclitaxel ( T ) or not . Prognostic and predictive value of p53 protein expression was assessed , independent of treatment assignment , for escalating doses of doxorubicin or addition of T with endpoints of relapse-free ( RFS ) and overall survival ( OS ) . Results : Of 3,121 patients , 1,887 patient specimens treated on C9344 were obtained , passed quality control , and evaluated for p53 expression . Expression was 23 % and 27 % for mAbs 1801 and D07 , respectively , with 92 % concordance . In univariate analysis , p53 positivity was associated with worse OS with either antibody , but only p53 staining with monoclonal antibody 1801 had significantly worse RFS . In multivariate analysis , p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody . Conclusion : Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node-positive patients treated with adjuvant doxorubicin-based chemotherapy  but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel . Clin Cancer Res ; 17(15 ) ; 5170–8 . © 2011 AACR 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 Taxanes are among the most active drugs for the treatment of metastatic breast cancer , and , as a consequence , they have also been studied in the adjuvant setting . METHODS After breast cancer surgery , women with lymph node-positive disease were r and omly assigned to treatment with fluorouracil , epirubicin , and cyclophosphamide ( FEC ) or with FEC followed by weekly paclitaxel ( FEC-P ) . The primary endpoint of study -5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis . Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular ( hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization ) markers . Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates : age , menopausal status , tumor size , lymph node status , type of chemotherapy , tumor size , positive lymph nodes , HER2 status , and hormone receptor status . All statistical tests were two-sided . RESULTS Among the 1246 eligible patients , estimated rates of DFS at 5 years were 78.5 % in the FEC-P arm and 72.1 % in the FEC arm ( difference = 6.4 % , 95 % confidence interval [ CI ] = 1.6 % to 11.2 % ; P = .006 ) . FEC-P treatment was associated with a 23 % reduction in the risk of relapse compared with FEC treatment ( 146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm , hazard ratio [ HR ] = 0.77 , 95 % CI = 0.62 to 0.95 ; P = .022 ) and a 22 % reduction in the risk of death ( 73 and 95 deaths , respectively , HR = 0.78 , 95 % CI = 0.57 to 1.06 ; P = .110 ) . Among the 928 patients for whom tumor sample s were central ly analyzed , type of chemotherapy ( FEC vs FEC-P ) ( P = .017 ) , number of involved axillary lymph nodes ( P < .001 ) , tumor size ( P = .020 ) , hormone receptor status ( P = .004 ) , and HER2 status ( P = .006 ) were all associated with DFS . We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment . CONCLUSIONS Among patients with operable breast cancer , FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy Purpose : Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens . We examined this hypothesis on NCIC.CTG MA.5 , a clinical trial r and omizing premenopausal women with node-positive breast cancer to adjuvant CMF ( cyclophosphamide-methotrexate-fluorouracil ) versus CEF ( cyclophosphamide-epirubicin-fluorouracil ) chemotherapy . Experimental Design : Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test . Luminal A , luminal B , HER2-enriched ( HER2-E ) , and basal-like subtypes were correlated with relapse-free survival ( RFS ) and overall survival ( OS ) , estimated using Kaplan – Meier plots and log-rank testing . Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes . Results : Intrinsic subtypes were associated with RFS ( P = 0.0005 ) and OS ( P < 0.0001 ) on the combined cohort . The HER2-E showed the greatest benefit from CEF versus CMF , with absolute 5-year RFS and OS differences exceeding 20 % , whereas there was a less than 2 % difference for non – HER2-E tumors ( interaction test P = 0.03 for RFS and 0.03 for OS ) . Within clinical ly defined Her2 + tumors , 79 % ( 72 of 91 ) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF ( 62 % vs. 22 % , P = 0.0006 ) . There was no significant difference in benefit between CEF and CMF in basal-like tumors [ n = 94 ; HR , 1.1 ; 95 % confidence interval ( CI ) , 0.6–2.1 for RFS and HR , 1.3 ; 95 % CI , 0.7–2.5 for OS ] . Conclusion : HER2-E strongly predicted anthracycline sensitivity . The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF , suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required . Clin Cancer Res ; 18(8 ) ; 2402–12 . © 2012 AACR BACKGROUND Predictive markers of response to chemotherapy are lacking in breast cancer patients . Forkhead Box Protein 3 ( FOXP3 ) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent . So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival ( OS ) benefit over anthracyclines alone , in patients with FOXP3-negative tumors . PATIENTS AND METHODS Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor sample s from 1097 patients who participated in the PACS01 r and omized trial that evaluated in adjuvant setting the adjunction of docetaxel ( Taxotere ) to anthracyclines in patients with localized breast cancer . Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells . RESULTS Four hundred and five tumors were found to express FOXP3 ( 37 % ) . FOXP3 expression in breast cancer cells was associated with better OS ( P = 0.003 ) . Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy , but not in patients treated with sequential anthracycline-taxane . Moreover , in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances  anthracyclines efficacy . CONCLUSION FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer BACKGROUND We compared docetaxel plus doxorubicin and cyclophosphamide ( TAC ) with fluorouracil plus doxorubicin and cyclophosphamide ( FAC ) as adjuvant chemotherapy for operable node-positive breast cancer . METHODS We r and omly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery . The primary end point was disease-free survival . RESULTS At a median follow-up of 55 months , the estimated rates of disease-free survival at five years were 75 percent among the 745 patients r and omly assigned to receive TAC and 68 percent among the 746 r and omly assigned to receive FAC , representing a 28 percent reduction in the risk of relapse ( P=0.001 ) in the TAC group . The estimated rates of overall survival at five years were 87 percent and 81 percent , respectively . Treatment with TAC result ed in a 30 percent reduction in the risk of death ( P=0.008 ) . The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group ( P<0.001 ) ; rates of febrile neutropenia were 24.7 percent and 2.5 percent , respectively ( P<0.001 ) . Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC ( P=0.05 ) ; no deaths occurred as a result of infection . Two patients in each group died during treatment . Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group . Quality -of-life scores decreased during chemotherapy but returned to baseline levels after treatment . CONCLUSIONS Adjuvant chemotherapy with TAC , as compared with FAC , significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer BACKGROUND Patients with an early response to neoadjuvant chemotherapy  have chemosensitive tumors and a high probability for a pathological complete response at surgery . The relationship between extended chemotherapy and pathological complete response at surgery was investigated in a clinical trial . METHODS Untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m(2 ) , doxorubicin at 50 mg/m(2 ) , and cyclophosphamide at 500 mg/m(2 ) ( TAC ) . Those whose tumor size decreased by 50 % or more by sonographic measurement ( ie , reduction in the product of the two largest perpendicular diameters by at least 50 % ) were classified as responders and r and omly assigned to receive four or six more cycles of TAC , for a total of six or eight TAC cycles . The primary aim was to increase the rate of a pathological complete response ( defined as no invasive or in situ residual tumor masses in the breast and lymph nodes ) from 20 % to 26 % . Sonographic response rates and rates of breast-conserving surgery and adverse effects were also assessed . All statistical tests were two-sided . RESULTS Of the 2090 patients in the GeparTrio trial , 1390 ( 66.5 % ) were r and omly assigned as responders after two initial TAC cycles to receive an additional four ( n = 704 ) or six ( n = 686 ) TAC cycles . Rates of pathological complete response were not statistically significantly different between the arms ( 21.0 % with six TAC cycles and 23.5 % with eight TAC cycles ; difference = 2.5 % , 95 % confidence interval [ CI ] = -1.8 % to 6.8 % ; P = .27 ) . More clinical ( 48.2 % vs 52.9 % , difference = 4.7 % ; 95 % CI = -0.55 % to 9.95 % ; P = .08 ) and sonographic ( 22.6 % vs 27.6 % , difference = 5 % ; 95 % CI = 0.45 % to 9.55 % ; P = .033 ) complete responses at surgery were observed with eight TAC cycles than with six TAC cycles . The rate of breast-conserving surgery was similar in both arms ( 67.5 % vs 68.5 % , respectively , P = .68 ) . Grade 3 or 4 leukopenia and edema and various grade 1 or 2 adverse events were more frequent in patients receiving eight TAC cycles than in those receiving six cycles . CONCLUSION Patients receiving eight TAC cycles had statistically significantly higher sonographic response rates but not pathological complete response rates than those receiving six TAC cycles . However , they also had more toxic effects . So far , eight cycles of TAC can not be recommended for the whole group of patients responding to two initial cycles of TAC PURPOSE Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer . This trial ( NSABP B-38 ; Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer ) asked whether the incorporation of a fourth drug could improve outcomes relative to two st and ard regimens and provided a direct comparison of those two regimens . PATIENTS AND METHODS We r and omly assigned 4,894 women with node-positive early-stage breast cancer to six cycles of docetaxel , doxorubicin , and cyclophosphamide ( TAC ) , four cycles of dose-dense ( DD ) doxorubicin and cyclophosphamide followed by four cycles of DD paclitaxel ( P ; DD AC→P ) , or DD AC→P with four cycles of gemcitabine ( G ) added to the DD paclitaxel ( DD AC→PG ) . Primary granulocyte colony-stimulating factor support was required ; erythropoiesis-stimulating agents ( ESAs ) were used at the investigator 's discretion . RESULTS There were no significant differences in 5-year disease-free survival ( DFS ) between DD AC→PG and DD AC→P ( 80.6 % v 82.2 % ; HR , 1.07 ; P = .41 ) , between DD AC→PG and TAC ( 80.6 % v 80.1 % ; HR , 0.93 ; P = .39 ) , in 5-year overall survival ( OS ) between DD AC→PG and DD AC→P ( 90.8 % v 89.1 % ; HR , 0.85 ; P = .13 ) , between DD AC→PG and TAC ( 90.8 % v 89.6 % ; HR , 0.86 ; P = .17 ) , or between DD AC→P versus TAC for DFS ( HR , 0.87 ; P = .07 ) and OS ( HR , 1.01 ; P = .96 ) . Grade 3 to 4 toxicities for TAC , DD AC→P , and DD AC→PG , respectively , were febrile neutropenia ( 9 % , 3 % , 3 % ; P < .001 ) , sensory neuropathy ( < 1 % , 7 % , 6 % ; P < .001 ) , and diarrhea ( 7 % , 2 % , 2 % ; P < .001 ) . Exploratory analyses for ESAs showed no association with DFS events ( HR , 1.02 ; P = .95 ) . CONCLUSION Adding G to DD AC→P did not improve outcomes . No significant differences in efficacy were identified between DD AC→P and TAC , although toxicity profiles differed Purpose : The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described . Experimental Design : Participants of the GeparTrio study with primary breast cancer r and omly received neoadjuvant response-guided  [ 8 cycles  TAC ( docetaxel/doxorubicin/cyclophosphamide ) in responding and TAC-NX ( vinorelbine/capecitabine ) in nonresponding patients ] or  conventional ( 6 cycles TAC ) chemotherapy  according to interim response assessment . Ki-67 levels were central ly measured immunohistochemically after neoadjuvant treatment if tumor tissue was available . Here , we analyze 1,151 patients having a pathologic complete response ( pCR ; n , 484 ) , or residual disease with low ( 0–15 % ) , intermediate ( 15.1–35 % ) , or high ( 35.1–100 % ) posttreatment Ki67 levels in 488 , 77 , and 102 patients , respectively . Results : Patients with high posttreatment Ki67 levels showed higher risk for disease relapse ( P < 0.0001 ) and death ( P < 0.0001 ) compared with patients with low or intermediate Ki67 levels . Patients with low Ki67 levels showed a comparable outcome to patients with a pCR ( P = 0.211 for disease-free and P = 0.779 for overall survival ) . Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment . Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone – receptor-positive disease [ hazard ratios ( HR ) , 1.82–5.88 ] but not in hormone – receptor-negative disease ( HR : 0.61–1.73 ) . Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 ( P = 0.965 ) . Conclusions : Posttreatment Ki67 levels provide prognostic information for patients with hormone – receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy . Levels were not prognostic for outcome after response-guided chemotherapy . High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments . Clin Cancer Res ; 19(16 ) ; 4521–31 . © 2013 AACR BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting . Micrometastases are dependent on angiogenesis , suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting . We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer . METHODS For this open-label , r and omised phase 3 trial we recruited patients with central ly confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries . We r and omly allocated patients aged 18 years or older ( 1:1 with block r and omisation ; stratified by nodal status , chemotherapy  [ with an anthracycline , taxane , or both ] , hormone receptor status [ negative vs low ] , and type of surgery ) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab ( equivalent of 5 mg/kg every week for 1 year ) . The primary endpoint was invasive disease-free survival ( IDFS ) . Efficacy analyses were based on the intention-to-treat population , safety analyses were done on all patients who received at least one dose of study drug , and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample . This trial is registered with Clinical Trials.gov , number NCT00528567 . FINDINGS Between Dec 3 , 2007 , and March 8 , 2010 , we r and omly assigned 1290 patients to receive chemotherapy alone  and 1301 to receive bevacizumab plus chemotherapy . Most patients received anthracycline-containing therapy ; 1638 ( 63 % ) of the 2591 patients had node-negative disease . At the time of analysis of IDFS , median follow-up was 31·5 months ( IQR 25·6 - 36·8 ) in the chemotherapy-alone group and 32·0 months ( 27·5 - 36·9 ) in the bevacizumab group . At the time of the primary analysis , IDFS events had been reported in 205 patients ( 16 % ) in the chemotherapy-alone group and in 188 patients ( 14 % ) in the bevacizumab group ( hazard ratio [ HR ] in stratified log-rank analysis 0·87 , 95 % CI 0·72 - 1·07 ; p=0·18 ) . 3-year IDFS was 82·7 % ( 95 % CI 80·5 - 85·0 ) with chemotherapy alone and 83·7 % ( 81·4 - 86·0 ) with bevacizumab and chemotherapy . After 200 deaths , no difference in overall survival was noted between the groups ( HR 0·84 , 95 % CI 0·64 - 1·12 ; p=0·23 ) . Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab ( Cox interaction test p=0·029 ) . Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension ( 154 patients [ 12 % ] vs eight patients [ 1 % ] ) , severe cardiac events occurring at any point during the 18-month safety reporting period ( 19 [ 1 % ] vs two [ < 0·5 % ] ) , and treatment discontinuation ( bevacizumab , chemotherapy , or both ; 256 [ 20 % ] vs 30 [ 2 % ] ) ; we recorded no increase in fatal adverse  events with bevacizumab ( four [ < 0·5 % ] vs three [ < 0·5 % ] ) . INTERPRETATION Bevacizumab can not be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer . Further follow-up is needed to assess the potential effect of bevacizumab  on overall survival LBA1000 Background : The primary aims were to determine whether adjuvant DD AC→PG will be superior to DD AC→P as well as to TAC in DFS and to compare the relative DFS of TAC and DD AC→P. Secondary endpoints include survival and toxicity . METHODS From Nov 3 , 2004 to May 3 , 2007 , 4894 women were r and omized ; 1630 to TAC ( docetaxel [ T ] 75 mg/m2 , doxorubicin [ A ] 50 mg/m2 , cyclophosphamide [ C ] 500 mg/m2 q3 wks x 6 ) , 1634 to DD AC→P ( A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 followed by P 175 mg/m2 q2 wks x 4 ) , and  1630 to DD AC→PG ( A 60 mg/m2 and C 600 mg/m2 q2 wks x 4 → P 175 mg/m2 + G 2000 mg/m2q2 wks x 4 ) . Primary G-CSF support was required and erythropoiesis-stimulating agents ( ESA ) were used at investigator discretion . 52 % were postmenopausal , 65 % had 1 - 3 positive nodes , and 80 % had HR+ breast cancer . Log-rank tests were used for pair-wise comparisons of the primary ( DFS ) and secondary ( OS ) endpoints among the three treatment arms . RESULTS With 64 months median follow-up , 5-year DFS in DD AC→PG group was 80.6 % compared with 82.2 % in DD AC→P group ( HR=1.1 ; p=0.27 ) and 80.1 % ( HR=0.97 ; p=0.71 ) in TAC group . 5-year OS was 90.8 % in DD AC→PG group as compared with 89.1 % ( HR=.89 ; p=0.25 ) in DD AC→P group and 89.6 % ( HR=0.90 ; p=0.32 ) in TAC group . HR for DFS and OS  of DD AC→P vs. TAC were 0.89 ( p=0.14 ) and 1.01 ( p=0.92 ) respectively . Toxicities for TAC , DD AC→P , DD AC→PG , respectively : febrile neutropenia ( Gr 3/4 : 9 % , 4 % , 4 % [ p<0.001 ] ) , sensory neuropathy ( Gr 3/4 : < 1 % , 7 % , 6 % [ p<0.001 ] ) , diarrhea ( Gr 3/4 : 8 % , 2 % , 2 % [ p<0.001 ] ) . Hgb was < 10 in 12 % , 26 % , 33 % with ESA use in 35.2 % , 47 % , 51.6 % and transfusions in 3.7 % , 6.3 % , 9.4 % . Deaths on treatment : N=13 , 5 , 7 ( p=0.2 ) . AML/MDS N=5 , 8 , 11 . All cycles completed in 91 % for TAC and 88 % for DD regimens . CONCLUSIONS Addition of G to DD AC→P did not improve outcomes . No significant differences in efficacy endpoints were identified between DD AC→P and TAC , though toxicity profiles differed . FUNDING NCI PHS U10-CA-37377 , -69974 , -12027 , -69651 and NCCTG U10-CA25224 , with additional funding from Eli Lilly & Company , and Amgen , PURPOSE A phase III trial ( Cancer and Leukemia Group B CALGB-49907 ) was conducted to test whether older patients with early-stage breast cancer would have equivalent relapse-free and overall survival with capecitabine compared with st and ard chemotherapy . The quality of life ( QoL ) sub study tested whether capecitabine treatment would be associated with a better QoL  than st and ard chemotherapy . PATIENTS AND METHODS QoL was assessed in 350 patients r and omly assigned to either st and ard chemotherapy ( cyclophosphamide , methotrexate , and fluorouracil [ CMF ] or doxorubicin and cyclophosphamide [ AC ] ; n = 182 ) or capecitabine ( n = 168 ) . Patients were interviewed by telephone before treatment ( baseline ) , midtreatment , within 1 month post-treatment , and at 12 , 18 , and 24 months postbaseline by using question naires from the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ( EORTC QLQ-C30 ) , a breast systemic adverse effects scale ( EORTC BR23 ) , and the Hospital Anxiety and Depression Scale ( HADS ) . RESULTS Compared with patients who were treated with st and ard chemotherapy , patients who were treated with capecitabine had significantly better QoL , role function , and social function , fewer systemic adverse effects , less psychological distress , and less fatigue during and at the completion of treatment ( P ≤ .005 ) . Capecitabine treatment was associated with less nausea , vomiting , and constipation and with better appetite  than st and ard treatment ( P ≤ .004 ) , but worse h and -foot syndrome and diarrhea ( P < .005 ) . These differences all resolved by 12 months . CONCLUSION St and ard chemotherapy was superior to capecitabine in improving relapse-free and overall survival for older women with early-stage breast cancer .  Although capecitabine was associated with better QoL during treatment , QoL was similar for both groups at 1 year . The brief period of poorer QoL with st and ard treatment is a modest price to pay for a chance at improved survival PURPOSE To evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic ( neoadjuvant ) therapy . PATIENTS AND METHODS A total of 1,355 women with operable breast cancer were r and omly assigned to one of three treatments : surgery followed by adjuvant doxorubicin ( 75 mg/m(2 ) ) followed by cyclophosphamide , methotrexate , and fluorouracil ( CMF ; arm A ) ; surgery followed by adjuvant paclitaxel ( 200 mg/m(2 ) ) plus doxorubicin ( 60 mg/m(2 ) ) , followed by CMF ( arm B ) ; or paclitaxel ( 200 mg/m(2 ) ) plus doxorubicin ( 60 mg/m(2 ) ) followed by CMF followed by surgery ( arm C ) . The two co primary objectives were to assess the effects on relapse-free survival ( RFS ) of the addition of paclitaxel to postoperative chemotherapy ( arm B v arm A ) and primary chemotherapy versus adjuvant chemotherapy ( arm B v arm C ) . RESULTS Doxorubicin plus paclitaxel followed by CMF was well-tolerated as adjuvant or as primary chemotherapy . The addition of paclitaxel to adjuvant doxorubicin followed by CMF significantly improved RFS compared with adjuvant doxorubicin alone followed by CMF ( hazard ratio [ HR ] , 0.73 ; P = .03 ) . Distant RFS was similarly improved ( HR , 0.70 ; P = .027 ) . There was no significant difference in RFS when the paclitaxel/doxorubicin/CMF chemotherapy was given before surgery compared with the same regimen given after surgery ( HR , 1.21 ; P = .18 ) . However , the rate of breast-conserving surgery was significantly higher with preoperative chemotherapy ( 63 % v 34 % ; P < .001 ) . CONCLUSION Incorporating paclitaxel into anthracycline-based adjuvant therapy result ed in a significant improvement in RFS and distant RFS . When given as primary systemic therapy , the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients BACKGROUND The NEAT/BR9601 trial showed benefit for addition of anthracyclines to cyclophosphamide , methotrexate , and fluorouracil ( CMF ) as adjuvant treatment for early breast cancer . We investigated prospect ively predictive biomarkers of anthracycline benefit including HER2 and TOP2A . METHODS 1941 tumours from 2391 women recruited to NEAT/BR9601 were analysed on tissue microarrays for HER2 and TOP2A amplification and deletion , HER1 - 3 and Ki67 expression , and duplication of chromosome 17 centromere enumeration probe ( Ch17CEP ) . Log-rank analyses identified factors affecting relapse-free and overall survival , and regression models tested independent prognostic effect of markers , with adjustment for known prognostic factors ( age , nodal status , oestrogen-receptor status , grade , and tumour size ) . The predictive value of markers was tested by treatment interactions for relapse-free and overall survival . FINDINGS 1762 patients were analysed . 21 % of tumours ( n=367 ) were HER2 amplified , 10 % were TOP2A amplified ( n=169 ) , 11 % showed TOP2A deleted ( n=191 ) , 23 % showed Ch17CEP duplication ( n=406 ) , and 61 % had high ( > 13.0 % ) Ki67 ( n=1136 ) . In univariate analyses , only HER2 amplification and TOP2A deletion were significant prognostic factors for relapse-free ( hazard ratio [ HR ] 1.59 , 95 % CI 1.32 - 1.92 , p<0.0001 ; and 1.52 , 1.20 - 1.92 , p=0.0006 , respectively ) and overall survival ( 1.79 , 1.47 - 2.19 , p<0.0001 ; and 1.62 , 1.26 - 2.08 , p=0.0002 respectively ) . We detected no significant interaction with anthracycline benefit for Ki67 , HER2 , HER1 - 3 , or TOP2A . By contrast , in multivariate analyses , Ch17CEP duplication was associated with significant improvements in both relapse-free ( HR 0.92 , 95 % CI 0.72 - 1.18 for tumours with normal Ch17CEP vs 0.52 , 0.34 - 0.81 for tumours with abnormal Ch17CEP ; p for interaction=0.004 ) and overall survival ( 0.94 , 0.72 - 1.24 vs 0.57 , 0.36 - 0.92 ; p for interaction=0.02 ) with anthracycline use . INTERPRETATION In women with early breast cancer receiving adjuvant chemotherapy  , the most powerful predictor of benefit from anthracyclines is Ch17CEP duplication . In view of the location of HER2/TOP2A on chromosome 17 , Ch17CEP duplication might explain the inconsistencies in previous studies of factors predicting benefit from anthracyclines . FUNDING Cancer Research UK and the Scottish Breast Cancer Clinical Trials Group A r and omized multicenter phase III study was conducted to compare the sequential docetaxel followed by epirubicin/cyclophosphamide combination with that of FEC regimen as adjuvant chemotherapy in women with axillary node-positive early breast cancer . Seven hundred and fifty-six women with axillary lymph node-positive breast cancer were r and omized to receive either 4 cycles of docetaxel ( 100 mg/m2 ) followed by 4 cycles of epirubicin ( 75 mg/m2 ) plus cyclophosphamide ( 700 mg/m2 ) ( experimental arm ) or 6 cycles of FEC ( epirubicin 75 mg/m2 , cyclophosphamide 700 mg/m2 , and 5-fluorouracil 700 mg/m2 ; control arm ) . All regimes were administered every 3 weeks . The primary end point was five-year disease-free survival ( DFS ) . After a median follow-up period of 5 years , 233 ( 30.8 % ) relapses had occurred ( 108 and 125 in the experimental and control arms , respectively ; P = 0.181 ) . The five-year DFS was 72.6 % ( 95 % CI 63.8–81.3 % ) and 67.2 % ( 95 % CI 58.0–76.4 % ) for women r and omized in the experimental and control arms , respectively ( P = 0.041 ; log rank test ) . There was no difference in the overall survival between the two arms ( 83.8 and 81.4 % in the experimental and control arms , respectively ; P = 0.533 ) . The experimental arm was associated with increased neutropenia requiring administration of granulocyte colony-stimulating factor in 90.5 % of the patients as compared with 74.1 % in the control arm ( P = 0.0001 ) . The sequential docetaxel followed by epirubicin/cyclophosphamide adjuvant chemotherapy regimen result ed in improved five-year DFS in women with axillary node-positive early breast cancer at the expense of increased but manageable myelotoxicity PURPOSE The indications of adjuvant chemotherapy for patients