Switching Adjuvant Breast Cancer Therapy from Tamoxifen to Exemestane Proves Beneficial
A new study has found a strong benefit of an aromatase inhibitor (AI) as adjuvant therapy in postmenopausal breast cancer patients. Published last week in the New England Journal of Medicine, the study found that switching adjuvant therapy after two to three years from tamoxifen to the AI exemestane significantly improved disease-free survival at approximately two and a half years' follow-up. Conducted under the auspices of the Intergroup Exemestane Study (IES), the results were made available at the recommendation of the study's data and safety monitoring board following the second interim data analysis review.
More than 4,700 patients - all of whom had primary, estrogen-receptor-positive breast cancer - were enrolled in the double-blind, randomized trial, with slightly less than half assigned to undergo the midstream switch in adjuvant therapy from tamoxifen to exemestane. After a median follow-up of nearly 31 months, there were 266 first events (defined as breast cancer recurrence, contralateral breast cancer, or death) in the tamoxifen group and 183 in the exemestane group, leading to a 32 percent relative reduction in the risk of an event and an overall benefit of disease-free survival of 4.7 percent. Because these are early release results, the authors explained, it is too soon to expect a statistically significant difference in overall survival. Patients in the exemestane group also had a reduced risk of contralateral breast cancer, endometrial cancer, and other primary cancers.
"These findings are consistent with results from two other large, adjuvant trials testing AIs, some smaller adjuvant trials, and trials comparing AIs to tamoxifen for metastatic disease," said Dr. Jeff Abrams, associate chief of medicine in the NCI Cancer Therapy Evaluation Program. The extent and early appearance of the benefit "is impressive," he added.
The two large trials Dr. Abrams referred to had different designs than the IES. In the ATAC trial, published in The Lancet in June 2002, there was a statistically significant improvement in disease-free survival for postmenopausal women who received adjuvant monotherapy with the AI anastrozole compared to tamoxifen. The Food and Drug Administration has since approved anastrozole for monotherapy in this patient population. In a study published last November in the New England Journal of Medicine, use of the AI letrozole in postmenopausal women who successfully underwent five years of monotherapy with tamoxifen yielded a statistically significant reduction in breast-cancer-related events compared to placebo.
As a result of these trials, the most effective role of AIs and tamoxifen in adjuvant therapy in postmenopausal women has been hotly debated. An American Society of Clinical Oncology working group has recommended five years of monotherapy with tamoxifen as the preferred adjuvant therapy. But the results of the IES study, the trial's authors argued, challenge "the concept of five years of monotherapy with endocrine agents after the surgical treatment of primary breast cancer."
Data are still lacking for AIs on overall survival, however, and there are unanswered questions about long-term toxicity, Dr. Abrams explained, including whether long-term estrogen deprivation (AIs work by decreasing the blood levels of estrogen) causes other symptoms.
Despite these lingering questions, AIs definitely have an important role in the treatment of breast cancer, he added. "AIs are a good choice for women with hormone-sensitive breast cancer, either as first-line treatment or as a switch-over after some period of time," he said. "Whether switching or going with an AI from the start is best will have to be decided by future research." A number of such studies are under way, including a European trial testing both letrozole and tamoxifen in monotherapy and midstream-switching regimens.
"Future trial results should help us resolve the question of whether AIs should totally replace tamoxifen or whether they should both be used in sequence," Dr. Abrams said. "And with more time, the ATAC trial will provide information on AI long-term side effects."