Joint Analysis Confirms Benefit of Anthracyclines for High-Risk Early-Stage Breast Cancer


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For the treatment of high-risk, HER2-negative early-stage breast cancer, anthracyclines were confirmed as beneficial in a joint analysis of the Anthracyclines in Early Breast Cancer (ABC) trials. Presented at the 2016 ASCO Annual Meeting, the joint analysis of the ABC trials validated taxane plus anthracycline as the preferred regimen for high-risk patients.1

This joint analysis pooled patients from three large trials and compared several taxane-plus-anthracycline regimens (TaxAC) with a non–anthracycline-based control arm of six cycles of docetaxel plus cyclophosphamide (TC). The trial had a noninferiority endpoint and involved more than 4,000 patients.


In terms of the study’s primary endpoint—invasive disease–free survival—docetaxel plus cyclophosphamide × 6 was significantly inferior to taxane plus anthracycline.
— Joanne L. Blum, MD, PhD

“Statistical noninferiority of the non–anthracycline regimen could not be demonstrated,” said Joanne L. Blum, MD, PhD, of Texas Oncology at the Baylor-Sammons Cancer Center in Dallas. “In terms of the study’s primary endpoint—invasive disease–free survival—docetaxel plus cyclophosphamide × 6 was significantly inferior to taxane plus anthracycline.”

Study Rationale

Describing the rationale for the study, Dr. Blum noted the ongoing debate over the role of anthracyclines in patients with HER2-negative breast cancer. In some of the early studies, only patients with HER2-positive tumors seemed to derive benefit from anthracyclines, but these subset analyses were never conclusive and were dramatically underpowered, she revealed.

Although mortality reduction has been established for the combination of taxanes and anthracyclines, these benefits must be considered in the context of the slight—but real—risk for cardiotoxicity and acute leukemia associated with anthracyclines. And there have been challenges in evaluating ways to de-escalate taxane-plus-anthracycline regimens through the elimination of anthracyclines.

The comparison of docetaxel plus cyclophosphamide with taxane plus anthracycline was founded upon the pivotal USOR 9735 study of docetaxel plus cyclophosphamide × 4 vs AC × 4, which showed an overall survival superiority for docetaxel plus cyclophosphamide.2 “This established docetaxel plus cyclophosphamide as an effective non–anthracycline regimen appropriate for comparing with taxane plus anthracycline regimens,” said Dr. Blum.

Schema of ABC Trials

The ABC trials represented collaboration between US Oncology Research and the National Surgical Adjuvant Breast and Bowel Project (NSABP). US Oncology Research and NSABP collaborated with separate sponsors on three independent clinical trials, which randomized women with resected high-risk, early-stage breast cancer to receive docetaxel plus cyclophosphamide × 6 or one of several standard taxane-plus-anthracycline regimens. The studies were USOR 06-090 (N = 1,295), NSABP B-46I/USOR 07132 (N = 1,077) and NSABP B-49 (N = 1,870).

The researchers prospectively agreed to combine the efficacy data in an analysis, which was prespecified in the most recent study, NSABP B-49. Collectively referred to as the “ABC trials,” the joint analysis included 4,156 patients with node-positive or high-risk node-negative breast cancer. Follow-up ranged from 2.2 years to 6.3 years in the separate studies.

Anthracyclines in High-Risk Breast Cancer

  • A joint analysis of three large early breast cancer trials compared various taxane-plus-anthracycline regimens with docetaxel plus cyclophosphamide and confirmed the superiority of anthracyclines in high-risk early-stage breast cancer patients.
  • The hazard ratio (HR) on the initial 334 events was 1.202, which exceeded the prespecified threshold for futility (> 1.18).
  • Four-year invasive disease–free survival was 88.2% in the docetaxel-plus-cyclophosphamide arm vs 90.7% for the taxane-plus-anthracycline arm (HR = 1.23; P = .04), demonstrating that docetaxel plus cyclophosphamide × 6 is significantly inferior to the anthracycline and taxane–containing regimens.

The taxane-plus-anthracycline options included TaxAC every 3 weeks for six cycles, or AC every 2 or 3 weeks followed by paclitaxel every week or, AC followed by paclitaxel every 2 weeks; all options were compared with docetaxel plus cyclophosphamide every 3 weeks for six cycles. Patients were stratified for the parent trial, positives nodes (0, 1–3, 4–9, 10+), and hormonal status (negative, positive).

The analysis was designed to test noninferiority of docetaxel plus cyclophosphamide to taxane plus anthracycline with respect to invasive disease–free survival. A hazard ratio from a stratified Cox model of 1.18 or more was predefined as inferior. Hazard ratios above 1 favored taxane plus anthracycline, Dr. Blum explained.

Study Results

As of the data cutoff for the interim analysis, October 31, 2015, the observed hazard ratio on the initial 334 events was 1.202, which exceeded the prespecified threshold for futility (> 1.18) “and triggered consideration for early reporting,” she said.

The 4-year invasive disease–free survival was 88.2% in the docetaxel-plus-cyclophosphamide arm vs 90.7% for the taxane-plus-anthracycline arm—an absolute 2.5% benefit for taxane plus anthracycline (HR = 1.23; P = .04). Overall survival was approximately 95% in each group.

Exploratory subgroup analyses suggested that taxane plus anthracycline provides minimal, if any, benefit in estrogen receptor–positive/node-negative cohorts; a small benefit in estrogen receptor–positive patients with one to three positive nodes and in estrogen receptor–negative/node-negative cohorts (2.0%—a 2.5% improvement); and a large benefit in estrogen receptor–positive patients with four or more positive nodes and estrogen receptor–negative/node-positive cohorts (5.8%—an 11.0% improvement). That said, there were no significant differences in treatment effect by prespecified stratification variables, including hormone receptor status.

There were more first invasive disease–free survival events, both distant and local regional, in the docetaxel-plus-cyclophosphamide arm (220) than in the taxane-plus-anthracycline arm (179), but acute leukemia occurred as a first event in 5 of 2,050 patients (0.24%) assigned to taxane plus anthracycline, whereas none were seen with docetaxel plus cyclophosphamide.

“Additional follow-up and correlative studies to identify biomarkers of anthracycline benefit will be crucial for fully determining the utility of anthracyclines across the heterogeneous patient population,” Dr. Blum concluded. ■

Disclosure: Dr. Blum reported no potential conflicts of interest.

References

1. Blum JL, Flynn PJ, Yothers G, et al: Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090), NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide v anthracycline/taxane-based chemotherapy regimens in women with high-risk HER2-negative breast cancer. 2016 ASCO Annual Meeting. Abstract 1000. Presented June 4, 2016.

2. Jones S, Holmes FA, O’Shaughnessy J, et al: Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-Year follow-up of US Oncology Research Trial 9735. J Clin Oncol 27:1177-1183, 2009.


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Expert Point of View: Tiffany A. Traina, MD


As of today, anthracycline and taxane-based adjuvant regimens remain an appropriate choice for node-positive or high-risk, node-negative breast cancers. While not perfect, it’s highly encouraging to see how well this entire study population performed.
— Tiffany A. Traina, MD
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