In a large patient-level meta-analysis of 16 trials, presented at the 2021 San Antonio Breast Cancer Symposium (SABCS),1 the combination of an anthracycline plus a taxane achieved a substantial 15% reduction in breast cancer recurrence at 10 years vs taxane chemotherapy alone, representing an absolute reduction of 2.5% in recurrence.The concurrent schedule of an anthracycline plus a taxane achieved a much larger proportional reduction in recurrence (42%) compared with a taxane alone, and little if any benefit was observed in trials of sequential anthracycline and taxane vs a higher-dose taxane in the control group. The proportional reduction in disease recurrence with a concurrent schedule did not differ by estrogen receptor or nodal status.
Jeremy Braybrooke, BSc, BM, FRCP, PhD
“It is known that anthracycline-plus-taxane–based chemotherapy for early-stage breast cancer reduces the risk of breast cancer mortality by about one-third compared with no chemotherapy. But there are concerns about toxicity: with anthracyclines, the long-term risk of cardiovascular toxicity and leukemia, and with taxanes, neuropathy,” said lead author Jeremy Braybrooke, BSc, BM, FRCP, PhD, of the University of Oxford and University Hospitals Bristol and Weston NHS Foundation Trust, United Kingdom.
“These concerns have led to increasing use of non–anthracycline-based chemotherapy for early breast cancer. We conducted our patient-level meta-analysis from eligible randomized trials initiated before 2012. All trials included at least six cycles of chemotherapy in each arm. The primary outcomes were disease recurrence and breast cancer–specific mortality analyzed by standard Early Breast Cancer Trialists’ Collaborative Group methods,” he explained.
Meta-analysis Details
The meta-analysis included data from more than 18,000 patients randomly assigned to treatment in 16 trials. Four different comparisons were analyzed:
- Group A: six cycles of concurrent anthracycline plus docetaxel plus cyclophosphamide vs six cycles of the same dose of docetaxel plus cyclophosphamide (three trials, 2,469 participants)
- Group B: sequential anthracycline plus docetaxel vs a higher cumulative dose of docetaxel plus cyclophosphamide (eight trials, 11,386 participants)
- Group C: taxane plus anthracycline vs a higher cumulative dose of taxane with or without concurrent capecitabine (three trials, 1,552 participants)
- Group D: taxane plus anthracycline vs a higher cumulative dose of taxane plus carboplatin (two trials, 2,796 participants).
First, Dr. Braybrooke presented results for the combined analysis of first invasive recurrence in all four groups. At 10 years, the proportional risk of recurrence was reduced by 15% in the anthracycline-plus-taxane–treated groups vs a taxane alone: 16.4% for the anthracycline/taxane combination and 19% for taxane, with an absolute gain of 2.5% (P = .0003).
Looking at breast cancer–specific mortality for the combined analysis, again the anthracycline/taxane combination was superior (P = .02): 10.4% for the combination and 12% for taxane monotherapy, representing an absolute gain of 1.6% at 10 years.
“The trial designs varied, and there was heterogeneity among the four groups. The greatest proportional reduction in recurrence was seen in group A, with concurrent anthracycline plus taxane,” Dr. Braybrooke noted.
Groups A and B
The rest of Dr. Braybrooke’s presentation focused on groups A and B—taxane plus anthracycline vs the same control arm of docetaxel plus cyclophosphamide. This analysis included 13,855 individuals in 11 of 11 eligible trials, with a median follow-up of 5.3 years.
In these 11 trials, the majority of patients had hormone receptor–positive disease: 66% in group A and 75% in group B. Node-positive disease was present in 61% and 46%, respectively. HER2-positive breast cancer was identified in 2% and 3%, respectively.
“There were differences in cumulative chemotherapy doses in groups A and B,” Dr. Braybrooke emphasized. In group A, most participants received the same cumulative doses of docetaxel and cyclophosphamide in both arms, with the only difference being the addition of anthracycline. By contrast, group B explored sequential anthracycline/taxane vs higher cumulative doses of taxane as docetaxel plus cyclophosphamide. “The cumulative taxane dose was about one-third lower than the control group and, for the anthracycline, most investigators used epirubicin at 300 mg/m2 [considered equivalent to approximately 200 mg/m2 doxorubicin],” he noted.
The risk of recurrence was reduced by 42% in group A, favoring concurrent taxane plus anthracycline over docetaxel and cyclophosphamide. The 10-year absolute gain was 8.7% (P < .00001). “In this analysis, we should highlight there were just 2,469 participants, 61% with node-positive disease and 66% with estrogen receptor–positive disease. We need to interpret this with caution,” Dr. Braybrooke commented. By contrast, in group B—the sequential arm—there was no significant difference in recurrence between anthracycline plus taxane vs taxane alone.
Group A had an absolute 10-year gain of 4.2% in breast cancer–specific mortality (P = .003): 8.9% for anthracycline plus taxane vs 13.2% for taxane alone. Group B had an absolute 10-year gain of 0.3% in breast cancer–specific mortality for anthracycline plus taxane, but the difference between the two arms was not statistically significant.
“Most of the differences in breast cancer–specific mortality come from group A, with concurrent anthracycline plus taxane,” Dr. Braybrooke emphasized. “Results suggest a benefit for anthracycline plus taxane in both estrogen receptor–positive and –negative disease, as well as in lymph node–positive and –negative disease.”
In a combined analysis of toxicity in all 16 trials, there was no statistically significant difference in death without recurrence, and deaths from cardiovascular causes or leukemia. However, longer follow-up is needed, and “no quality-of-life data were available,” he said.
Discussion of Trial Findings
William J. Gradishar, MD, FACP, FASCO
Session co-moderator William J. Gradishar, MD, FACP, FASCO, the Betsy Bramsen Professor of Breast Oncology and Chief of Hematology/Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, pointed out that that there has been a shift away from concurrent taxane/anthracycline therapy due to toxicity.
“Do these data speak to the idea that we should reevaluate concurrent taxane and anthracycline treatment?” he asked.
Dr. Braybrooke pointed out that this question was not addressed in the analysis. “What we need to consider is that cumulative doses of anthracycline and taxane seem to be important. The study results challenge us to think about cumulative doses. In group B, sequential schedules were predominantly 3-week schedules. It has been previously shown that sequential schedules—if dose-dense—were as good as concurrent schedules, if not more effective. Balancing benefit and toxicity is important,” he said.
Dr. Gradishar then noted: “In contemporary practice, rather than six cycles of docetaxel/cyclophosphamide, we often give four cycles. How do your data square with that?”
“We don’t know the answer to that,” Dr. Braybrooke said. “We don’t have large trials comparing four vs six cycles of docetaxel/cyclophosphamide. In future work, we plan to analyze longer vs shorter schedules of chemotherapy. We need to think about how much we can safely cut back on chemotherapy and, where indicated, consider the cumulative doses. A discussion of risks and benefits with the patient is important. Not all patients need chemotherapy.”
DISCLOSURE: Dr. Braybrooke reported no conflicts of interest. Dr. Gradishar has served as a consultant or advisor to Genentech/Roche, AstraZeneca, Pfizer, Puma, Seattle Genetics, Merck, and Beyond Spring.
REFERENCE
1. Braybrooke J, Bradley R, Gray R, et al: Taxane with anthracycline versus taxane without anthracycline: An individual patient-level meta-analysis of 16,500 women with early-stage breast cancer in 13 randomised trials. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-06. Presented December 8, 2021.