with estrogen receptor ( ER ) -positive breast cancer are controversial . We analyzed the predictive value of Ki67 , HER2 , and progesterone receptor ( PR ) expression for the efficacy of docetaxel in patients with ER-positive , node-positive breast cancer . PATIENTS AND METHODS Expression of Ki67 , HER2 , and PR was measured by immunohistochemistry in tumor sample s from 798 patients with ER-positive breast cancer who participated in PACS01 , a r and omized trial that evaluated the efficacy of docetaxel . Risk reduction was evaluated using a Cox model adjusted for age , tumor size , nodal involvement , treatment arm , and biomarkers . The predictive value of biomarkers was assessed by an interaction test . Disease-free survival ( DFS ) was the primary end point . Results Ki67 , HER2 , and PR were expressed in 21 % , 9 % , and 62 % of sample s , respectively . Hazard ratios for relapse associated with docetaxel were 0.51 ( 95 % CI , 0.26 to 1.01 ) in ER-positive/Ki67-positive tumors and 1.03 ( 95 % CI , 0.69 to 1.55 ) in ER-positive/Ki67-negative tumors ( ratio for interaction : 0.53 ; 95 % CI , 0.24 to 1.16 ; P = .11 ) . Five-year DFS rates were 81 % ( 95 % CI , 76 % to 86 % ) and 84 % ( 95 % CI , 75 % to 93 % ) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81 % ( 95 % CI , 76 % to 86 % ) and 62 % ( 95 % CI , 52 % to 72 % ) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil , epirubicin , and cisplatin . No trend for interaction was observed between docetaxel and HER2 ( ratio for interaction : 0.83 ; 95 % CI , 0.35 to 1.94 ; P = .66 ) , nor between docetaxel and PR ( ratio for interaction : 0.89 ; 95 % CI , 0.47 to 1.66 ; P = .71 ) . CONCLUSION Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting Background To compare the cyclophosphamide , methotrexate , and fluorouracil ( CMF ) chemotherapy and the anthracycline-containing regimen cyclophosphamide , epirubicin , and fluorouracil ( CEF ) to evaluate the efficacy and safety of the latter . Methods A total of 294 patients with axillary node-positive primary breast cancer of STAGE I – IIIa were r and omly assigned to either CEF [ cyclophosphamide ( CPA ) 500 mg/m2 i.v . days 1 and 8 ; epirubicin ( EPI ) 60 mg/m2 i.v . day 1 ; and 5-fluorouracil ( 5-FU ) 500 mg/m2 i.v . days 1 and 8 ] or CMF [ CPA 500 mg/m2 i.v . days 1 and 8 ; methotrexate ( MTX ) 40 mg/m2 i.v . days 1 and 8 ; and 5-FU 500 mg/m2 i.v . days 1 and 8 ] . Both treatment regimens were comprised of six cycles at 4-week intervals . Tamoxifen ( TAM ) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years . Results The overall 5-year survival was 77.1 % for CEF and 71.4 % for CMF [ p = 0.24 ; hazard ratio 0.79 ( 95 % CI 0.50–1.24 ) ] , and the 5-year disease-free survival was 55.7 % for CEF and 48.9 % for CMF [ p = 0.15 ; hazard ratio 0.80 ( 95 % CI 0.57–1.12 ) ] . Although the log-rank test did not show a significant difference , both overall and disease-free survivals were higher for CEF according to the point estimates . Adverse drug reactions ( ADRs ) occurred more frequently in CEF . Conclusion Whereas CEF had a good trend compare with CMF , it could not be proven statistically significant . The principal cause of the failure seems to be insufficient power , that is , the dose intensity ( EPI : 60 mg/m2 ) set 10 years ago , when the trial began , was low , and the number of trial subjects was small because of the background of the times , which made the accumulation of cases extremely difficult . However , the trial should be considered to be meaningful , as it was the first , formally conducted controlled trial on chemotherapy in Japan Purpose To eluci date whether adjuvant taxane monotherapy is a feasible and tolerable for postoperative breast cancer patients , we evaluated the severity of chemotherapy-induced peripheral neuropathy ( CIPN ) and the relative tolerability of regimens by health-related quality of life ( HRQOL ) assessment in node-positive breast cancer patients treated with taxane-containing regimens . Methods We evaluated CIPN and HRQOL in the first 300 patients enrolled in a larger ( 1,060 total ) multicenter phase III trial r and omized to one of four adjuvant regimens :  ( 1 ) anthracycline – cyclophosphamide followed by paclitaxel ( ACP ) , ( 2 ) AC followed by docetaxel ( ACD ) , ( 3 ) paclitaxel alone ( PTX ) , or ( 4 ) docetaxel alone ( DTX ) . CIPN was assessed by the Patient Neurotoxicity Question naire ( PNQ ) and the National Cancer Institute Common Toxicity Criteria , and HRQOL by Functional Assessment of Cancer Therapy-General ( FACT-G ) . CIPN and HRQOL scores were compared between ACP and ACD vs. PTX and DTX , and ACP and PTX vs. ACD and DTX . Results PNQ sensory scores were significantly higher in patients treated with taxane monotherapy compared to treatment with AC followed by taxane ( P = .003 ) . No significant differences in PNQ sensory scores were observed between the ACP and PTX vs. ACD and DTX regimens ( P = .669 ) . Regardless of taxane regimen , PNQ severity scores for CIPN appear to be largely reversible within 1 year of adjuvant treatment . No significant difference in FACT-G scores was observed between any regimens during the study treatments . Conclusions Patient-reported CIPN was significantly more severe with single-agent adjuvant taxane compared to AC followed by taxane treatment ; however , the HRQOL findings support that single-agent taxane treatment is tolerable To explore the impact of dose intensity ( DI ) in the adjuvant setting of breast cancer , a r and omized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin , paclitaxel , and cyclophosphamide , methotrexate and fluorouracil (CMF)in  high-risk breast cancer patients . From Oct 2000 to June 2005 , 1,121 node-positive patients were r and omized to dose-dense sequential epirubicin 110 mg/m2 and paclitaxel ( Taxol ® , Bristol Myers-Squibb , Princeton , NJ ) 250 mg/m2 ( group A ) , or concurrent epirubicin 83 mg/m2 and paclitaxel 187 mg/m2 ( group B ) , both followed by three cycles of “ intensified ” combination chemotherapy with CMF . By protocol design total cumulative dose and duration of treatment were identical in both groups . Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm . Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments . Disease-free survival ( DFS ) was the primary endpoint . At a median follow-up of 76 months , 253 patients ( 23 % ) had documented disease relapse ( 123 vs. 130 in groups A and B , respectively ) and 208  deaths  ( 101 , group A and 107 , group B ) had been observed . The 5-year DFS rate of 74 and 74 % and OS rate of 86 and 85 % were observed for group A and group B , respectively . No differences were found in DFS or OS between the two treatment groups ( P = 0.78 and P = 0.45 for DFS and OS , respectively ) . Safety analysis results showing that both regimens were well tolerated and safe have been previously published ( Fountzilas et al. Ann Oncol 2008 ) . No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs . No additional safety issues were raised with long-term follow-up 10625 Background : Patients with hormone receptor positive breast cancer and 1 - 3 positive lymph nodes ( LN ) belong to the intermediate risk-group . Among these patients chemo-endocrine therapy may be considered according to the St. Gallen guidelines . We compared evidence -based cut-offs of Ki-67 for definition of molecular subtypes to central grade regarding their predictive value for benefit from taxane-based chemotherapy . METHODS The EC-Doc trial r and omized 1950 patients with 1 - 3 positive LN to 6x CEF/CMF vs. 4xEC-4xDoc .  Significantly better DFS and OS favoring EC-Doc have been previously reported ( Nitz et al. , SABCS 2008 ) . Protein expression data ( ER , PR , HER2[+FISH ] , Ki-67 , Ck 5 , and EGFR ) and central histology/ grade were available for 772 patients . Molecular subgroups were classified using Ki-67 cut-off 's of 13.25 % and 20 % ( due to correlation with genomic grade index [ GGI ] ) . GGI analysis is planned . RESULTS The entire and the investigated study population s did not differ regarding baseline characteristics . After median follow up of 64 months , both DFS ( 5y 90 % vs. 80 % , p=0.006 ) and OS ( 5y 95 % vs. 92 % , p=0.022 ) rates significantly favored EC-Doc vs. CEF also in this cohort . 5-y DFS was longest in luminal A and shortest in basal-like tumors ( 97 % vs. 72 % , p<0.001 ) . Both Ki-67 cut-offs ( 13.25 % and 20 % ) used for defining luminal B subtype were predictive for taxane benefit . However , only Ki-67 cut-off of 20 % was significant regarding interaction with therapy ( HR=0.467 , p=0.02 ) in multivariate analysis including central grade , age , nodal status , tumor size , molecular subtypes , therapy , and predictive interactions between all factors and therapy . Only central grade ( HR=4.315 , p<0.001 ) and luminal A subtype ( HR=0.343 , p<0.001 ) were shown as significant prognostic factors for the whole collective . CONCLUSIONS These data provide evidence that luminal B subtype defined by HR positive and KI-67>20 % or HER2 + is the only predictive factor for taxane benefit in intermediate risk BC and that both central grade and luminal A subtype are strong prognostic markers . These results are currently vali date d within the prospect i ve WSG PlanB trial PURPOSE According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials , we investigated whether node-negative breast cancer patients , defined as high-risk cases on the basis of tumor cell proliferation , could benefit from cyclophosphamide , methotrexate , and fluorouracil ( CMF ) adjuvant therapy . PATIENTS AND METHODS Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors , defined according to thymidine labeling index ( TLI ) , were r and omized to receive six cycles of CMF or no further treatment after surgery + /- radiotherapy . RESULTS The 5-year disease-free survival ( DFS ) was 83 % for patients treated with CMF compared with 72 % in the control group ( P : = .028 ) . Adjuvant treatment reduced both locoregional and distant metastases . When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria , compared with patients in the control arm , 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second ( 78 % v 88 % , respectively ; P : = .037 ) and third tertiles ( 58 % v 78 % , respectively ; P : = .024 ) . CONCLUSION The results from this r and omized clinical study indicate that patients with node-negative , rapidly proliferating tumors significantly benefit from adjuvant CMF PURPOSE The primary aim of this study was to compare the effectiveness of oral uracil-tegafur ( UFT ) with that of classical cyclophosphamide , methotrexate , and fluorouracil ( CMF ) given as postoperative adjuvant treatment to women with node-negative , high-risk breast cancer . PATIENTS AND METHODS Women with node-negative , high-risk breast cancer were r and omly assigned to receive either 2 years of UFT or six cycles of CMF after surgery . The primary end point was relapse-free survival ( RFS ) . Overall survival ( OS ) , toxicity , and quality of life ( QOL ) were secondary end points . The hypothesis was that UFT was not inferior to CMF in terms of RFS . RESULTS Between October 1996 and April 2001 , a total of 733 patients were r and omly assigned to receive either treatment . The median follow-up time was 6.2 years . The RFS rates at 5 years were 88.0 % in the CMF arm and 87.8 % in the UFT arm . OS rates were 96.0 % and 96.2 % , respectively . The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS ( 95 % CI , 0.66 to 1.45 ; P = .92 ) and 0.81 for OS ( 95 % CI , 0.44 to 1.48 ; P = .49 ) . The toxicity profiles differed between the two groups . The QOL scores were better for patients given UFT than those given CMF . CONCLUSION RFS and OS with oral UFT were similar to those with classical CMF . Given the higher QOL scores , oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative , high-risk breast cancer OBJECTIVE To examine health-related quality of life , we investigated the effect of adjuvant chemotherapy regimens on utility scores assessed by the EuroQoL-5D ( EQ-5D ) instrument in a r and omized , controlled trial for breast cancer patients after surgery . We also investigated the relationship between Functional Assessment of Cancer Therapy ( FACT ) scale scores and EQ-5D utilities . METHODS Patients were r and omly assigned to the following four chemotherapy regimens : four cycles of anthracycline followed by paclitaxel ( ACP ) , four cycles of anthracycline-containing regimens followed by docetaxel ( ACD ) , eight cycles of paclitaxel ( PTX ) , and eight cycles of docetaxel ( DTX ) .  