Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer

Abstract

Purpose: To determine long-term outcomes in a clinical trial evaluating the role of taxane type and schedule in operable breast cancer and evaluate the impact of obesity and black race on outcome.

Patients and methods: A total of 4,954 eligible women with stage II to III breast cancer treated with four cycles of doxorubicin plus cyclophosphamide were randomly assigned to receive paclitaxel or docetaxel every 3 weeks for four doses or weekly for 12 doses using a 2 × 2 factorial design. The primary end point was disease-free survival (DFS). Results are expressed as hazard ratios (HRs) from Cox proportional hazards models. All P values are two sided.

Results: When compared with the standard every-3-week paclitaxel arm, after a median follow-up of 12.1 years, DFS significantly improved and overall survival (OS) marginally improved only for the weekly paclitaxel (HR, 0.84; P = .011 and HR, 0.87; P = .09, respectively) and every-3-week docetaxel arms (HR, 0.79; P = .001 and HR, 0.86; P = .054, respectively). Weekly paclitaxel improved DFS and OS (HR, 0.69; P = .010 and HR, 0.69; P = .019, respectively) in triple-negative breast cancer. For hormone receptor-positive, human epidermal growth factor receptor 2-nonoverexpressing disease, no experimental arm improved OS, and black race and obesity were associated with increased risk of breast cancer recurrence and death.

Conclusion: Improved outcomes initially observed for weekly paclitaxel were qualitatively similar but quantitatively less pronounced with longer follow-up, although exploratory analysis suggested substantial benefit in triple-negative disease. Further research is required to understand why obesity and race influence clinical outcome in hormone receptor-positive disease.

Trial registration: ClinicalTrials.gov NCT00004125.

Fig 1.

CONSORT diagram showing No. of patients enrolled (N = 5,052), No. of eligible patients included in efficacy analysis (n = 4,954), and clinical outcomes for patients with predefined breast cancer subtypes of triple-negative breast cancer (TN), hormone receptor–positive, human epidermal growth factor receptor 2 (HER2) –nonoverexpressing breast cancer (HR+), and HER2-overexpressing breast cancer (HER2+). DFS, disease-free survival.

Fig 2.

(A, B) Disease-free survival (DFS) and (C, D) overall survival (OS) in entire population of 4,954 eligible patients, based on (A, C) Kaplan-Meier estimates by treatment arm and (B, D) estimated hazard ratios (HRs) and 95% CIs from stratified univariable Cox models in experimental arms (weekly paclitaxel [P1], docetaxel every 3 weeks [D3], and weekly docetaxel [D1]) compared with standard arm (paclitaxel every 3 weeks [P3]).

Fig 3.

Disease-free survival (DFS) and overall survival (OS) hazard ratios (HRs) and 95% CIs for weekly paclitaxel (P1) and docetaxel every 3 weeks (D3) compared with paclitaxel every 3 weeks (P3) in overall population (A, B) and in patients with triple-negative breast cancer (TNBC) and hormone receptor–positive/human epidermal growth factor receptor 2–nonoverexpressing disease (HR+; C, D), including the prior report and current report.

Fig 4.

(A, B) Disease-free survival (DFS) and (C, D) overall survival (OS) in 1,025 patients with triple-negative breast cancer, based on (A, C) Kaplan-Meier estimates by treatment arm and (B, D) estimated hazard ratios (HRs) and 95% CIs from univariable Cox models in experimental arms (weekly paclitaxel [P1], docetaxel every 3 weeks [D3], and weekly docetaxel [D1]) compared with standard arm (paclitaxel every 3 weeks [P3]).

Fig 5.

(A, B) Disease-free survival (DFS) and (C, D) overall survival (OS) in 2,879 patients with hormone receptor–positive, human epidermal growth factor receptor 2–nonoverexpressing breast cancer, based on (A, C) Kaplan-Meier estimates by treatment arm and (B, D) estimated hazard ratios (HRs) and 95% CIs from univariable Cox models in experimental arms (weekly paclitaxel [P1], docetaxel every 3 weeks [D3], and weekly docetaxel [D1]) compared with standard arm (paclitaxel every 3 weeks [P3]).

Fig 6.

Smoothed average hazard rate for breast cancer recurrence estimated by Kernel estimator according to breast cancer subtype in presence or absence of obesity. HER2, human epidermal growth factor receptor 2; HER2+, HER2-overexpressing breast cancer; HR+, hormone receptor–positive, HER2–nonoverexpressing breast cancer; TN, triple-negative breast cancer.