Treating patients upfront with five years of the aromatase inhibitor exemestane is just as effective in terms of preventing breast cancer recurrence as is a strategy of treatment with two to three years of tamoxifen followed by exemestane, a study of nearly 10,000 women suggests.
“In the intent-to-treat analysis, which is the primary endpoint of the trial, there is not any difference,” said Daniel Rea, MD, PhD, Senior Lecturer in Medical Oncology at the University of Birmingham, UK, speaking at the CTRC-AACR San Antonio Breast Cancer Symposium. “We cannot detect a clear difference between the strategy of starting with an aromatase inhibitor at diagnosis or waiting two to three years before beginning aromatase inhibitors.”
Dr. Rea noted that in previous studies, switching patients from tamoxifen to an aromatase inhibitor after two to three years proved better at preventing recurrence than treating patients with tamoxifen alone.
In the trial, called TEAM for Tamoxifen Exemestane Adjuvant Multinational, he and his co-researchers assigned 4,875 women to treatment with tamoxifen (20 mg a day) for two to three years followed by exemestane (25 mg a day) and 4,904 patients to treatment with five years of exemestane (25 mg a day).
The patients accrued about 5.1 years of follow-up. The average age of the women in the study was about 64; 58% of the women had Grade T1 breast cancer, and about 55% underwent breast-conserving surgery.
There were 712 disease events recorded in the tamoxifen-plus-exemestane arm and 714 in the exemestane-monotherapy arm. There were 68 local recurrences in the combination group, compared with 59 in the exemestane group.
Dr. Rea illustrated that the Kaplan-Meier outcome curves so overlapped that the lines were indistinguishable, resulting in a hazard ratio of 1.0. The findings were similar regardless of whether the women had lymph-node involvement or were node negative.
“One of the problems we have with early breast cancer trials it that we are getting much better at looking after our patients, and detecting differences is getting more and more challenging,” he said.
Base Treatment on Safety Profile
Dr. Rea said that in reviewing the safety data, “patients who got exemestane upfront got more of the aromatase inhibitor side effects. We saw more osteoporosis—9.9%—more patients with fractures—5.1%—more getting stiff painful joints—23.5%—more who got carpal tunnel syndrome—3.4%—and a little more vaginal dryness—6.6%. And we also saw a little bit more hypertension—6.0%—and hyperlipidemia—4.7%—with patients taking exemestane.
“When you look at the patients who started with tamoxifen and then switched to exemestane, there were a different set of toxicities,” he continued. “We saw more hot flushes—44.7%—more postmenopausal bleeding—5.0%—more vaginal discharge—8.4%—and more patients had to undergo endometrial investigations upon having found endometrial pathology—3.9%.
“There were 17 endometrial cancers among patients exposed to tamoxifen and seven endometrial cancers among women exposed to exemestane, a difference that was not statistically significant. We saw more venous thrombosis—2.0%—in patients taking tamoxifen and more muscle cramps—6.3%. These are typical tamoxifen side effects,” he said.
So what is a clinician to do? Dr. Rea suggested that treatment decisions be based on the side effect profiles and known adverse events associated with the drugs.
“Both of these strategies appear to be reasonable approaches to patients with hormone-receptor-positive early breast cancer, and the choice of which one you are going to use is going to be based on the toxicity profile.”
He said that researchers are studying tumor specimens collected in the trial to determine if there are biomarkers that would suggest that a specific therapy might be a better choice for specific patients.
Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/ Oncology at the Mayo Clinic in Jacksonville, FL, said at a news briefing that some physicians expected that using the less expensive tamoxifen followed by exemestane would be less beneficial than treatment with exemestane alone. Other people expected just the opposite.
“What this study is showing is that there are options,” she said.
The trial received funding support from Pfizer.
Benefits of Letrozole Greater than Previously Reported
In other aromatase inhibitor research reported at the symposium, researchers said that updated figures for the landmark Breast International Group (BIG) 1-98 trial suggest that treatment with the aromatase inhibitor letrozole confers a significant survival benefit over tamoxifen when used after surgery in postmenopausal women with hormone-receptor-positive early breast cancer.
“BIG 1-98 provides evidence of a statistically significant overall survival benefit for five years of letrozole compared with five years of tamoxifen therapy,” said Meredith M. Regan, ScD, Assistant Professor of Medicine at Harvard Medical School and Senior Research Scientist in Biostatistics and Computational Biology at Dana-Farber Cancer Institute.
The new analysis, she said, shows that the superiority of letrozole over tamoxifen is larger than that shown in the original intent-to-treat analysis.
At the 2008 symposium, researchers reported that letrozole was associated with a nonsignificant 13% reduction in the risk for death in the intent-to-treat population. The censored analysis, which included patient data only up to time of crossover, showed that letrozole was associated with a 19% overall survival benefit.
The original analysis did not take into consideration crossover from one arm of the study to another that might have diluted the impact of letrozole, Dr. Regan said.
For the new analysis, the researchers utilized an inverse probability of censoring weighted analysis to estimate the clinical benefit of letrozole that would have been observed had there been no selective crossover in the trial.
Results showed that five years of treatment with letrozole after surgery significantly improved the disease-free survival rate by 15% and the overall survival rate by 17%.
The BIG 1-98 study included 8,010 postmenopausal women who had completed surgery for estrogen-sensitive breast cancer and who had no evidence of metastasis.
The study was supported by Novartis and NCI grants.