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. Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-013-2691-y) contains supplementary material, which is available to authorized users.

An interobserver reproducibility analysis of ki67 visual assessment in breast cancer

“…The nuclear protein Ki67 is often used as a marker of cellular proliferation, and is a good predictive and prognostic marker widely used in clinical practice of breast cancer [1][2][3][4][5][6][7]. Studies have demonstrated that Ki67 assessment helped to more reliably define prognosis in patients with ER-positive and HER2-negative breast cancers [2,4].…”

“…The nuclear proliferation marker Ki67 is used as a predictive marker for response to chemotherapy and is associated with patient prognosis in breast cancer [1][2][3][4][5][6][7]. Assessment of Ki67 labeling index (LI) by immunohistochemical staining has been widely used in pathological evaluation of breast cancer clinical practice.…”

The Efficacy and Safety of Preoperative Chemotherapy With Triweekly Abraxane and Cyclophosphamide Followed by 5-Fluorouracil, Epirubicin, and Cyclophosphamide Therapy for Resectable Breast Cancer: A Multicenter Clinical Trial

“…To date, studies have examined dose-dense therapy and the combination of agents, such as capecitabine, gemcitabine, carboplatin, and bevacizumab, with the standard preoperative chemotherapy with anthracyclines and taxanes. [7][8][9][10][11][12][13] Although these regimens generally tend to increase the pCR rate, they also increase the incidence of serious adverse events and there have been no reports indicating that they improve long-term prognosis; therefore, no new treatment regimens showing better efficacy and safety than the existing standard treatments have been established.…”

“…These include dose-dense therapy and chemotherapy with agents that do not show crosstolerance, including capecitabine, gemcitabine, carboplatin, and bevacizumab. [7][8][9][10][11][12][13] Abraxane (nab-paclitaxel) is a human albumin-bound formulation of paclitaxel nanoparticles of 130 nm in size. It is a novel taxane formulation developed to avoid side effects, such as neuropathy and allergic reactions, caused by Cremophor/ethanol found in conventional Cremophorepaclitaxel formulations.…”

Current status of the prognostic molecular biomarkers in breast cancer: A systematic review

“…Therefore, the development of treatments targeting osteopontin-c may be beneficial for the treatment of breast cancer. (21) examined the role of Ki-67 as a predictive biomarker of treatment response in a randomized, multicenter study to compare the effectiveness of docetaxel subsequent to treatment with fluorouracil/epirubicin/cyclophosphamide with or without capecitabine, in patients with operable breast cancer. The endpoint was the rate of pathological complete response (pCR).…”