Of 1060 registered , the first 300 consecutive patients were included in the current utility study . Utility scores were assessed using the EQ-5D instrument at baseline ; cycles 3 , 5 , and 7 ; 7 months ; and 1 year . We also evaluated the correlation between these scores and FACT-G , -B , and -Taxane scores at each time point . RESULTS Utility scores were significantly lower in the DTX group than in the ACP and ACD groups . Mean utility scores in the DTX group were lowest at 7 months and tended to remain low for a long time . The combined anthracycline followed by taxane group had significantly higher utility scores that the taxane-alone group , with no significant difference depending on the type of taxane . Only the FACT-G social/family well-being subscale had no relationship with EQ-5D responses and utility scores . CONCLUSIONS Although the regimens in this study were similar in that they included taxane , the mean utility scores and longitudinal patterns of utility scores were different among regimens We aim ed to determine the efficacies of a non-anthracycline-containing regimen , docetaxel/capecitabine ( TX ) , in comparison with an anthracycline-containing regimen , doxorubicin/cyclophosphamide ( AC ) , as primary chemotherapy for node-positive early stage breast cancer . In this phase-III single center r and omized study , we r and omized 209 women with axillary node positive , stage II/III breast cancer to receive four cycles of either TX or AC followed by surgery and cross-over to the other treatment as an adjuvant therapy . The primary endpoint was tumor pathologic complete response ( pCR ) . Clinical response rates , toxicity profiles , disease free survival ( DFS ) , and overall survival were secondary objectives . In total , 204 patients had clinical and radiological evaluation of response , and underwent surgery . Compared with AC , TX increased pCR in primary tumors ( 21 % vs. 10 % , respectively , P = 0.024 ) and clinical response ( 84 % vs. 65 % , P = 0.003 ) . TX was associated with less nausea and vomiting , but more stomatitis , diarrhea , myalgia , and skin/nail changes than AC . With a median follow-up of 37 months , there was no significant difference in DFS by treatment groups ( P = 0.932 ) . Fewer patients developed recurrence who achieved pCR in lymph node ( LN ) ( P = 0.025 ; hazard ratio , 0.189 ; 95 % CI , 0.044–0.815 ) in the multivariate analysis . TX showed superior efficacies to AC with increased pathologic and clinical complete response rates . Although these findings did not translate into a gain in DFS , the patients who achieved pCR in LN developed significantly less recurrence PURPOSE The primary aim of National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B-28 was to determine whether four cycles of adjuvant paclitaxel ( PTX ) after four cycles of adjuvant doxorubicin/cyclophosphamide ( AC ) will prolong disease-free survival ( DFS ) and overall survival ( OS ) compared with four cycles of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes . PATIENTS AND METHODS Between August 1995 and May 1998 , 3,060 patients were r and omly assigned ( AC , 1,529 ; AC followed by PTX [ AC -- > PTX ] , 1,531 ) . Patients > or = 50 years and those younger than 50 years with estrogen receptor ( ER ) or progesterone receptor ( PR ) -positive tumors also received tamoxifen for 5 years , starting with the first dose of AC . Postlumpectomy radiotherapy was m and ated . Postmastectomy or regional radiotherapy was prohibited . Median follow-up is 64.6 months . RESULTS The addition of PTX to AC significantly reduced the hazard for DFS event by 17 % ( relative risk [ RR ] , 0.83 ; 95 % CI , 0.72 to 0.95 ; P = .006 ) . Five-year DFS was 76 % + /- 2 % for patients r and omly assigned to AC -- > PTX compared with 72 % + /- 2 % for those r and omly assigned to AC . Improvement in OS was small and not statistically significant ( RR , 0.93 ; 95 % CI , 0.78 to 1.12 ; P = .46 ) . Five-year OS was 85 % + /- 2 % for both groups . Subset analysis of the effect of paclitaxel according to hormone receptors or tamoxifen administration did not reveal statistically significant interaction ( for DFS , P = .30 and P = .44 , respectively ) . Toxicity with the AC -- > PTX regimen was acceptable for the adjuvant setting . CONCLUSION The addition of PTX to AC result ed in significant improvement in DFS but no significant improvement in OS with acceptable toxicity . No significant interaction between treatment effect and receptor status or tamoxifen administration was observed There are no vali date d predictors of benefit from anthracyclines . We compared cyclophosphamide , methotrexate , 5-fluorouracil ( CMF ) , and epirubicin in different sequences with CMF alone in a phase III trial on operable breast cancers . Outcomes were analyzed in relation to tumor biological profiles to identify potential predictors of the efficacy of different treatments/drug combinations . Patients with N− or 1–3N+ tumors , were r and omized to receive ( a ) epirubicin ( 4 cycles ) followed by CMF ( 4 cycles ) ; ( b ) CMF ( 4 cycles ) followed by epirubicin ( 4 cycles ) , or ( c ) CMF ( 6 cycles ) alone . Immunohistochemical assessment s of estrogen ( ER ) and progesterone ( PgR ) receptors , HER2 and Ki67 were available for 705 patients ( arm A/B/C : 276/269/160 ) . Prognostic and predictive relevance was analyzed by log-rank tests and Cox models . Ki67 > 20 % and absent/low expression of ER and PgR were associated with worsen disease-free ( DFS ) and overall survival ( OS ) . In patients with triple negative tumors ( ER− , PgR− , HER2− ) , epirubicin-containing regimens yielded better DFS ( HR 0.33 , 95 % CI 0.17–0.62 , P = 0.0007 ) and OS ( HR 0.24 , 95 % CI 0.10–0.57 , P = 0.001 ) compared with CMF alone , whereas no differences were found in patients with HER2-positive ( HER2 + , ER− , PgR− ) subtype . Treatment by subtype interaction ( HER2-positive vs. others ) was significant for DFS ( χ2 = 6.72 , P = 0.009 ) . In triple unfavorable ( ER− , PgR− , Ki67 > 20 % ) tumors , the use of epirubicin yielded better DFS ( HR 0.45,95 % CI 0.26–0.78 , P = 0.005 ) and OS ( HR 0.30 , 95 % CI 0.15–0.63 , P = 0.001 ) . Epirubicin-containing regimens seem to be superior to CMF alone in patients with highly proliferating , triple negative or triple unfavorable tumors Adjuvant cyclophosphamide , methotrexate , and 5-fluorouracil ( CMF ) have proven highly effective in rapidly proliferating breast cancer ( RPBC ) . It has also been seen that sequential administration of doxorubicin and CMF is superior to their alternation , especially in indolent tumors . In a phase III study , we evaluated whether adjuvant epirubicin ( E ) followed by CMF is superior to the inverse sequence in RPBC . Patients with node-negative or 1–3 node-positive RPBC ( Thymidine Labeling Index > 3 % or histological grade 3 or S-phase > 10 % or Ki67 > 20 % ) were r and omized to receive E ( 100 mg/m2 i.v . d1 , q21 days for 4 cycles ) followed by CMF ( 600 , 40 , 600 mg/m2 i.v . d1 and 8 , q28 days for 4 cycles ) ( E → CMF ) or CMF followed by E ( CMF → E ) or CMF for 6 cycles . From November 1997 to December 2004 , 1066 patients were enrolled :  E → CMF 440 , CMF → E 438 , and CMF 188 . At a median follow-up of 69 months , 5-year OS was 91 % ( 95 % CI 88–94 ) for E → CMF and 93 % ( 95 % CI 90–95 ) for CMF → E , with adjusted hazard ratio of 0.88 ( 95 % CI 0.58–1.35 ) , and DFS was 80 % in both arms , with adjusted hazard ratio of 0.99 ( 95 % CI 0.73–1.33 , Cox model ) . Adverse events were similar , apart from a higher rate of neutropenia in the CMF → E arm . No important differences in clinical outcome were observed between the two different sequences , making both a valid option in early breast cancer . Further molecular characterization of the tumors might help to identify subgroups achieving higher benefit from either sequence PURPOSE The Docetaxel Epirubicin Adjuvant ( DEVA ) trial evaluated the efficacy and toxicity of incorporating docetaxel after epirubicin to create a sequential anthracycline-taxane regimen in early breast cancer . PATIENTS AND METHODS After complete tumor excision , postmenopausal women with node-positive early breast cancer were r and omly assigned to either epirubicin 50 mg/m(2 ) on days 1 and 8 every 4 weeks for six cycles ( EPI × 6 ) or three cycles of epirubicin 50 mg/m(2 ) on days 1 and 8 every 4 weeks followed by three cycles of docetaxel 100 mg/m(2 ) on day 1 every 3 weeks ( EPI-DOC ) . A subset of patients also participated in a quality of life ( QOL ) study . The primary end point was disease-free survival ( DFS ) . RESULTS From 1997 to 2005 , 803 patients entered DEVA ( EPI × 6 , n = 397 ; EPI-DOC , n = 406 ) . At a median follow-up of 64.7 months ( interquartile range , 45.2 to 84.4 months ) , 198 DFS events had been reported ( EPI × 6 , n = 114 ; EPI-DOC , n = 84 ) . The 5-year DFS rates were 72.7 % ( 95 % CI , 68.0 % to 77.3 % ) for epirubicin alone and 79.5 % ( 95 % CI , 75.2 % to 83.8 % ) for epirubicin followed by docetaxel ; evidence of improvement in DFS was observed with EPI-DOC ( hazard ratio [ HR ] , 0.68 ; 95 % CI , 0.52 to 0.91 ; P = .008 ) . One hundred twenty-seven patients have died ( EPI × 6 , n = 75 ; EPI-DOC , n = 52 ) ; a reduction in deaths was observed with EPI-DOC ( HR , 0.66 ; 95 % CI , 0.46 to 0.94 ; P = .02 ) . The 5-year overall survival rates were 81.8 % ( 95 % CI , 77.7 % to 85.9 % ) for epirubicin and 88.9 % ( 95 % CI , 85.5 % to 92.2 % ) for epirubicin followed by docetaxel . Assessment of toxicity and QOL showed that EPI-DOC was associated with greater toxicity but with no difference in QOL between arms during follow-up . CONCLUSION These results suggest , within a relatively small trial , that substitution of docetaxel for epirubicin for the last three cycles of chemotherapy results in improved outcome in postmenopausal women with node-positive , early breast cancer compared with six cycles of epirubicin monotherapy BACKGROUND The National Epirubicin Adjuvant Trial ( NEAT ) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer . METHODS In NEAT , we compared four cycles of epirubicin followed by four cycles of cyclophosphamide , methotrexate , and fluorouracil ( CMF ) with six cycles of CMF alone . In the BR9601 trial , we compared four cycles of epirubicin followed by four cycles of CMF , with eight cycles of CMF alone every 3 weeks . The primary end points were relapse-free and overall survival . The secondary end points were adverse effects , dose intensity , and quality of life . RESULTS The two trials included 2391 women with early breast cancer ; the median follow-up was 48 months . Relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups ( 2-year relapse-free survival , 91 % vs. 85 % ; 5-year relapse-free survival , 76 % vs. 69 % ; 2-year overall survival , 95 % vs. 92 % ; 5-year overall survival , 82 % vs. 75 % ; P<0.001 by the log-rank test for all comparisons ) . Hazard ratios for relapse ( or death without relapse ) ( 0.69 ; 95 % confidence interval [ CI ] , 0.58 to 0.82 ; P<0.001 ) and death from any cause ( 0.67 ; 95 % CI , 0.55 to 0.82 ; P<0.001 ) favored epirubicin plus CMF over CMF alone . Independent prognostic factors were nodal status , tumor grade , tumor size , and estrogen-receptor status ( P<0.001 for all four factors ) and the presence or absence of vascular or lymphatic invasion ( P=0.01 ) . These factors did not significantly interact with the effect of epirubicin plus CMF . The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life . CONCLUSIONS Epirubicin plus CMF is superior to CMF alone as adjuvant treatment for early breast cancer . ( Clinical Trials.gov number , NCT00003577 [ Clinical Trials.gov ] . ) 1070 Background : Taxane-based anthracycline containing chemotherapy has been established as treatment option in the adjuvant setting of early breast cancer . Indication was recently enlarged for high risk node negative breast cancer . Promising retrospective data indicate equi-efficacy of anthracycline-free chemotherapy in Her2/neu-negative patients ( Gennari et al. , Slamon et al. ) . Anthracycline-free regimens are probably associated with less long-term toxicities , especially cardiac toxicities . METHODS The SUCCESS-C trial is an open-label , multicenter , 2x2 factorial design , r and omized controlled , phase III study comparing the disease free survival in patients treated with 3 cycles fluorouracil 500mg/m2-epirubicine 100mg/m2-cyclophosphamide 500mg/m2 ( FEC ) chemotherapy , followed by 3 cycles docetaxel 100mg/m2 ( D ) chemotherapy , versus 6 cycles docetaxel 75mg/m2-cyclophosphamide 600mg/m2 ( DC ) chemotherapy .  