SAN ANTONIO – Extended follow-up of the nearly 5,000 women enrolled in the phase III multicenter E1199 trial has provided a wealth of new findings – and additional leads – regarding optimal adjuvant chemotherapy in patients with axillary lymph node–positive or high-risk, lymph node–negative breast cancer.
“The relative effectiveness of weekly paclitaxel and every-3-week docetaxel may vary by subtype,” Dr. Joseph A. Sparano reported at the San Antonio Breast Cancer Symposium.
The E1199 trial, conducted in 1999-2001, included 4,950 breast cancer patients who first received four cycles of standard adjuvant chemotherapy consisting of intravenous doxorubicin and cyclophosphamide at 3-week intervals. They were then assigned in a 2x2 factorial design to intravenous paclitaxel (Abraxane) at the then-standard 3-week intervals for four cycles, to weekly paclitaxel for 12 weeks, or to docetaxel (Taxotere) given at either of the same two dosing schedules.
Bruce Jancin/Frontline Medical News
Dr. Joseph A. Sparano
The goal was to determine the optimally effective adjuvant taxane and dosing regimen. And in the initial report based upon a median 5.3 years of follow-up (N. Engl. J. Med. 2008;358:1663-71), weekly paclitaxel was the clear winner. It was associated with a 27% improvement in the likelihood of disease-free survival (DFS) and a 32% gain in overall survival (OS), compared with paclitaxel given every 3 weeks. Docetaxel every 3 weeks also resulted in improved DFS, but not in OS.
Dr. Sparano’s newly updated analysis was based upon a median 12.1 years of follow-up. By this point the number of DFS events – defined as recurrence, contralateral breast cancer, or death – had climbed to 1,639, compared with 1,058 in the initial report. The all-cause death count had risen from 686 to 1,283.
With the extended follow-up, both weekly paclitaxel and docetaxel every 3 weeks still remained superior to every-3-weeks paclitaxel in terms of DFS, with relative risk reductions of 16% and 21% for DFS events, respectively. However, trends favoring these two regimens in terms of OS didn’t reach statistical significance, reported Dr. Sparano, professor of medicine and women’s health at Albert Einstein College of Medicine, New York.
Among the more interesting findings to emerge from the extended analysis was the differential treatment response based upon breast cancer subtype. Among the 1,025 women with triple-negative breast cancer (TNBC), weekly paclitaxel was associated with highly significant relative risk reductions of 31% both for DFS events and mortality. This regimen boosted the 10-year DFS rate from 59% with every-3-weeks paclitaxel to 69%, while improving 10-year overall survival from 66% to 75%.
“Our findings also show that there remains substantial room for improvement in this population, despite the improvement seen with weekly paclitaxel,” the medical oncologist observed.
This is the rationale for the pending NRG-BR003 trial, in which patients with TNBC are randomized to four cycles of adjuvant chemotherapy followed by weekly paclitaxel for 12 weeks, as in the most effective arm of E1199, or to the same regimen supplemented by carboplatin in an effort to enhance outcomes.
In E1199, TNBC was associated with a very high annual risk of cancer recurrence within the first 3 years, which declined substantially thereafter. In contrast, for the 2,785 participants with hormone receptor (HR)-positive/HER2-negative breast cancer, the recurrence risk remained persistently strong beyond 5 years.
Obesity, which was present in 35% of all E1199 participants, was associated with worse outcomes in the HR-positive/HER2-negative group, where in a multivariate analysis it was independently associated with a 23% reduction in OS and a recurrence risk peaking 3-8 years after diagnosis.
“I think an important finding from this study is that obesity tends to be associated with later relapse. So if dietary and lifestyle and other metabolic-type interventions are going to be successful, there may be an adequate window to implement those changes and have a real impact on outcomes,” according to Dr. Sparano.
Black race was also independently associated with worse outcomes in HR-positive/HER2-negative patients but not in those with TNBC. In nonobese women with HER-positive/HER2-negative disease, black race was associated with roughly 2.3-fold increased risks of DFS events and mortality.
“These findings indicate an effect of race independent of obesity. That’s an important finding given the fact that obesity rates were twofold higher in patients of black race,” Dr. Sparano said.
In women with HR-positive/HER2-negative breast cancer, the only study regimen that proved more effective than paclitaxel every 3 weeks was docetaxel every 3 weeks, which in the extended follow-up resulted in a 24% reduction in the risk of DFS events but no significant advantage in OS.
“This suggests that attention to extended adjuvant endocrine therapy may be more relevant in this subpopulation, which is at risk for late relapse, particularly at the time of this study, when extended adjuvant therapy was not common practice,” he noted.