Many post-menopausal women take hormonal therapy medicine -- either an aromatase inhibitor or tamoxifen -- after breast cancer surgery and other treatments for hormone-receptor-positive, early-stage breast cancer. Hormonal therapy medicine can reduce the risk of the cancer coming back (recurrence). Hormonal therapy medicine taken after surgery and other treatments is called adjuvant hormonal therapy.
The study reviewed here, called the BIG 1-98 trial, found that taking the aromatase inhibitor Femara (chemical name: letrozole) for 5 years as the first adjuvant hormonal therapy medicine improved overall survival by 13% compared to taking tamoxifen for 5 years.
These results are similar to earlier results from the same study presented at the 2008 San Antonio Breast Cancer Symposium. The BIG 1-98 trial is the first study to show an overall survival benefit for Femara compared to tamoxifen.
The researchers divided the more than 8,000 post-menopausal women diagnosed with hormone-receptor-positive breast cancer in the study into four groups:
While Femara alone for 5 years was better than tamoxifen alone for 5 years, there was little difference in the risk of the cancer coming back between the women who got Femara alone or Femara and then tamoxifen. The women who took tamoxifen first and then switched to Femara were more likely to have the cancer come back someplace else in the body compared to women who took Femara first and then switched to tamoxifen.
Research continues to show that an aromatase inhibitor is the best hormonal therapy medicine to start with after initial breast cancer treatment for post-menopausal women diagnosed with early-stage, hormone-receptor-positive breast cancer. But tamoxifen is still a good choice, depending on your unique situation. For a number of reasons, including side effects and cost, tamoxifen may be a better choice for some women.
When you're deciding on a treatment plan, keep two things in mind:
If you're a post-menopausal woman being treated for hormone-receptor-positive, early-stage breast cancer, talk to your doctor about the differences in benefits and side effects of aromatase inhibitors and tamoxifen. If you're currently taking tamoxifen, discuss whether switching to an aromatase inhibitor makes sense for you. Together, you can decide on a treatment plan that is best for YOU.
For postmenopausal women with endocrine-responsive early breast cancer, a sequence of the aromatase inhibitor letrozole (Femara) and tamoxifen holds no advantage over letrozole alone, although it may be better than tamoxifen alone.
Five years of letrozole monotherapy improved overall survival 13% (P=0.08) to a significant 19% compared with tamoxifen monotherapy, according to Henning Mouridsen, MD, of Rigshospitalet in Copenhagen, and colleagues.
Disease-free survival did not significantly differ whether women got the aromatase inhibitor alone or in sequence with tamoxifen, they reported in the Aug. 20 issue of the New England Journal of Medicine.
These findings from the randomized controlled Breast International Group (BIG) 1-98 trial matched those reported at the San Antonio Breast Cancer Symposium late last year.
The researchers concluded that letrozole should be preferred for initial adjuvant endocrine therapy, but if women needed to quit the aromatase inhibitor for any reason, "a switch to tamoxifen to complete five years of therapy would be acceptable."
The trial initially randomized women only to five years of monotherapy with either letrozole or tamoxifen. Then, in 1999, two more arms were added to the study.
A total of 3,088 patients of the 8,010 postmenopausal women with receptor-positive breast cancer included in the trial were randomized to two years of tamoxifen followed by three years of letrozole or two years of letrozole then three years of tamoxifen.
After an interim report in 2005 showed prolonged disease-free survival and reduced risk of distant metastases with the aromatase inhibitor, women on tamoxifen monotherapy were allowed to cross over to letrozole.
Because prior studies had shown overall survival advantages with tamoxifen followed by an aromatase inhibitor through five years, many oncologists expected that one of the two switch strategies would prove superior to monotherapy.
But that wasn't the case.
The primary endpoint of disease-free survival at five years post-randomization was reached by 87.9% of patients with letrozole alone, 87.6% with letrozole then tamoxifen, 86.2% with tamoxifen then letrozole, and 84.6% with tamoxifen alone.
At a median 71 months of follow up, disease-free survival was no different with sequential treatment than with letrozole alone (hazard ratio 1.05 for tamoxifen followed by letrozole, 99% confidence interval 0.84 to 1.32, and 0.96 for letrozole followed by tamoxifen, 99% CI 0.76 to 1.21).
Patients who switched to letrozole from tamoxifen tended to have earlier distant recurrence than those who started with letrozole (HR 1.22 versus 1.05).
For comparison of the monotherapy arms, however, analysis was muddied by the 39.5% of tamoxifen-only women who crossed over to letrozole.
Whereas the intention-to-treat analysis showed at least a trend for superiority in all outcomes with letrozole monotherapy, the results censored for these crossovers were consistently significant compared with tamoxifen monotherapy:
Both analyses were biased, though, the researchers warned.
Crossover to letrozole likely boosted survival in the tamoxifen-only arm based on prior trials; censored analysis likely overestimated letrozole benefits because women with recurrent disease were excluded from crossing over.
The true results likely lie somewhere between the two extremes, they said.
Another limitation of the study was an inability to determine the influence of a potential carryover effect of letrozole, Mouridsen's group acknowledged.
The study was supported by Novartis. The International Breast Cancer Study Group, which coordinated the study, is also supported by the Swedish Cancer Society, the Cancer Council Australia, the Australian New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, the National Cancer Institute, Cancer Research Switzerland and Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland.
Dr. Mouridsen reported receiving consulting and lecture fees from Novartis. Coauthors reported conflicts of interest with Novartis, AstraZeneca, Eli Lilly, and Pfizer.
Novartis contracted with the International Breast Cancer Study Group for provision of services related to the conduct and management of the trial.
Primary source: New England Journal of Medicine Source reference: The BIG 1-98 Collaborative Group "Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer" N Engl J Med 2009; 361: 766-76.
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