Monitored toxicity data after end of treatment are available from 1,452 patients . RESULTS Chemotherapy was prematurely stopped in 51 pts ( 7.2 % ) receiving FEC-D and in 57 pts ( 7.7 % ) with DC ( p=0.71 ) . Dose reductions occurred significantly more often in the FEC-D arm ( 2.7 % ) than in the DC arm ( 1.9 % , p=0.024 ) , reasons did not differ significantly between both arms ( p=0.093 ) . Incidence of treatment-postponement was significantly higher for FEC-D ( 9.4 % FEC-D vs. 7.6 % DC ; p=0.0008 ) . Haematological toxicity as a reason for treatment-postponement occurred significantly more frequent within the FEC-D-arm ( FEC-D : 18.1 % , DC : 6.6 % , p<0,0001 ) ; non-haematological toxicity as a reason for treatment postponement was nearly equal within both arms ( 8.6 % FEC-D vs. 8.8 % DC , p=0.9 ) . G-CSF support was applied in 22.7 % of all chemotherapy cycles ( FEC-D : 22.2 % vs. DC : 23.2 % , p=0.21 ) . Severe toxicities ( NCI- grade > 2 ) were reported in 910 cases for FEC-D and in 848 cases for DC arm ( p= 0.02 ) . CONCLUSIONS Significantly more dose-reductions of chemotherapy and a significant higher incidence of treatment-postponement occurred in the FEC-D arm . The toxicity profiles of both treatment arms differ discretely and support the continuation of the trial until target recruitment ( n=3,547 ) PURPOSE This study compared disease-free survival ( DFS ) obtained with two different regimens of adjuvant therapy in high-risk breast cancer . METHODS Women ( who had performance status [ PS ] of 0 to 1 ) with operable , histologically confirmed , stage I to III adenocarcinoma of the breast were eligible . Patients had undergone primary surgery with no residual tumor . Treatments were as follows : arm 1 was doxorubicin 60 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) every 3 weeks for four cycles followed by paclitaxel 175 mg/m(2 ) every 3 weeks for four cycles ( ie , AC-P ) ; and arm 2 was doxorubicin 50 mg/m(2 ) plus paclitaxel 200 mg/m(2 ) every 3 weeks for four cycles followed by paclitaxel 80 mg/m(2 ) weekly for 12 weeks . RESULTS Overall , 1,830 patients were enrolled and 1,801 were treated : arm 1 ( n = 906 ; AC-->P ) and arm 2 ( n = 895 ; AP-WP ) . Overall , patients had a PS of 0 ( 88 % ) , had estrogen receptor and progesterone receptor-positive disease ( 52 % ) , had one to three positive nodes ( 46 % ) , and were postmenopausal ( 57 % ) ; the median age was 52 years . Currently , 1,640 patients ( 90 % ) are alive . The 6-year DFS was 79 % to 80 % in both groups . Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2 . Overall 6-year survival rates were 82 % and 87 % in arms 1 and 2 , respectively . Reasons for patients being taken off study treatment included toxicity ( 13 % in arm 1 v 20 % in arm 2 ) , progressive disease or recurrence ( 7 % v 5 % ) , and consent withdrawn ( 9 % v 8 % ) , respectively . The most frequent toxicities were hematologic , including neutropenia and leukopenia followed by neuropathy , myalgia , nausea , fatigue , headache , arthralgia , and vomiting . CONCLUSION The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer . The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen BACKGROUND The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of st and ard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer . PATIENTS AND METHODS A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2 ) every 3 weeks ( EC→T ) , or three cycles of epirubicin 150 mg/m(2 ) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2 ) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide , methotrexate , and fluorouracil ( E(dd)→T(dd)→CMF ) . The patients were r and omly assigned to receive darbepoetin or none . The primary objective was to demonstrate a superior disease-free survival ( DFS ) of E(dd)→T(dd)→CMF compared with EC→T. RESULTS Estimated 3-year DFS was 75.8 % with EC→T versus 78.8 % with E(dd)→T(dd)→CMF [ hazard ratio ( HR ) 1.14 ; P = 0.37 ] and overall survival ( OS ) 88.4 % versus 91.5 % ( HR 1.26 ; P = 0.237 ) . Three-year DFS was 74.3 % with darbepoetin versus 80.0 % without ( HR 1.31 ; P = 0.061 ) and OS 88.0 % versus 91.8 % ( HR 1.33 ; P = 0.139 ) . Patients with  a pathologically documented complete response [ pathological complete response ( pCR ) ] had a significantly better DFS compared with those without achieving a pCR ( estimated 3-year DFS : 89.2 % versus 74.9 % ; HR 2.27 ; P = 0.001 ) . CONCLUSION Neoadjuvant dose-intensified chemotherapy compared with st and ard chemotherapy did not improve DFS , whereas the addition of darbepoetin might have detrimental effects on DFS A previous r and omized trial ( CALGB 9344/Intergroup 0148 ) compared four cycles of adjuvant doxorubicin/cyclophosphamide ( AC ) to four cycles of AC plus four cycles of paclitaxel ( AC + T ) and demonstrated that the addition of paclitaxel  improved locoregional control ( LRC ) in patients with node-positive breast cancer . However , it could not be determined whether it was the paclitaxel or the increased duration of chemotherapy that led to this improvement . The present study aim ed to analyze whether the addition of paclitaxel to a doxorubicin-based regimen  improves LRC in a cohort of patients who all received eight total cycles of chemotherapy . Five hundred eleven women with operable breast cancer were r and omized on a single-institution prospect i ve trial to receive 5-fluorouracil , doxorubicin , cyclophosphamide ( FAC ) × 8 cycles ( n = 252 ) or FAC × 4 cycles plus paclitaxel × 4 cycles ( TFAC ) ( n = 259 ) . Rates of LRC and overall survival ( OS ) were analyzed . Median follow-up was 124 months ( range 5–167 months ) . The 10-year LRC rate was 92.6 versus 93.1 % in the FAC versus TFAC arms , respectively ( P = 0.26 ) . The LRC between treatment arms did not differ when analyzed by locoregional treatment group : breast conservation therapy ( BCT ) , mastectomy alone ( M ) , and mastectomy + radiation ( M + RT ) . The 10-year LRC rates were 95.1 % ( FAC ) versus 91.2 % ( TFAC ) after BCT ( P = 0.98 ) , 89.5 % ( FAC ) versus 93.4 % ( TFAC ) after M ( P = 0.24 ) , and 94.7 % ( FAC ) versus 96.5 % ( TFAC ) after M + RT ( P = 0.59 ) . Additionally , there was no difference in OS between the treatment arms , with 10-year OS rates of 78.4 % ( FAC ) versus 81.7 % ( TFAC ) ( P = 0.93 ) . The addition of paclitaxel to a doxorubicin-based regimen had no impact on LRC , regardless of the type of local therapy received . Historically inferior LRC with AC chemotherapy alone versus AC + T may have been due to an inadequate duration of systemic therapy and not due to the absence of paclitaxel TPS103 Background : There has been a recent convergence of epidemiologic , clinical and pre clinical evidence suggesting metformin ( a biguanide used to treat type 2 diabetes ) may lower BC risk and improve BC outcomes . This evidence raises the intriguing possibility that metformin may act ( i ) indirectly by lowering circulating insulin levels ( secondary to reduced hepatic gluconeogenesis ) leading to reduced insulin/IGF-I receptor mediated PI3 K signaling in BC cells or ( ii ) directly on tumor cells , largely via an AMPK mediated mechanism , leading to mTOR inhibition . METHODS NCIC CTG led , CTEP sponsored , r and omized , phase III trial of metformin 850 mg po bid vs placebo bid for 5 years . Eligibility criteria : pTIcNO ( and > one : grade 3 , ER/PR- , HER2Neu+ , lymphovascular invasion , Oncotype DX recurrence score>25 , Ki67>14 % ) or pT2/T3 N0 or pT1 - 3 N1 - 3 . St and ard adjuvant therapy ( chemotherapy , hormone , biologics ) Adequate organ function and PS Age 18 - 75 Endpoints : Primary : invasive disease free survival ( IDFS ) . Secondary : overall survival , distant disease free survival , BC free survival , adverse events , new diabetes , cardiovascular hospitalizations , BMI , insulin resistance syndrome attributes ( ATP III criteria ) , Quality of Life , diet and physical activity . Correlative studies : Embedded correlative research examines prognostic factors and targets and predictors of metformin benefit . Variables include : Fasting Insulin , glucose , Homeostasis Model Assessment ( HOMA ) ( baseline , 6 months , end of treatment ) : genomic/gene expression analysis of blood and tumour , tumor insulin receptor ( IR ) , IGF-IR , tumor molecular markers of target pathways ( LKBI , PI3 K ( STMN1 ) , PKB/Akt ( P-PKB/Akt , ) mTOR ( P-4E-BP1 ) and IRS-1 ( P-IRS-1 ) ; Fatigue sub- study with biological correlates ( NSABP led ) . Statistical design : Planned accrual is 3,582 subjects over 3 years with 3 more years follow-up . Target hazard ratio is 0.76 ( 5 year IDFS of 88.4 % vs 85 % , power 0.80 , 2-tail type 1 error of 0.05 ) . Two interim analyses are planned . Conduct to Date : Study activation : June 2010 . Enrollment : 145 subjects . In Nov 2010 a DSMC review supported trial continuation The Danish Breast Cancer Cooperative Group ( DBCG ) 77B trial examined the relative efficacy of levamisole , single‐agent oral cyclophosphamide , and the classic combination of cyclophosphamide , methotrexate , and 5‐fluorouracil ( CMF ) against no adjuvant systemic therapy in high‐risk breast cancer patients . The authors report the results from that trial after a potential follow‐up of 25 years PURPOSE The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known . Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles . We also sought to determine whether paclitaxel ( T ) is as efficacious as doxorubicin/cyclophosphamide ( AC ) , but with reduced toxicity . PATIENTS AND METHODS Between 2002 and 2008 , the study enrolled women with operable breast cancer and zero to three positive nodes . Patients were r and omly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor ( ER/PgR ) , human epidermal growth factor receptor 2 ( HER2 ) , and menopausal status . After 2003 , all treatment was administered in dose-dense fashion . The primary efficacy end point was relapse-free survival ( RFS ) . RESULTS A total of 3,171 patients were enrolled ; 94 % were node-negative and 6 % had one to three positive nodes . At a median follow-up of 5.3 years , the 4-year RFS was 90.9 % and 91.8 % for six and four cycles , respectively . The adjusted hazard ratio ( HR ) of six to four cycles regarding RFS was 1.03 ( 95 % CI , 0.84 to 1.28 ; P=.77 ) . The 4-year OS was 95.3 % and 96.3 % for six and four cycles , respectively , with an HR of six to four cycles of 1.12 ( 95 % CI , 0.84 to 1.49 ; P=.44 ) . There was no interaction between treatment duration and chemotherapy regimen , ER/PgR , or HER2 status on RFS or OS . CONCLUSION For women with resected primary breast cancer and zero to three positive nodes , we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome Background In women with node-positive breast cancer , the Breast International Group ( BIG ) 02 - 98 tested the incorporation of docetaxel ( Taxotere ) into doxorubicin (Adriamycin)-based chemotherapy , and compared sequential and concurrent docetaxel . At 5 years , there was a trend for improved disease-free survival ( DFS ) with docetaxel . We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes . Methods Patients were r and omly assigned to one of four treatments : ( i ) sequential control : doxorubicin ( A ) ( 75 mg/m(2 ) ) × 4 →classical cyclophosphamide , methotrexate , 5-fluorouracil ( CMF ) ; ( ii ) concurrent control : doxorubicin , cyclophosphamide (AC)(60/600 mg/m(2 ) ) × 4 →CMF ; ( iii ) sequential docetaxel : A ( 75 mg/m(2 ) ) × 3 → docetaxel ( T ) ( 100 mg/m(2 ) ) × 3 → CMF and ( iv ) concurrent docetaxel : AT(50/75 mg/m(2 ) ) × 4 →CMF . The primary comparison evaluated  docetaxel efficacy regardless of the schedule . Exploratory analyses were undertaken within biologically defined subtypes . Results Two thous and eight hundred and eighty-seven patients were enrolled . After 93.4 months of median follow-up , there were 916 DFS events . For the primary comparison , there was no significant improvement in DFS  from docetaxel [ hazard ratio ( HR ) = 0.91 , 95 % confidence interval ( CI ) = 0.80 - 1.05 , P = 0.187 ] . In secondary comparisons , sequential docetaxel  significantly improved DFS compared with sequential control ( HR = 0.81 , 95 % CI = 0.67 - 0.99 , P = 0.036 ) , and significantly improved DFS ( HR = 0.84 , 95 % CI = 0.72 - 0.99 , P = 0.035 ) and overall survival ( OS ) ( HR = 0.79 , 95 % CI = 0.65 - 0.98 , P = 0.028 ) compared with concurrent doxorubicin-docetaxel . Luminal-A disease had the best prognosis . HRs favored addition of sequential docetaxel in all subtypes , except luminal-A ; but this observation was not statistically supported because of limited numbers . Conclusion With further follow-up , the sequential docetaxel schedule result ed in significantly better OS than concurrent doxorubicin-docetaxel , and continued to show better  DFS than sequential doxorubicin-based control PURPOSE Premenopausal women with breast cancer receiving adjuvant chemotherapy  are at risk for amenorrhea . The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history ( MH ) and quality -of-life ( QOL ) studies to compare treatments on these outcomes . PATIENTS AND METHODS Patients were r and omly assigned to sequential doxorubicin ( A ) and cyclophosphamide ( C ) followed by docetaxel ( T ; AC→T ) , concurrent TAC , or AT , which varied in duration ( 24 , 12 , 12 weeks , respectively ) , and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors .  