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.

Fig. 1

Study completion. FEC: fluorouracil/epirubicin/cyclophosphamide; T: docetaxel alone; TX: docetaxel plus capecitabine

Fig. 2

a Disease-free survival. b Overall survival. FEC: fluorouracil/epirubicin/cyclophosphamide; T: docetaxel alone; TX: docetaxel plus capecitabine

Fig. 3

STEPP analysis of the treatment effect of docetaxel/capecitabine compared with single-agent docetaxel as measured by pCR. Values >0 suggested that the combination regimen was better; <0 indicated that single-agent docetaxel was better. Difference in pCR is shown (dashed black lines) with corresponding 95 % CI (dashed red lines) and corresponding 95 % confidence band (dashed blue lines). Overall difference in pCR (solid horizontal red line) is shown