Joint Trial Analysis Confirms Benefit of Anthracyclines in High-Risk Breast Cancer

Joanne Lorraine Blum, MD, PhD

A joint analysis of the “ABC” trials comparing anthracycline versus non-anthracycline treatment in patients with high-risk, HER2-negative breast cancer has failed to demonstrate non-inferiority of the non-anthracycline regimen.

According to data presented at the 2016 ASCO Annual Meeting, docetaxel plus cyclophosphamide (TC) was significantly inferior to various taxane-plus-anthracycline-based (TaxAC) chemotherapy regimens.

“Statistical non-inferiority of the non-anthracycline regimen could not be demonstrated,” said Joanne Lorraine Blum, MD, PhD, medical oncologist with Texas Oncology at the Baylor-Sammons Cancer Center in Dallas. “In terms of the study’s primary endpoint, invasive disease-free survival, TC x 6 was significantly inferior to TaxAC.”

As Dr. Blum, the lead study author, reported, the role for anthracyclines in patients with HER2-negative breast cancer has been hotly debated. Although subsets of early anthracycline trials suggested that only patients with HER2-positive tumors derived benefit from anthracyclines, these subset analyses were never conclusive.

Recent trials have shown, though, that when taxanes are added to anthracyclines, breast cancer mortality is reduced by more than a third compared with no chemotherapy at all. However, these benefits must be considered in the context of risk, said Dr. Blum, as anthracyclines are associated with a slight, but real, risk of cardiotoxicity and acute leukemia.

In addition, the sequential development of anthracyclines followed by taxanes has made evaluation of de-escalation of TaxAC regimens by removing anthracyclines challenging.

“The pivotal study of TC x 4 versus AC x 4 demonstrated overall survival superiority for TC,” said Dr. Blum. “This established TC as an effective non-anthracyclines regimen appropriate for comparing with TaxAC regimens.”

ABC Trials Schema

US Oncology Research (USOR) and National Surgical Adjuvant Breast and Bowel Project (NSABP) collaborated with separate sponsors on 3 sequential clinical trials that randomized women with resected high-risk, early-stage breast cancer to receive TC or one of several standard TaxAC regimens. The researchers prospectively agreed to combine the efficacy data in an analysis which was pre-specified in the third protocol (NSABP B-49). These are collectively referred to as the “ABC Trials.”

More than 4000 eligible patients with node-positive or high-risk node-negative breast cancer participated in the trials, which were designed to test non-inferiority of TC to TaxAC with respect to invasive disease-free survival (IDFS). A hazard ratio (HR) from a stratified Cox model of 1.18 or more was pre-defined as inferior. HRs above 1 favor TaxAC.

The TaxAC options included AC every 2 or 3 weeks followed by paclitaxel every week or every 2 weeks; all were compared to TC every 3 weeks for 6 cycles.

Patients were stratified for parent trial, positives nodes (0, 1-3, 4-9, 10+), and hormonal status (negative, positive).

Results

Of the 4242 patients randomized in the ABC Trials, researchers analyzed 4156. Follow-up ranged from 2.2 years to 6.3 years in the separate studies.

Data cutoff for the interim analysis was October 31, 2015. The observed HR on the initial 334 events was 1.202, which exceeded the pre-specified threshold for futility (>1.18) and triggered consideration for early reporting.

The 4-year IDFS was 88.2% in the TC arm versus 90.7% for patients on TaxAC. At approximately 95% in both groups, researchers observed no difference in overall survival, Dr. Blum reported.

Exploratory subgroup analyses suggested that TaxAC provided the following: minimal, if any, benefit in ER-positive/node-negative cohorts; a small benefit in ER-positive/1-3 positive nodes and ER-negative/node-negative cohorts; and a large benefit in ER-positive/≥4 positive nodes and ER-negative/node-positive cohorts.

There were more first IDFS events, both distant and local or regional, in the TC arm (220) versus TaxAC arm (179). However, said Dr. Blum, acute leukemia occurred as a first event in 5 of 2050 patients assigned to TaxAC, versus none in the TC arm.

“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.

Expert Commentary

Tiffany A. Traina, MD, Clinical Director of the Breast Medicine Service at Memorial Sloan Kettering and Assistant Professor of Medicine at Weill Cornell Medicine, said, “The overall trial results demonstrate that not only is TC not non-inferior to TaxAC in DFS, but TC x 6 is significantly inferior to the anthracycline and taxane-containing regimens in terms of DFS.”

Despite the small percentage of first events, leukemia risk associated with TaxAC remains low, she added, and subset analyses should be interpreted with caution.

“As of today, anthracycline and taxane-based adjuvant regimens are 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,” Dr. Traina concluded.

Blue 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 (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. Presented at: ASCO 2016; June 3-7, 2016; Chicago, IL. Abstract 1000.