MH and QOL were assessed with st and ardized question naires at baseline ; cycle 4 , day 1 ; and every 6 months through 24 months . Prespecified analyses examined rates of amenorrhea by treatment arm , the relationship between amenorrhea and QOL , and QOL by treatment arm . RESULTS Amenorrhea 12 months after r and om assignment was significantly different between treatment groups : 69.8 % for AC→T , 57.7 % for TAC , and 37.9 % for AT ( P < .001 ) . The AT group without tamoxifen had the lowest rate of amenorrhea . QOL was poorer for patients receiving AC→T at 6 months but similar to others by 12 months . Post-treatment symptoms were increased above baseline for all treatments . Multivariable repeated measures modeling demonstrated that treatment arm , time point , age , and tamoxifen use were significantly associated with symptom severity ( all P values < .002 ) . CONCLUSION Amenorrhea rates differed significantly by treatment arm , with the AT arm having the lowest rate . Patients treated with longer duration therapy ( AC→T ) had greater symptom severity and poorer QOL at 6 months , but did not differ from shorter duration treatments at 12 months 500 Background : First results of study USON 01062 comparing adjuvant AC→T vs AC→XT in high-risk EBC [ O'Shaughnessy , SABCS 2010 ] showed the primary endpoint , improvement in DFS , was not met ( median FU 5 yrs : HR 0.84 , 95 % CI : 0.67 - 1.05 ; p%0.125 ; 304 events ) , but a statistically significant improvement in OS was seen with AC→XT ( HR 0.68 , 95 % CI : 0.51 - 0.92 ; p%0.011 ; 183 events ) . Given the current underst and ing of a lesser benefit of adjuvant chemotherapy in indolent BC , we performed unplanned exploratory subset analyses of Ki-67 expression , distant DFS and benefit from XT . METHODS Pts aged 18 - 70 yrs with surgically resectable EBC received 4 x 3-weekly AC ( A : 60mg/m2 , C : 600mg/m2 , d1 ) → 4 x 3-weekly T ( 100mg/m2 d1 ) or XT ( X : 825mg/m2 bid , d1 - 14 ; T : 75mg/m2 d1 ) . ER+ pts received endocrine therapy , and , after 2005 , HER2 + pts were offered 1-yr of trastuzumab . Primary endpoint : DFS ; secondary endpoints : OS ; safety . Ki-67 staining was done locally . RESULTS 2,611 pts were r and omized : AC→T ( n%1304 ) ; AC→XT ( n%1307 ) . Treatment arms were balanced . Exploratory distant DFS analysis favored the XT group ( HR 0.80 , 95 % CI : 0.63 - 1.02 ; p%0.067 ) . Analyses by Ki-67 expression showed a treatment effect with XT vs T in pts with Ki-67 ≥10 % ( HR for DFS : 0.70 ; OS : 0.52 ) ( table ) . Very few events ( DFS/OS ) were seen in pts with Ki-67 < 10 % , with no difference in DFS with XT vs T. In pts with ER+/HER2- tumors and Ki-67 ≥10 % , a trend towards DFS ( HR 0.66 ) and OS ( 0.30 ) benefit with XT was also seen . CONCLUSIONS Exploratory Ki-67 analyses suggested benefit of X in more highly proliferative tumors , reflecting the importance of pt selection in adjuvant trials . [ Table : see text ] PURPOSE Cyclophosphamide , epirubicin , and fluorouracil ( CEF ) and doxorubicin and cyclophosphamide ( AC ) followed by paclitaxel ( T ) are commonly used adjuvant regimens in women with early breast cancer . In a previous trial in women with locally advanced breast cancer , 3 months of high-dose epirubicin and cyclophosphamide ( EC ) administered every 2 weeks ( dose-dense ) was equivalent to 6 months of CEF . We hypothesized that 3 months of paclitaxel after dose-dense EC ( EC/T ) would be superior to CEF or AC/T. METHODS After lumpectomy or mastectomy , women 60 years of age or younger with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive CEF , EC/T , or AC/T for 6 months . This article reports the interim analysis for recurrence-free survival ( RFS ) , which was planned after 227 recurrences . Results A total of 2,104 patients were enrolled . The median follow-up is 30.4 months . Hazard ratios for recurrence are as follows : AC/T versus CEF , 1.49 ( 95 % CI , 1.12 to 1.99 ) , P = .005 ; AC/T versus EC/T , 1.68 ( 95 % CI , 1.25 to 2.27 ) , P = .0006 ; and EC/T versus CEF , 0.89 ( 95 % CI , 0.64 to 1.22 ) , P = .46 . Three-year RFS rates for CEF , EC/T , and AC/T are 90.1 % , 89.5 % , and 85.0 % , respectively . There was more febrile neutropenia with CEF ( 22.3 % ) and EC/T ( 16.4 % ) compared with AC/T ( 4.8 % ) , but more neuropathy with the last two regimens . CONCLUSION Three-weekly AC/T is significantly inferior to CEF or EC/T in terms of RFS . It is too early to detect any difference between CEF and dose-dense BACKGROUND Docetaxel is more effective than doxorubicin for patients with advanced breast cancer . The Breast International Group 02 - 98 r and omized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel . METHODS Patients with lymph node-positive breast cancer ( n = 2887 ) were r and omly assigned to one of four treatments : 1 ) sequential control ( four cycles of doxorubicin at 75 mg/m2 , followed by three cycles of cyclophosphamide , methotrexate , and 5-fluorouracil [ CMF ] ) ; 2 ) concurrent control ( four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2 , followed by three cycles of CMF ) ; 3 ) sequential docetaxel ( three cycles of doxorubicin at 75 mg/m2 , followed by three cycles of docetaxel at 100 mg/m2 , followed by three cycles of CMF ) ; 4 ) concurrent docetaxel ( four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2 , followed by three cycles of CMF ) . The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival ( DFS ) events ( ie , relapse , second primary cancer , or death from any cause ) . Docetaxel and control treatment groups were compared by log-rank tests , and hazard ratios ( HR ) of DFS events were calculated by Cox modeling . All statistical tests were two-sided . RESULTS Due to a lower-than-anticipated rate of relapse , this analysis was performed after 5 years with 732 events . Patients in control arms had a 5-year DFS of 73 % ( 95 % confidence interval [ CI ] = 70 % to 75 % ) . Docetaxel treatment result ed in an improvement in DFS of borderline statistical significance compared with control treatment ( HR = 0.86 , 95 % CI = 0.74 to 1.00 ; P = .05 ) . However , DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm ( HR = 0.83 , 95 % CI = 0.69 to 1.00 ) and in the sequential control arm ( HR = 0.79 , 95 % CI = 0.64 to 0.98 ) . CONCLUSIONS Incorporating docetaxel into anthracycline-based therapy result ed in an improvement in DFS that was of borderline statistical significance . However , important differences may be related to doxorubicin and docetaxel scheduling , with sequential but not concurrent administration , appearing to produce better DFS than anthracycline-based chemotherapy Purpose To evaluate the impact that pre- and postoperatively administered chemotherapy with cyclophosphamide , methotrexate and fluorouracil ( CMF ) and postoperative chemotherapy vs. postoperative chemotherapy alone have on long-term prognosis . Patients and Methods The ABCSG conducted a nationwide r and omized phase III trial in high-risk endocrine non-responsive breast cancer patients comparing pre- and postoperative chemotherapy containing CMF as preoperative treatment vs. postoperative chemotherapy alone between 1991 and 1999 . From 1996 the ABCSG-07 protocol was amended to also allow r and omization of high-risk endocrine-responsive patients . Of 423 eligible patients with high-risk primary breast cancer , 203 patients were r and omly assigned to preoperatively receive three cycles of CMF ( cyclophosphamide , methotrexate , fluorouracil ; 600/40/600 mg/m2 ) intravenously on day 1 and 8 , while 195 patients received postoperative chemotherapy alone . In both groups , three cycles of CMF were given initially , and another three cycles of CMF were administered in node-negative patients , whereas node-positive patients received three cycles of EC ( epirubicin , cyclophosphamide ; 70/600 mg/m2 ) . Results Overall response rate to preoperative chemotherapy with three cycles of CMF was 56.2 % ; complete pathological response was achieved in 12 patients ( 5.9 % ) . Recurrence-free survival was significantly better in patients receiving chemotherapy postoperatively ( HR 0.7 , 0.515–0.955 ; P = 0.024 ) . No survival difference was observed between the two therapy groups ( HR 0.800 , 0.563–1.136 ; P = 0.213 ) . Discussion Preoperative chemotherapy with CMF has to be considered as insufficient in high-risk breast cancer patients . Delayed surgery and anthracycline-based chemotherapy result in shorter recurrence-free survival but not overall survival This trial compared 6 cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) with a sequential regimen of 3 cycles of FEC followed by 3 cycles of docetaxel ( FEC-D ) as adjuvant treatment for women with node-positive or/ and T3 or T4 breast cancer . Between January 2006 and January 2010 , 657 patients with operable breast cancer were r and omly assigned to either FEC every 21 days for 6 cycles , or 3 cycles of FEC followed by 3 cycles of docetaxel , both given every 21 days . Radiotherapy was m and atory for all patients who had undergone breast conserving surgery . Radiation to the chest wall , supraclavicular area , was recommended following mastectomy . Hormone-receptor – positive patients received tamoxifen for 5 years after chemotherapy . The primary end point was 5-year disease-free survival ( DFS ) . Median follow-up was 61 months . Five-year DFS rates were 74 % with FEC and 78 % with FEC-D ( P = 0.013 ) . Multivariate analysis adjusted for prognostic factors showed a 17 % reduction in the relative risk of relapse with FEC-D.  Five-year overall survival rates were 85 % with FEC and 89.4 % with FEC-D , demonstrating a 27 % reduction in the relative risk of death ( P = 0.014 ) . The incidence of grade 3–4 neutropenia , the need for hematopoietic growth factor , and incidence of nausea/vomiting were higher with FEC . Docetaxel was associated with more febrile neutropenia , stomatitis , edema , and nail disorders . Though rare overall , there were fewer cardiac events after FEC-D , attributable mainly to the lower anthracycline cumulative dose . Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive or/ and T3 or T4 breast cancer patients . Although the magnitude of the benefit observed with FEC-D , differences in the toxicity profiles of FEC and FEC-D may influence the choice of treatment for patients PURPOSE Anthracyclines , taxanes , and alkylating agents are among the most active agents in treatment of adjuvant breast cancer ( BC ) , but the optimal schedule for their administration is unknown . We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide ( AC ) followed by docetaxel ( ie , AC > T ) with the combination regimen of TAC . PATIENTS AND METHODS Women with node-positive , human epidermal growth factor receptor 2-nonamplified , operable BC were stratified by number of axillary nodes and hormone receptor status and were r and omly assigned to adjuvant chemotherapy with six cycles of TAC ( 75/50/500 mg/m² every 3 weeks ) or four cycles of AC ( 60/600 mg/m² every 3 weeks ) followed by four doses of docetaxel at 100 mg/m² every 3 weeks ( AC > T ) . After completion of chemotherapy , radiation therapy was given as indicated , and patients with hormone receptor ( HR ) -positive disease received adjuvant hormonal therapy with tamoxifen and /or aromatase inhibitors . RESULTS In 30 months , 3,298 patients were enrolled ( n = 1,649 in each arm ) . The major baseline characteristics were well balanced between the groups . At a median follow-up of 65 months , estimated 5-year disease-free survival rates were 79 % in both groups ( log-rank P = .98 ; hazard ratio [ HR ] , 1.0 ; 95%CI , 0.86 to 1.16 ) , and 5-year overall survival rates for both arms were 88 % and 89 % , respectively ( log-rank P = .37 ; HR , 0.91 ; 95 % CI , 0.75 to 1.11 ) . TAC was associated with more febrile neutropenia and thrombocytopenia , and AC > T was associated with more sensory neuropathy , nail changes , and myalgia . The incidence of neutropenic infection was similar in both groups . CONCLUSION The sequential and combination regimens incorporating three drugs were equally effective but differed in toxicity profile CRA1008 Background : S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1 ) the weekly AC+G regimen is superior to ddAC x 6 and 2 ) 12 weeks of weekly paclitaxel ( wP ) is superior to q 2 week paclitaxel x 6 ( ddP ) . METHODS Between December 2003 and November 2010 , 2,716 patients were r and omized in a 2 x 2 factorial design to 1 ) AC+G vs ddAC and 2 ) P 80 mg/m2/week x 12 vs P 175 mg/m2 q 2 weeks x 6 . If there was no significant interaction between the factors , the trial was powered to find a disease-free survival hazard ratio ( HR ) ≤ 0.82 for weekly vs q 2 week for each factor . At the first interim analysis , the AC r and omization was halted for futility , and S0221 was closed to accrual 10 November 2010 . S0221 reopened 15 December 2010 , after which time all patients received 4 cycles of ddAC and r and omization to P weekly x 12 and ddP x 6 continued . Accrual halted at a total of 3,294 in January 2012 . RESULTS By September 7 , 2012 , 487 events and 340 deaths had occurred , prompting the third planned interim analysis . The Data Safety and Monitoring Committee recommended reporting the results since the futility boundary was crossed . A Cox model adjusting for the AC arms had a HR = 1.08 ( 95 % CI 0.90 - 1.28 ; p=0.42 ) , with the 99.5 % CI excluding the original alternative hypothesis that the HR=0.82 . There was no significant interaction of the two factors . Estimated 5-year progression-free survivals were 82 % for weekly P and 81 % for ddP. Toxicity data were available for 1,385 patients treated with ddP and 1,367 treated with weekly P. Grade 5 toxicity occurred in 4 patients on ddP and 2 on weekly P. Percent grade 3 - 4 toxicity per arm are shown in the Table . CONCLUSIONS Either ddPx6 or weekly P x 12 are acceptable schedules of P administration . The differences in leukopenia likely reflect ascertainment bias against weekly P. If this is accepted , weekly P x 12 produces less overall toxicity than 6 cycles of ddP. Support : NCI grants CA32102 , CA38926 , CA21115 , CA21076 , CA77597 , CA25224 , CA77202 , CCSRI15469 , and Amgen , Inc. CLINICAL TRIAL INFORMATION NCT00070564 . [ Table : see text ] We compared the efficacy of CEF ( cyclophosphamide , epirubicin , and fluorouracil ) against CMF ( cyclophosphamide , methotrexate , and fluorouracil ) in moderate or high risk breast cancer patients . We r and omly assigned 1224 patients with completely resected unilateral breast cancer to receive nine cycles of three-weekly intravenous CMF or CEF . Patients were encouraged to take part in a parallel trial comparing oral pamidronate 150 mg twice daily for 4 years versus control ( data not shown ) . Substitution of methotrexate with epirubicin significantly reduced the unadjusted hazard for disease-free survival ( DFS ) by 16 % ( hazard ratio 0.84 ; 95 % CI ; 0.71 - 0.99 ) and for overall survival by 21 % ( hazard ratio 0.79 ; 95 % CI ; 0.66 - 0.94 ) . The risk of secondary leukaemia and congestive heart failure was similar in the two groups . Overall CEF was superior over CMF in terms of DFS and OS  in patients with operable breast cancer without subsequent increase in late toxicities PURPOSE The PACS 01 trial compared six cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel ( FEC-D ) as adjuvant treatment for women with node-positive early breast cancer . PATIENTS AND METHODS Between June 1997 and March 2000 , 1,999 patients with operable node-positive breast cancer were r and omly assigned to either FEC every 21 days for six cycles , or three cycles of FEC followed by three cycles of docetaxel , both given every 21 days . Hormone-receptor-positive patients received tamoxifen for 5 years after chemotherapy . The primary end point was 5-year disease-free survival ( DFS ) . RESULTS Median follow-up was 60 months . Five-year DFS rates were 73.2 % with FEC and 78.4 % with FEC-D ( unadjusted P = .011 ; adjusted P = .012 ) . Multivariate analysis adjusted for prognostic factors showed an 18 % reduction in the relative risk of relapse with FEC-D.  