SABCS: Five-Year Cutoff on Tamoxifen Adjuvant Therapy Called Off Base Advice

Michael Smith
SAN ANTONIO, Dec. 16 -- The consensus that tamoxifen is limited to a five-year therapeutic lifetime against a recurrence of breast cancer is flawed, found a major international trial that suggests longer treatment is better.
Action Points --->
Explain to interested patients that tamoxifen has been shown to prevent recurrence if women take it for five years after treatment for early breast cancer but that most authorities believe the therapy has no value beyond that point.
Note that this study suggests that a longer period of tamoxifen may confer an additional benefit.
This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.
The early results of the Adjuvant Tamoxifen, Longer Against Shorter (ATLAS) trial fly in the face of advice from the National Cancer Institute, which concluded in 2002 that more than five years of the drug was of no value, according to Richard Peto, Ph.D., of the University of Oxford.
That advice was "wrong," said Dr. Peto during a session of late-breaking trials at the San Antonio Breast Cancer Symposium here. The ATLAS study is comparing five years of tamoxifen against 10 years in women diagnosed with early breast cancer. Since the study began, however, aromatase inhibitors have begun to steadily supplant tamoxifen as the adjuvant hormonal therapy of choice.
The researchers enrolled 11,500 women who had been treated for five years with tamoxifen, a selective estrogen receptor modulator, and randomized them to stay on it for five more years or stop therapy.
They've now been followed for an average of between four and five years since the second randomization, Dr. Peto said, for a total of 42,000 woman-years of follow-up.
Also, he said, some women have completed the second five years of the study -- and stopped taking the drug if they were randomized to the tamoxifen arm -- and there are about 8,000 woman-years of follow-up in that group.
The researchers have "plenty of data" about years five through nine of the study, he said, but still relatively little for the following five years.
The bottom line, Dr. Peto said, is that continuing on tamoxifen for an additional five years confers about a 12% reduction in the risk of breast cancer recurrence, compared with stopping. The rate ratio was 0.88, which was statistically significant with a two-sided P=0.005.
For women in the second five-year period, there's a carry-over effect if they were treated with tamoxifen -- an additional risk reduction of about 22% compared with women who had only five years of treatment -- but it wasn't statistically significant, Dr. Peto said.
All told, he said, there have been 739 recurrences among women allocated to continue tamoxifen and 835 among those who stopped. Of those, 221 occurred among women in years 10 through 14 of the study -- 96 among women who took 10 years of tamoxifen and 115 among those who got five.
Although the numbers remain small, Dr. Peto said, "it's clear that the early adverse results were wrong."
He was referring to surprising findings in the small NSABP B-14 trial, which was stopped early in 1995 when investigators found an excess of breast cancer in the tamoxifen arm, suggesting that longer tamoxifen use was no longer a benefit and was causing actual harm.
So far, he said, that danger signal has not been seen in ATLAS or any of the other studies looking at the issue.
"On the whole," he said, "it seems to be safe, except for the known side effect of endometrial cancer," which is increased among women taking tamoxifen.
The analysis showed that "there does appear to be a benefit -- although slight -- to longer term tamoxifen," commented C. Kent Osborne, M.D., of Baylor College of Medicine in Houston, who was not involved in the study.
Dr. Osborne, the symposium's co-director, agreed with Dr. Peto that the findings show "in this first analysis of this very large trial that the small studies that suggested there wasn't a benefit were probably wrong."
Dr. Osborne said the large size of the study -- the largest ever in adjuvant therapy in breast cancer -- is a major strength.
Also, he said, the patient population includes an unknown number of women with estrogen receptor-negative disease, which means that the benefit Dr. Peto reported may be an underestimate.
While the aromatase inhibitors have taken the spotlight in preventing breast cancer recurrence, he added, there are many parts of the world where the much cheaper tamoxifen remains the mainstay of therapy.
For patients and physicians in those areas, knowing that longer tamoxifen has a benefit will be useful, he said.
The study was designed and is coordinated by the Clinical Trial Service Unit at Oxford. Dr. Peto reported he had no conflicts.
Primary source: Breast Cancer Research and TreatmentSource reference:Peto R, et al "ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): international randomized trial of 10 versus 5 years of adjuvant tamoxifen among 11,500 women -- preliminary results" Breast Cancer Res Treat 2007; 106 (Supp1): Abstract 48.