There is no statistical advantage with regard to disease-free and overall survival for AC-TH over TCH, with only 10 disease-free survival events now separating the two experimental arms.
—Dennis Slamon, MD
The final analysis of the BCIRG-006 trial confirmed the long-term efficacy of trastuzumab (Herceptin) in early breast cancer and also validated the concept that anthracyclines increase toxicity and they are not always necessary for a good outcome.1 The 10-year follow-up of the landmark trial was presented at the 2015 San Antonio Breast Cancer Symposium by principal investigator Dennis Slamon, MD, of the University of California, Los Angeles.
In a study of 3,222 HER2-positive, node-positive or high-risk node-negative early breast cancer patients, BCIRG-006 compared doxorubicin plus cyclophosphamide followed by docetaxel (AC-T); AC-T plus trastuzumab (AC-TH); and a nonanthracycline-containing arm, docetaxel, carboplatin, and trastuzumab (TCH). Trastuzumab was given for 1 year.
Although the benefit conveyed by trastuzumab has never been questioned, the idea of eliminating anthracyclines was a much-debated issue when the initial results debuted in 2005. Dr. Slamon spoke to this issue.Error loading Partial View script (file: ~/Views/MacroPartials/TAP Article Image Widget.cshtml)
After 10.3 years of follow-up, the two trastuzumab arms showed a “sustained and significant efficacy advantage” over AC-T; however, the differences between the two trastuzumab arms was slight.
“There is no statistical advantage with regard to disease-free and overall survival for AC-TH over TCH, with only 10 disease-free survival events now separating the two experimental arms,” Dr. Slamon reported.
“This numerical advantage, however, comes at a cost of fivefold more clinical congestive heart failures in the AC-TH arm than in the TCH arm and a higher rate of leukemia and sustained left ventricular ejection fraction decline > 10% from baseline,” he indicated (Table 1).
Comparison of Benefits Across a Decade
Compared with the standard at the time, the first analysis showed a 51% improvement with AC-TH and a 39% improvement with TCH. In the second analysis, improvements were 36% and 25%, respectively. In the final analysis reported in San Antonio, risk reductions were 28% and 23%, respectively, over AC-T. So although the margins narrowed over time, both experimental arms remained significantly better than the chemotherapy arm, Dr. Slamon noted.
At the final analysis, 10-year disease-free survival was 74.6% with AC-TH (P < .0001), 73.0% with TCH (P = .0011), and 67.9% with AC-T. Overall survival at 10 years was 85.9%, 83.3% and 78.7%, representing risk reductions of 27% (P < .0001) and 24% (P = .0075), respectively.
The comparability of TCH to AC-TH in these outcomes triggers the question, “Do higher-risk HER2-positive breast cancers require anthracycline-based treatment?” Dr. Slamon asked.
In a subset analysis of node-positive patients, disease-free survival rates were 69.6% for AC-TH (P < .001), 68.4% for TCH (P = .0018), and 62.2% for AC-T. In patients with at least four nodes involved, disease-free survival was 62.9% (P = .0039), 62.8% (P = .0018), and 53.6%, respectively.
Although disease-free survival for these high-risk patients was lower than for better-risk patients, the treatment-related outcomes were similar to the whole study population. This finding suggests that the benefit for anthracyclines, even in this high-risk group, may be minimal.
Important Safety Differences
What did emerge as a difference, continued Dr. Slamon, was the incidence of adverse events related to anthracycline use. For grades 3/4 nonhematologic toxicities, the three arms were generally similar. TCH-treated patients had less arthralgia, myalgia, hand-foot syndrome, stomatitis, vomiting, sensory and motor neuropathy, and nail changes than the other two regimens. For hematologic toxicities, the TCH arm had less neutropenia and leukopenia than the AC-TH arm but more anemia and thrombocytopenia.
Cardiac toxicity and second malignancies were where differences became notable, including:
At baseline, cardiovascular risk factors were fairly well balanced among the three arms. By the third and final analyses, left ventricular ejection fraction had recovered to some degree in the AC-TH arm but still remained far below the better left ventricular ejection fraction levels in TCH-treated patients, which had returned almost to baseline. ■
Disclosure: Dr. Slamon is a consultant for and receives research support from Novartis and has ownership interests in Amgen.
1. Slamon DJ, Eiermann W, Robert NJ, et al: Ten-year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2-positive early breast cancer patients. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 11, 2015.
The general consensus of breast cancer experts of the initial findings of BCIRG-006 triggered a more judicious use of anthracyclines, and this trend continues. Kathy S. Albain, MD, FACP, FASCO, Professor of Medicine at Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, said...