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 hormone 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 test letrozole and tamoxifen head to head. 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 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 women who had completed surgery for early, ER-positive breast cancer and who had no evidence of metastasis.
The women were randomly assigned to one of four groups: some women took letrozole and some took tamoxifen for five years (monotherapy); others took letrozole for two years and then switched to tamoxifen while the final group took tamoxifen for two years and then switched to letrozole (sequential therapy).
In the current report, researchers compared 4,007 women in the two tamoxifen groups to 4,003 women in the two letrozole groups. More follow-up is needed before the authors can tell whether the two monotherapy groups (tamoxifen alone; letrozole alone) do any better or worse compared to the two sequential therapy groups (one drug followed by the other).
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 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.
Some of the women in the study received chemotherapy after 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 enrolling in the study, and concluded that this would be true for 84 percent of those in the letrozole groups and 81.4 percent of those in the tamoxifen groups. At the two year mark, there was no difference in overall survival between the letrozole and tamoxifen groups.
As in other trials, side effects such as joint pain and fractures were more common in women who took letrozole, and they were more likely to have heart attacks 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 by the Journal of Clinical Oncology online Nov. 12, 2007, in print Dec. 20, 2007, 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 metastasis. 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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