Letrozole More Effective Than Tamoxifen in Early Breast Cancer: Results from the BIG 1-98 TrialKey Words
Breast cancer, BIG 1-98, letrozole (Femara®), tamoxifen (Nolvadex®),
aromatase inhibitors, hormone therapy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
In this large international trial of postmenopausal women surgically treated for early-stage, hormone responsive breast cancer, letrozole (Femara®) did better to prevent a recurrence of disease (especially distant metastases) than the commonly prescribed tamoxifen (Nolvadex®).
Source
The New England Journal of Medicine, December 29, 2005 (see the journal abstract).
(N Engl J Med. 2005 Dec 29;353(26):2747-57)
Background
Women whose early-stage breast tumors grow in response to estrogen usually receive anti-estrogen therapy after surgery to reduce their risk that the disease will recur. Approximately seven in ten breast cancer patients have estrogen receptor (ER) positive tumors and so are candidates for this kind of adjuvant treatment.
Since the 1980s, the anti-estrogen drug tamoxifen has been considered the standard of care. However, women taking tamoxifen face an increased risk of endometrial cancer and blood clot disorders, and the risks start outweighing the benefits after five years on the drug for many women.
An alternative anti-estrogen treatment is letrozole (Femara®), which belongs to a class of drugs called aromatase inhibitors (AIs). Letrozole is one of three AIs approved by the U.S. Food and Drug Administration, the other two being anastrazole (Arimidex®) and exemestane (Aromasin®).
While studies have shown letrozole to be effective compared to a placebo, the trial described here was designed to compare the efficacy of letrozole and tamoxifen. It is one of a number of large phase III clinical trials undertaken to clarify what role AIs might play in the treatment and prevention of ER-positive breast cancer. (See related stories at Aromatase Inhibitors.)
The Study
The Breast International Group (BIG) 1-98 study (see the protocol summary) was a phase III clinical trial designed to compare letrozole and tamoxifen. Between 1998 and 2003, researchers at 27 institutions around the world enrolled 8,010 postmenopausal women who had completed surgery for early, ER-positive invasive breast cancer and who had no evidence of metastasis.
The women were randomly assigned to one of four groups: some women were assigned to take letrozole for five years and some to take tamoxifen for five years (monotherapy); others were assigned to take letrozole for two years and then to switched to tamoxifen for the remaining three years, and the final group was assigned to take tamoxifen for two years and then to switched to letrozole (sequential therapy).
In the current report, researchers compared the 4,007 women in the two groups assigned to take tamoxifen initially to the 4,003 women in the two groups assigned to take letrozole initially. Combining the monotherapy and sequential groups was possible because this analysis was limited to events that occurred in the first twenty-five months on treatment—that is, to events that would reflect only the effects of the initial therapy received by women in the sequential groups. More follow-up is needed before the authors will be able to compare outcomes among women in the monotherapy groups to those among women in the sequential therapy groups.
The study was conducted by the BIG 1-98 Collaborative Group, with Beat Thurlimann, M.D., as the chair of the Writing Committee. Novartis AG supported the trial and also supplied the drugs.
Results
After a median follow-up period of just over two years, women in the letrozole groups were 19 percent less likely to have a recurrence. The advantage was even more pronounced when it came to protection against cancer far from the original tumor (distant metastases), with women in the letrozole groups 27 percent less likely to experience a distant recurrence. There was no difference in overall survival between the letrozole and tamoxifen groups.
Some of the women in the study received chemotherapy in addition to surgery. Among these women, those in the letrozole groups were 30 percent less likely to have a recurrence than those in the tamoxifen groups. Among women whose cancer had spread to their lymph nodes, those in the letrozole groups were 29 percent less likely to have a recurrence than those in the tamoxifen groups.
Researchers also analyzed the data to come up with estimates of how many women would likely be alive and free of disease five years after beginning treatment. They concluded that 84 percent of those in the letrozole groups and 81.4 percent of those in the tamoxifen groups would be disease-free at five years.
(Note: In a subsequent analysis of the trial reported in the Feb. 10, 2007, Journal of Clinical Oncology, outcomes among only the women in the monotherapy groups were reported after a follow-up period of four years and three months. This analysis included 2,463 women assigned to letrozole only and 2,459 women assigned to tamoxifen only and found that women taking letrozole were 18 percent less likely to have a recurrence than women taking tamoxifen. The corresponding estimated five-year disease-free survival rates were 84 percent for women taking letrozole and 81.1 percent for those on tamoxifen. For details, see the journal abstract.)
As in other trials, side effects such as joint pain and bone fractures were more common in women who took letrozole, and they were more likely to have heart attacks, high cholesterol, and other cardiovascular problems. Women who took tamoxifen were more likely to have blood clots, endometrial cancer, and vaginal bleeding.
(Note: In a subsequent paper published in the Dec. 20, 2007, Journal of Clinical Oncology, researchers with the trial report a safety analysis of the cardiovascular adverse events in BIG 1-98. The analysis found a low overall incidence of such events. For details, see the journal abstract.)
Comments
The letrozole advantage reported in this trial confirms other results showing the aromatase inhibitors to be generally more effective than tamoxifen, said the study authors, who emphasized the risk reduction in distant metastases. Sandra M. Swain, M.D., a senior investigator with the National Cancer Institute’s (NCI) Center for Cancer Research, in an accompanying editorial said it was clear that these trials, “with close to 30,000 participants, consistently demonstrate that treatment with an aromatase inhibitor alone or after tamoxifen treatment is beneficial.”
Limitations
Jo Anne Zujewski, M.D., of NCI’s Cancer Therapy Evaluation Program, agreed that letrozole was likely to produce slightly better results than tamoxifen, but emphasized that many women on tamoxifen still do very well, noting that “in this trial more than 80 percent were free of recurrence.” The challenge, she said, “is to sort out which patients may be treated with tamoxifen, to avoid the increased risk letrozole poses to bone health.”
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