Ligibel, Jennifer A.

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.

Abstract Background: We had previously reported after a median followup of 5.3 years that disease free survival (DFS) was improved with either adjuvant weekly paclitaxel (hazard ratio [HR] 0.73, p=0.0006) or every 3 week docetaxel (HR 0.77, p=0.02) compared with every 3 week paclitaxel (N Eng J Med 2008; 358; 1663), and that obesity and black race were independently associated with inferior outcomes in estrogen receptor (ER)-positive disease after a longer followup (Cancer 2012: 118: 5937 & JNCI 2012; 104: 406). We now report updated results after a median followup of 12.1 years. Methods: Eligibility included axillary lymph node positive or high-risk (tumor at least 2 cm) node-negative breast cancer. All patients received 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks, followed by either: (1) paclitaxel 175 mg/m2 every 3 weeks x 4 (P3), (2) paclitaxel 80 mg/m2 weekly x 12 (P1), (3) docetaxel 100 mg/m2 every 3 weeks x 4 (D3), or (4) docetaxel 35 mg/m2 weekly x 12 (D1). Patients with ER-positive breast cancer also received endocrine therapy for at least 5 years, including either tamoxifen and/or an aromatase inhibitor. The primary comparisons included taxane (P vs. D) and schedule (every 3 weeks vs. weekly), and the primary endpoint was DFS, defined as local, regional, and/or distant relapse, second primary breast cancer, or death without recurrence. Results: A total of 4954 eligible patients were accrued between October 1999 and January 2002. At the time of this analysis, 90% of surviving patients were followed for at least 10 years, and there were substantially more DFS events (1639 vs. 1048) and deaths (1283 vs. 686) than the original report. For the primary comparison, there remains no significant difference in DFS by taxane (p=0.33) or schedule (p=0.88), although there was a significant interaction between taxane and schedule (p<0.007). When comparing the standard arm (P3) to the other arms (with a hazard ratio [HR] < 1 favoring the experimental arms using a stratified Cox model), the HRs for DFS were 0.84 (p = 0.011) for arm P1 and 0.79 (p=0.001) for arm D3 arm, and for overall survival (OS) were 0.87 (p=0.09) and 0.86 (p=0.054), respectively. When evaluated by subtypes in exploratory analyses, the P1 arm (but not the D3 arm) was associated with improved DFS (HR 0.69, p=0.01) and OS (HR 0.69, p=0.019) in the 1025 patients with triple negative breast cancer (TNBC), and the D3 arm (but not P1 arm) was associated with improved DFS (HR 0.76, p=0.004) but not OS (HR 0.87, p=0.20) in the 2785 patients with ER-positive, HER2-negative/unknown breast cancer (ERBC). In ERBC but not other subtypes, black race (HR 1.60, p=0.002) and obesity (HR 1.23, p=0.009) were associated with inferior OS, and obesity was associated with a higher recurrence risk between 3-8 years after diagnosis. Conclusions: Improvements in DFS observed at 10 years for the P1 and D3 arms compared with the P3 arm are qualitatively similar but quantitatively less than at 5 years, and the effects on OS are marginal in the overall population. The relative effectiveness of weekly paclitaxel and every 3 week docetaxel may vary by subtype. Citation Format: Joseph A Sparano, Fengmin Zhao, Silvana Martino, Jennifer Ligibel, Thomas Saphner, Antonio C Wolff, George W Sledge Jr, Edith A Perez, William C Wood, Nancy E Davidson. Ten year update of E1199: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-03.