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Aromatase inhibitors have surpassed tamoxifen in treatment of recurrent breast cancer. Will the same be true for early disease? An expert examines the evidence from ongoing clinical trials.
About 60% of breast cancers test positive for estrogen receptors (ERs) and/or progesterone receptors (PRs), and such hormonal sensitivity increases with age at diagnosis. In fact, two thirds of postmenopausal women with breast cancer have ER-positive tumors. Epidemiologic studies continue to suggest that estrogen has some role in tumor promotion. Yet women with receptor-positive tumors survive longer and have longer disease-free survival (DFS) after mastectomy than those with receptor-negative tumors. This is true regardless of the presence of positive axillary nodes or size and location of tumors.
In the face of these clinical realities, tamoxifen-which binds to the ER and competitively inhibits estrogen bindings-has been the standard for more than 20 years in adjuvant therapy of breast cancer. Adjuvant treatment with the drug, which is an estrogen antagonist and agonist, achieves highly significant reductions in recurrence and increases survival. It produces about a 25% increase in survival at 5 years, a benefit most evident in women older than age 50. And most women treated with tamoxifen have a lower rate of second primary breast cancer in the contralateral breast.
Raloxifene and toremifene both have been studied as alternatives to tamoxifen. But aromatase inhibitors (AIs), which block the conversion of androgen precursors to estrogen at all tissue sites, are the compounds that have shown the most progress. This article reviews accumulating data on AIs in managing early breast cancer.
The first studies of AIs showed that anastrozole (1 mg daily)and letrozole (2.5 mg daily) were more effective than tamoxifen in women with advanced breast cancer.1-3 Similar results were then reported for exemestane.4 At least five trials now are examining the role of AIs in early breast cancer.
The ATAC trial. More than 9,000 women in 380 sites in 23 countries were enrolled in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial.5,6 One third of the women had positive lymph nodes and 85% had ER-positive tumors. Randomization was to daily treatment with 1 mg anastrozole, 20 mg tamoxifen, or a combination of both for 5 years.
In a subgroup analysis, tamoxifen was associated with a great increase in endometrial thickness and a 16.7% incidence of abnormalities, compared with 8.7% in the anastrozole group (almost exclusively polyps without atypia).7 In this same subgroup, three cases of endometrial cancer were seen in women taking anastrozole, versus 11 cases in those on tamoxifen.8
The BIG trial. More than 8,000 women were randomized to either tamoxifen or letrozole for 5 years in the Breast International Group (BIG) trial. The first report after 2 years of follow-up indicated improved DFS in those on letrozole.9
The ITA trial. The Italian Tamoxifen-Anastrozole (ITA) trial of 448 women compared 5 years of tamoxifen with 2 to 3 years of tamoxifen followed by a switch to anastrozole.10 In the sequentially treated group, DFS was significantly increased.