Adjuvant Cyclophosphamide and Docetaxel With or Without Epirubicin for Early TOP2A-Normal Breast Cancer: DBCG 07-READ, an Open-Label, Phase III, Randomized Trial

Abstract

Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m) and cyclophosphamide (600 mg/m) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m) and cyclophosphamide (600 mg/m) followed by three cycles of docetaxel (100 mg/m; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer.

Identification of key candidate genes and pathways in hepatocellular carcinoma by integrated bioinformatical analysis

“…The results showed low mutation frequency of the three hub genes-TOP2A, PCNA, and AURKA in HCC samples-investigated in the present study ( Fig. 5B ), but in the TCGA breast cancer, the three genes showed high alteration frequency ( 23 , 24 ) ( Fig. 5C ).…”

Forty years of landmark trials undertaken by the Danish Breast Cancer Cooperative Group (DBCG) nationwide or in international collaboration

“…This was confirmed in a prospectively planned joint analysis of 89D and four other phase three trials [100] but only a trend toward greater benefit was show for patients with HER2-amplified tumors. The DBCG 07-READ compared six cycles of docetaxel and cyclophosphamide with three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel and confirmed no overall benefit from adjuvant epirubicin in patients with early and TOP2A-normal breast cancer [101]. Other mechanisms of action have been proposed including protection from apoptosis by tissue inhibitor of matrix metalloproreinases-1 (TIMP-1).…”

The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer

“…The MA.5 and DBCG 89D trials and a pooled analysis with three additional phase III trials showed a greater benefit of anthracyclines in patients with TOP2A alterations and a trend towards greater benefit in patients with Her2-amplified tumors [ 12 – 15 ]. More recently, the DBCG READ trial gave no evidence to support a benefit from anthracyclines in patients with early TOP2A -normal breast cancer while the Anthracyclines in early breast cancer (ABC) trials suggested that patients with Her2-normal breast cancer derive some benefit from anthracyclines [ 16 , 17 ]. The association between the Her2-enriched subtype and alteration of TOP2A has not yet been clarified but may improve the clinical utility of both markers.…”