Abstract
BackgroundDe-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. MethodsIt is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. FindingsIncluded in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. InterpretationBoth TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. FundingThis work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).
Highlights
Adjuvant chemotherapy improves outcomes of operable breast cancer
Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intentionto-treat population
A non-statistically significant increase in the hazard of 7% was observed between TC and A+T in disease-free survival (DFS), with a 95% confidence interval ranging from a 3% reduction to a 19% increase (HR 1.07, 95% CI 0.97–1.19). Both adjuvant TC and CEF-T met the non-inferior standard to EC followed by weekly paclitaxel (EC-P) mainly in patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- operable breast cancer
Summary
Adjuvant chemotherapy improves outcomes of operable breast cancer. Since the landmark study of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil [1], there has been an ongoing effort to identify better regimens to improve survival and decrease toxicity. A meta-analysis done by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed the effectiveness of 6-months of anthracycline-based adjuvant regimens for patients with operable breast cancer [2]. For the last 20 years, anthracycline and taxane (AT)-based regimens have been the standard adjuvant treatment for operable breast cancer. The US Oncology 9735 reported that 4 cycles of docetaxel and cyclophosphamide (TCx4) was superior to 4 cycles of doxorubicin and cyclophosphamide (ACx4) in terms of disease-free survival (DFS) and overall survival (OS) [4]. These results promulgated TC as an effective alternative. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracyclinebased regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer
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