Five-year overall survival rates were 86.7 % with FEC and 90.7 % with FEC-D , demonstrating a 27 % reduction in the relative risk of death ( unadjusted P = .014 ; adjusted P = .017 ) . The incidence of grade 3 to 4 neutropenia , the need for hematopoietic growth factor , and incidence of nausea/vomiting were higher with FEC . Docetaxel was associated with more febrile neutropenia in the fourth cycle , stomatitis , edema , and nail disorders . Though rare overall , there were fewer cardiac events after FEC-D ( P = .03 ) , attributable mainly to the lower anthracycline cumulative dose . CONCLUSION Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile PURPOSE To compare the clinical and pathologic response rates of doxorubicin and cyclophosphamide ( AC ) with doxorubicin and docetaxel ( AD ) as primary chemotherapy in women with primary or locally advanced breast cancer . PATIENTS AND METHODS Eligible patients with histologically proven breast cancer with primary tumors > /= 3 cm , inflammatory or locally advanced disease , and no evidence of metastases were r and omly assigned to receive a maximum of six cycles of either doxorubicin ( 60 mg/m(2 ) ) plus cyclophosphamide ( 600 mg/m(2 ) ) administered intravenously ( IV ) every 3 weeks or doxorubicin ( 60 mg/m(2 ) ) plus docetaxel ( 75 mg/m(2 ) ) IV every 3 weeks , followed by surgery on completion of chemotherapy . Results A total of 363 patients were r and omly assigned to AC ( n = 180 ) or AD ( n = 183 ) . A complete clinical response was observed in 17 % and 20 % of patients treated with AC and AD , respectively ( P = .42 ) . Overall ( complete and partial ) clinical response rates for AC and AD were 61 % and 70 % , respectively ( P = .06 ) . There was no significant difference in either the pathologic complete response rates in the breast with AC ( 24 % ) and AD ( 21 % ; P = .61 ) or in the number of patients with positive axillary nodes at surgery with AC ( 61 % ) and AD ( 66 % ; P = .28 ) . At a median follow-up of 32 months , there is no significant difference between the two groups for the number of relapses . CONCLUSION In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer , our data do not suggest a benefit for simultaneous AD over AC PURPOSE We compared radiotherapy ( RT ) delivery and locoregional control in patients with node-positive breast cancer r and omly assigned on Cancer and Leukemia Group B 9344 to receive adjuvant doxorubicin/cyclophosphamide ( AC )  with patients assigned to receive AC followed by paclitaxel ( AC+T ) . METHODS Eligible patients were r and omly assigned to receive adjuvant AC versus AC+T chemotherapy .  RT was required if breast-conserving surgery was performed but was elective after mastectomy . Information about RT delivery was retrospectively collected . Cumulative incidence of locoregional recurrence ( LRR ) , use of elective RT , and RT delivery were compared between treatment arms . RESULTS For patients treated with breast-conserving surgery and RT , the 5-year cumulative incidence of isolated LRR was 9.7 % in the AC arm and 3.7 % in the AC+T arm ( P = .04 ) and of LRR as any component of failure was 12.9 % versus 6.1 % , respectively ( P = .04 ) . Although LRR rates in patients who did not receive postmastectomy RT were lower in the AC+T arm , the difference was not statistically significant . Despite the lack of protocol guidelines , RT use did not differ between arms , nor did RT dose , treatment interruption , or completion . CONCLUSION Despite the delay to RT during additional chemotherapy , adjuvant AC+T afforded better local control than AC alone in patients treated with breast-conserving therapy . Addition of paclitaxel did not adversely affect delivery or ability to tolerate RT , as indicated by similar rates of completion of timely , full-dose RT between arms 1004 Background : AC+G ( doxorubicin 24 mg/m2/week x 15 , cyclophosphamide 60 mg/m2/day po , and filgrastim daily except on the days of doxorubicin administration ) produced encouraging results in a SWOG Phase II trial of pre-operative chemotherapy in locally advanced breast cancer . S0221 is a SWOG-coordinated Phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer , which hypothesized that the AC+G regimen is superior to ddAC ( doxorubicin 60 mg/m2 , cyclophosphamide 600 mg/m2 IV and pegfilgrastim q 2 weeks x 6 ) and that weekly paclitaxel is superior to q 2 week paclitaxel . METHODS Between December 2003 and November 2010 , 2716 patients were r and omized in a 2x2 factorial design to 1 ) AC+G vs ddAC and 2 ) paclitaxel 80 mg/m2/week x 12 vs paclitaxel 175 mg/m2 q 2 weeks x 6 . If there was no significant interaction between the factors , the trial was powered to find a disease-free survival hazard ratio ( HR ) ≤ 0.82 for weekly vs q 2 week for each factor . RESULTS By September 8 , 2010 , 349 events ( 161 ddAC , 188 AC+G ) had occurred among 2,477 patients with follow-up , prompting the first planned interim analysis at 30 % of the expected events . The arms were balanced for st and ard prognostic factors , and a Cox model adjusting for the paclitaxel arms had a HR = 1.21 ( 95 % CI 0.98 - 1.50 ; p=0.071 ) favoring ddAC . The prescribed boundary for futility was the 99.5 % CI ( 0.90 - 1.64 ) excluding the original alternative hypothesis that HR=0.82 . No boundary was crossed for the paclitaxel comparison and there was no significant interaction of the two factors . Therefore , the Data Safety and Monitoring Committee recommended stopping r and omization to the AC+G arms due to futility . Analyses by nodal- , hormone-receptor- , and HER2 status found no subset in which AC+G appeared superior . S0221 has re-opened and r and omizes patients to the two paclitaxel arms after only 4 cycles of ddAC . CONCLUSIONS Accrual will continue to 3,250 patients and ancillary studies remain ongoing . We conclude that AC+G is not superior to ddAC x 6 , and do not recommend AC+G for routine use . Support : NCI grants CA32102 , CA38926 , CA21115 , CA21076 , CA77597 , CA25224 , CA77202 , CCSRI15469 , and Amgen , BACKGROUND Among breast cancer patients , nonresponse to initial neoadjuvant chemotherapy is associated with unfavorable outcome . We compared the response of nonresponding patients who continued the same treatment with that of patients who switched to a well-tolerated non-cross-resistant regimen . METHODS Previously untreated breast cancer patients received two 3-week cycles of docetaxel at 75 mg/m(2 ) , doxorubicin at 50 mg/m(2 ) , and cyclophosphamide at 500 mg/m(2 ) per day ( TAC ) . Patients whose tumors did not decrease in size by at least 50 % were r and omly assigned to four additional cycles of TAC or to four cycles of vinorelbine at 25 mg/m(2 ) and capecitabine at 2000 mg/m(2 ) ( NX ) . The outcome was sonographic response , defined as a reduction in the product of the two largest perpendicular diameters by at least 50 % . A difference of 10 % or less in the sonographic response qualified as noninferiority of the NX treatment . Pathological complete response was defined as no invasive or in situ residual tumor masses in the breast and lymph nodes . Toxic effects were assessed . All statistical tests were two-sided . RESULTS Of 2090 patients enrolled in the GeparTrio study , 622 ( 29.8 % ) who did not respond to two initial cycles of TAC were r and omly assigned to an additional four cycles of TAC ( n = 321 ) or to four cycles of NX ( n = 301 ) . Sonographic response rate was 50.5 % for the TAC arm and 51.2 % for the NX arm . The difference of 0.7 % ( 95 % confidence interval = -7.1 % to 8.5 % ) demonstrated noninferiority of NX ( P = .008 ) . Similar numbers of patients in both arms received breast-conserving surgery ( 184 [ 57.3 % ] in the TAC arm vs 180 [ 59.8 % ] in the NX arm ) and had a pathological complete response ( 5.3 % vs 6.0 % ) . Fewer patients in the NX arm than in the TAC arm had hematologic toxic effects , mucositis , infections , and nail changes , but more had h and -foot syndrome and sensory neuropathy . CONCLUSION Pathological complete responses to both regimens were marginal . Among patients who did not respond to the initial neoadjuvant TAC treatment , similar efficacy but better tolerability was observed by switching to NX than continuing with TAC BACKGROUND We compared st and ard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer . Here we report the final , 10-year follow-up analysis of disease-free survival , overall survival , and long-term safety . METHODS BCIRG 001 was an open label , phase 3 , multicentre trial in which 1491 patients aged 18 - 70 years with node-positive , early breast cancer and a Karnofsky score of 80 % or more were r and omly assigned to adjuvant treatment with docetaxel , doxorubicin , and cyclophosphamide ( TAC ) or fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) every 3 weeks for six cycles . R and omisation was stratified according to institution and number of involved axillary lymph nodes per patient ( one to three vs four or more ) . Disease-free survival was the primary endpoint and was defined as the interval between r and omisation and breast cancer relapse , second primary cancer , or death , whichever occurred first . Efficacy analyses were based on the intention-to-treat principle . BCIRG 001 is registered with Clinical Trials.gov , number NCT00688740 . FINDINGS Enrolement took place between June 11 , 1997 and June 3 , 1999 ; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC .  After a median follow-up of 124 months ( IQR 90 - 126 ) , disease-free survival was 62 % ( 95 % CI 58 - 65 ) for patients in the TAC group and 55 % ( 51 - 59 ) for patients in the FAC group ( hazard ratio [ HR ] 0·80 , 95 % CI 0·68 - 0·93 ; log-rank p=0·0043 ) . 