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Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil– epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

ABSTRACT: This randomized, 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 randomized 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 randomized; 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.

SUBMITTER: Ohno S

PROVIDER: S-EPMC3825616 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil– epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

Ohno S S Chow L W C LW Sato N N Masuda N N Sasano H H Takahashi F F Bando H H Iwata H H Morimoto T T Kamigaki S S Nakayama T T Nakamura S S Kuroi K K Aogi K K Kashiwaba M M Yamashita H H Hisamatsu K K Ito Y Y Yamamoto Y Y Ueno T T Fakhrejahani E E Yoshida N N Toi M M

Breast cancer research and treatment 20131101 1

This randomized, 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 randomized 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-fluoroura ...[more]

PMID: 24122389

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Project description:ImportanceCapecitabine is not considered a standard agent in the adjuvant treatment of early breast cancer. The results of this study suggest that addition of adjuvant capecitabine to a regimen that contains docetaxel, epirubicin, and cyclophosphamide improves survival outcomes of patients with triple-negative breast cancer (TNBC).ObjectiveTo investigate the effect of capecitabine on long-term survival outcomes of patients with early breast cancer, particularly in subgroups defined by cancer estrogen receptor (ER) and progesterone receptor (PR) content, and HER2 content (human epidermal growth factor receptor 2).Design, setting, and participantsThis is an exploratory analysis of the multicenter FinXX randomized clinical trial that accrued 1500 women in Finland and Sweden between January 27, 2004, and May 29, 2007. About half received 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (T+CEF), while the other half received 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (TX+CEX). Data analysis took place between January 27, 2004, and December 31, 2015.Main outcomes and measuresRecurrence-free survival (RFS).ResultsFollowing random allocation, 747 women received T+CEF, and 753 women received TX+CEX. Five patients were excluded from the intention-to-treat population (3 had overt distant metastases at the time of randomization; 2 withdrew consent). The median age of the remaining 1495 patients was 53 years at the time of study entry; 157 (11%) had axillary node-negative disease; 1142 (76%) had ER-positive cancer; and 282 (19%) had HER2-positive cancer. The median follow-up time after random allocation was 10.3 years. There was no significant difference in RFS or overall survival between the groups (hazard ratio [HR], 0.88; 95% CI, 0.71-1.08; P = .23; and HR, 0.84, 95% CI, 0.66-1.07; P = .15; respectively). Breast cancer-specific survival tended to favor the capecitabine group (HR, 0.79; 95% CI, 0.60-1.04; P = .10). When RFS and survival of the patients were compared within the subgroups defined by cancer steroid hormone receptor status (ER and/or PR positive vs ER and PR negative) and HER2 status (positive vs negative), TX+CEX was more effective than T+CEF in the subset of patients with TNBC (HR, 0.53; 95% CI, 0.31-0.92; P = .02; and HR, 0.55, 95% CI, 0.31-0.96; P = .03; respectively).Conclusions and relevanceCapecitabine administration with docetaxel, epirubicin, and cyclophosphamide did not prolong RFS or survival compared with a regimen that contained only standard agents. Patients with TNBC had favorable survival outcomes when treated with the capecitabine-containing regimen in an exploratory subgroup analysis.Trial registrationclinicaltrials.gov Identifier: NCT00114816.

Project description:Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30-65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy.This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292.From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56·5%, 95% CI 47·8-64·9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54·2%, 95% CI 45·7-62·6) who received concurrent treatment (difference 2·3%, 95% CI -9·3 to 13·9). No treatment-related deaths occurred. The most common severe toxic effects were neutropenia (35 [25·3%] of 138 patients in the sequential group vs 45 [31·7%] of 142 patients in the concurrent group) and fatigue (six [4·3%] vs 12 [8·5%]). Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one (0·8%) of 130 patients who received sequential treatment and four (2·9%) of 137 patients who received concurrent treatment; by week 24, it had dropped below this limit in nine (7·1%) of 126 patients and in six (4·6%) of 130 patients, respectively.Concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted.US National Cancer Institute.

Dataset Information

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil– epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

Publications

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil– epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy.

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