10-year overall survival was 76 % ( 95 % CI 72 - 79 ) for patients in the TAC group and 69 % ( 65 - 72 ) for patients in the FAC group ( HR 0·74 , 0·61 - 0·90 ; log-rank p=0·0020 ) . TAC improved disease-free survival  relative to FAC irrespective of nodal , hormone receptor , and HER2 status , although not all differences were significant in these subgroup analyses . Grade 3 - 4 heart failure occurred in 26 ( 3 % ) patients in the TAC group and 17 ( 2 % ) patients in the FAC group , and caused death in two patients in the TAC group and four patients in the FAC group . A substantial decrease in left ventricular ejection fraction ( defined as a relative decrease from baseline of 20 % or more ) was seen in 58 ( 17 % ) patients who received TAC and 41 ( 15 % ) patients who received FAC . Six patients who received TAC developed leukaemia or myelodysplasia , as did three patients who received FAC . INTERPRETATION Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years . However , a substantial percentage of patients had a decrease in left ventricular ejection fraction , probably caused by anthracycline therapy , which warrants further investigation . FUNDING Sanofi BACKGROUND Older women with breast cancer are underrepresented in clinical trials , and data on the effects of adjuvant chemotherapy in such patients are scant . We tested for the noninferiority of capecitabine as compared with st and ard chemotherapy in women with breast cancer who were 65 years of age or older . METHODS We r and omly assigned patients with stage I , II , IIIA , or IIIB breast cancer to st and ard chemotherapy ( either cyclophosphamide , methotrexate , and fluorouracil or cyclophosphamide plus doxorubicin ) or capecitabine . Endocrine therapy was recommended after chemotherapy in patients with hormone-receptor-positive tumors . A Bayesian statistical design was used with a range in sample size from 600 to 1800 patients . The primary end point was relapse-free survival . RESULTS When the 600th patient was enrolled , the probability that , with longer follow-up , capecitabine therapy was highly likely to be inferior to st and ard chemotherapy met a prescribed level , and enrollment was discontinued . After an additional year of follow-up , the hazard ratio for disease recurrence or death in the capecitabine group was 2.09 ( 95 % confidence interval , 1.38 to 3.17 ; P<0.001 ) . Patients who were r and omly assigned to capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who were r and omly assigned to st and ard chemotherapy ( P=0.02 ) . At 3 years , the rate of relapse-free survival was 68 % in the capecitabine group versus 85 % in the st and ard-chemotherapy group , and the overall survival rate was 86 % versus 91 % . Two patients in the capecitabine group died of treatment-related complications ; as compared with patients receiving capecitabine , twice as many patients receiving st and ard chemotherapy had moderate-to-severe toxic effects ( 64 % vs. 33 % ) . CONCLUSIONS St and ard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older . ( Clinical Trials.gov number , NCT00024102 . BACKGROUND Neoadjuvant systemic therapy ( NST ) before surgery is a st and ard option for patients with early breast cancer ( EBC ) that allows in vivo chemosensitivity testing . Given the promising activity of pemetrexed plus doxorubicin in metastatic breast cancer , it was reasonable to evaluate the utility of this combination as part of an NST regimen in EBC . PATIENTS AND METHODS Patients with untreated operable T2-T4a-c N0 - 2 M0 breast cancer were r and omly assigned to receive either four cycles of pemetrexed 500 mg/m(2 ) plus doxorubicin 60 mg/m(2 ) every 3 weeks ( q3w ) followed by four cycles of docetaxel 100 mg/m(2 ) q3w ( AP-D ) or four cycles of doxorubicin 60 mg/m(2 ) plus cyclophosphamide 600 mg/m(2 ) q3w followed by four cycles of docetaxel 100 mg/m(2 ) q3w ( AC-D ) . Surgery was carried out within 2 months after last chemotherapy . Primary end point was pathological complete response ( pCR ) rate in the breast . Secondary end points included clinical response rate , rate of histologically negative axillary lymph nodes , toxicity , and disease-free survival . RESULTS From September 2005 to August 2007 , 257 patients were r and omly allocated to 17 sites . Median age was 48 and 49 years for AP-D and AC-D , respectively . Overall pCR rates were 16.5 % for AP-D and 20.2 % for AC-D. With AP-D , pCR rate was 17.8 % for hormone receptor (HR)-negative patients and 15.9 % for HR-positive patients . With AC-D , pCR rates were 42.9 % and 7.8 % for HR-negative and HR-positive patients , respectively . Clinical response rates were 59.5 % in the AP-D group and 68.1 % in the AC-D group . The rate of histologically negative axillary lymph nodes was 53 % in both groups . Both treatments were well tolerated . Median disease-free survival is currently not mature . CONCLUSIONS AP-D and AC-D are well tolerated and active as NST in EBC . Of note , AC-D had a higher pCR rate in HR-negative tumors , whereas AP-D had more activity if HRs were expressed PURPOSE The combination of doxorubicin and cyclophosphamide ( AC ) is a st and ard adjuvant regimen . Doxorubicin and docetaxel ( AT ) is one of the most active cytotoxic regimens for metastatic breast cancer . The purpose of this trial was to determine whether adjuvant AT improved disease-free survival compared with AC in operable breast cancer . PATIENTS AND METHODS Women with invasive breast cancer were eligible if there were one to three positive lymph nodes or if the node-negative tumor was greater than 1 cm . Patients were r and omly assigned after surgery to receive doxorubicin ( 60 mg/m(2 ) ) plus either cyclophosphamide ( 600 mg/m(2 ) ; AC ) or docetaxel ( 60 mg/m(2 ) ; AT ) given every 3 weeks for four cycles , followed by hormone therapy for patients with estrogen receptor ( ER ) and /or progesterone receptor (PR)-positive tumors . RESULTS There were 2,882 eligible patients enrolled . After a median follow-up of 79.5 months , there was no significant difference in disease-free survival ( DFS ; 85 % in both arms ) or overall survival ( 91 % v 92 % ) at 5 years . The hazard ratio for AC versus AT was 1.02 ( 95 % CI for DFS , 0.86 to 1.22 ; P = .78 ) . In an exploratory analysis of prespecified stratification factors by ER and PR expression there were trends toward improved DFS for AT in ER/PR-negative disease . Grade 3 neutropenia associated with fever or infection occurred more often with AT ( 26 % v 10 % ; P < .05 ) . CONCLUSION AT did not improve DFS or overall survival in this population , and was associated with more toxicity PURPOSE The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide ( HEC ) is superior to a lower dose of epirubicin , 60 mg/m(2 ) ( EC ) , for event-free survival ( EFS ; 27 % reduction ) , but is not superior to classical oral cyclophosphamide , methotrexate , and fluorouracil ( CMF ) in the adjuvant treatment of node-positive breast cancer . Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial . PATIENTS AND METHODS Between March 1988 and December 1996 , 777 eligible patients were r and omly assigned to six cycles of CMF , eight cycles of EC , or eight cycles HEC . RESULTS The 15-year EFS was 45 % for patients who received CMF , 39 % for patients who received EC , and 50 % for patients who received HEC . The hazard ratios ( HR ) were 0.77 for HEC versus EC ( 95 % CI , 0.60 to 0.98 ; P = .03 ) , 0.90 for HEC versus CMF ( P = .39 ) , and 0.86 for EC versus CMF ( P = .21 ) . No difference in overall survival ( OS ) was seen . Cardiac toxicity was more frequent with HEC than with CMF ( 11 patients v 1 patient ; P = .006 ) , but no more than with EC ( P = .21 ) . CONCLUSION Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin . However , we do not recommend the use of HEC regimen in daily clinical practice , mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study PURPOSE To compare preoperative intense dose-dense ( IDD ) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer ( BC ) . PATIENTS AND METHODS In this r and omized phase III trial a total of 668 eligible primary BC patients stratified for tumors > or = 3 cm ( n = 567 ) or inflammatory BC ( n = 101 ) were r and omly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks . All patients received three cycles of cyclophosphamide , methotrexate , and fluorouracil chemotherapy after surgery . RESULTS IDD treatment significantly improved pathologic complete response rate ( 18 % v 10 % ; odds ratio [ OR ] 1.89 ; P = .008 ) , disease-free survival ( DFS ; hazard ratio [ HR ] , 0.71 ; P = .011 ) , and overall survival ( OS ; HR , 0.83 ; P = .041 ) compared to epirubicin/paclitaxel .  Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial ( DFS HR , 1.10 ; P = .739 ; OS HR , 1.25 ; P = .544 ) . In contrast , patients with noninflammatory BC significantly benefited from IDD treatment ( DFS HR , 0.65 , P = .005 ; OS HR , 0.77 , P = .013 ) . Treatment effects in multivariate analysis were significant for noninflammatory BC ( DFS HR , 0.65 , P = .015 ; OS HR , 0.79 , P = .034 ) , but not for all patients ( DFS HR , 0.76 ; P = .088 ; OS HR , 0.82 ; P = .059 ) . IDD therapy was associated with significantly more nonhematologic toxicities , anemia , and thrombocytopenia , but with similar neutropenia and infection rates . CONCLUSION Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy . IDD was less well tolerated compared to st and ard treatment , but improved clinical outcomes in patients with noninflammatory high-risk primary BC PURPOSE Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer .  Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 ( HER2 ) -positive cancer are unknown . PATIENTS AND METHODS One thous and ten women with axillary node-positive or high-risk node-negative breast cancer were r and omly assigned to receive three cycles of docetaxel or vinorelbine , followed in both groups by three cycles of fluorouracil , epirubicin , and cyclophosphamide ( FEC ) .  Women with HER2-positive cancer ( n = 232 ) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine . The median follow-up time was 62 months after r and om assignment . RESULTS Women assigned to docetaxel had better distant disease-free survival ( DDFS ) than those assigned to vinorelbine ( hazard ratio [ HR ] = 0.66 ; 95 % CI , 0.49 to 0.91 ; P = .010 ) . In the subgroup of HER2-positive disease , patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only ( HR = 0.65 ; 95 % CI , 0.38 to 1.12 ; P = .12 ; with adjustment for presence of axillary nodal metastases , HR = 0.57 ; P = .047 ) . In exploratory analyses , docetaxel , trastuzumab , and FEC improved DDFS compared with docetaxel plus FEC ( HR = 0.32 ; P = .029 ) and vinorelbine , trastuzumab , and FEC ( HR = 0.31 ; P = .020 ) . The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up ; only one woman treated with trastuzumab was diagnosed with a heart failure . CONCLUSION Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine . A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation BACKGROUND St and ard adjuvant chemotherapy regimens for patients with node positive ( N+ ) breast cancer consisted of anthracycline followed by taxane . The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol . Primary end-point was disease free survival . Secondary end-points were overall survival , local recurrence free interval , metastases free interval and safety . PATIENTS AND METHODS Between March 2000 and December 2002 , 837 patients were r and omised between 6FEC100 for 6 cycles ( 417 patients ) or FEC100 for 4 cycles then Taxol 175mg/m(2)/3 weeks for 4 cycles ( 4FEC100 - 4 T ) ( 420 patients ) . One thous and patients had been planned initially but the trial was closed earlier due to slow accrual . RESULTS Hazard ratios ( HRs ) were 0.99 for disease-free survival ( DFS ) ( 95%CI : 0.77 - 1.26 ; p=0.91 ) , and 0.85 for overall survival ( OS ) ( 95%CI : 0.62 - 1.15 ; p=0.29 ) . Nine-year DFS were 62.9 % versus 62.5 % for 6FEC100 and 4FEC100 - 4 T , respectively . Nine-year OS were 73.9 % versus 77 % for 6FEC100 and 4FEC100 - 4 T , respectively . Toxicity analyses based on 803 evaluable patients showed that overall grade 3 - 4 toxicities were similar in both arms ( 63 % versus 58 % for 6FEC100 arm and 4FEC100 - 4 T arm , respectively ; p=0.16 ) . CONCLUSION In this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage . The lack of a significant difference between the r and omised treatment arms may however be due to a lack of power of this trial to detect small , yet clinical ly worthwhile , treatment benefits BACKGROUND The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide ( EC ) with four cycles of docetaxel ( Taxotere , D ) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer . PATIENTS AND METHODS Patients were r and omly assigned to EC ( E 120 mg/m2 , C 600 mg/m2 , arm A ) for four cycles or four cycles of D ( 100 mg/m2 ) followed by four cycles of EC ( arm B ) , both regimens every 21 days . Hormone receptor-positive patients were given hormonal therapy for 5 years . Primary end point was 5-year disease-free survival ( DFS ) . Secondary objectives were overall survival ( OS ) and safety . RESULTS There were 750 patients enrolled . With a median follow-up of 64 months , 5-year DFS was 73.4 % in both arms , and 5-year OS was 89.5 % versus 90.7 % in arm A and B [ hazard ratio was 0.99 ( 95 % confidence interval for DFS 0.75 - 1.31 ; P = 0.95 ) ] , respectively . Grade 3 - 4 toxicity was more common in arm B. CONCLUSIONS This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer . The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms
target: In general , single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population .
  Anthracycline-taxane-based polychemotherapy regimens are , overall , considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes .
  Regimens with varying anthracycline and taxane doses and schedules are options ; in general , paclitaxel given every 3 weeks is inferior .
  Evidence does not support the use of bevacizumab in the adjuvant setting ; other systemic therapy agents such as metformin and vaccines remain investigatory .
background: BACKGROUND The Program in Evidence -Based Care ( pebc ) of Cancer Care Ontario recently created an evidence -based consensus guideline on the systemic treatment of early breast cancer .
  The evidence for the guideline was compiled using a systematic review to answer the question " What is the optimal systemic therapy for patients with early-stage , operable breast cancer , when patient and disease factors are considered ? "
  The question was addressed in three parts : cytotoxic chemotherapy , endocrine treatment , and human epidermal growth factor receptor 2 (her2)-directed therapy .