Preliminary Data from Ongoing Adjuvant Aromatase Inhibitor Trials I

With recent results showing letrozole and anastrozole to be superior to tamoxifen as initial therapy for advanced disease, the aromatase inhibitors are poised to establish their place in the adjuvant therapy of postmenopausal receptorpositive breast cancer. A review of the rationale, design, and prel iminary results of the ongoing adjuvant trials that include aromatase inhibitors will be presented, along with the ongoing or planned substudies. Two strategies employing aromatase inhibitors after tamoxifen are being evaluated. The MA.17 international intergroup trial is randomizing postmenopausal patients who are disease-free after 5 years of adjuvant tamoxifen to an additional 5 years of ietrozole or placebo. In a similar design, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B33 trial is randomizing this patient population to 2 years of exemestane or placebo after the s tandard 5 years of adjuvant tamoxifen. The second approach under study is the use of both aromatase inhibitor and tamoxifen in sequence within the first 5 postoperative years. The Internat ional Cancer Collaboration Group (ICCG) trial is comparing 2 years of exemestane after 3 years of tamoxifen to a s tandard 5-year course of tamoxifen. Similarly, the ARNO trial is comparing 5 years of tamoxifen versus 2 years of tamoxifen followed by 3 years of anastrozole. In a four-arm study Breast Internat ional Group/Femara-Tamoxifen (BIG/FEMTA) conducted by the BIG, one arm contains letrozole given for 3 years after 2 years of tamoxifen. Several trials are investigating the role of anastrozole, letrozole, or exemestane as a 5-year ad juvant therapy to replace the s tandard 5 years of tamoxifen. Only the Arimidex and Tamoxifen, Alone or in Combinat ion (ATAC) trial is testing a 5-year combination of tamoxifen plus an aromatase inhibitor in this setting. Companion studies of effects on end-organs other than the breast are ongoing in a number of these trials. Aromatase inhibitors are poised to alter the t reatment paradigm of breast cancer and hopefully improve outcome for a substantial number of patients. Introduction The growth of hormone receptor-positive breast cancer can be altered clinically by several classes of agents that antagonize the effects of estrogen (1). The SERMs, 3 exemplified by tamoxifen, constitute one such class of drugs. Pure antiestrogens such as fulvestrant (Faslodex) also exert a potent antiestrogenic effect and show efficacy in tamoxifen-resistant cell lines in preclinical models. Thus, unlike tamoxifen, which exerts both an agonist and an antagonist effect, fulvestrant is a pure antagonist and acts by down-regulating ER content (2). Aromatase (estrogen synthetase) inhibitors antagonize the action of estrogen by reducing its levels both in the circulation and in normal and malignant breast tissue (3). They were initially tested in postmenopausal women with breast cancer progression after tamoxifen treatment. A superior outcome with these drugs compared to either megestrol acetate or aminoglutethimide resulted in their becoming the established second-line treatment for ER-positive metastatic breast cancer (4-13). More recently, three of the selective third-generation inhibitors, anastrozole, letrozole, and exemestane, have been compared to tamoxifen in the same setting (14-17). On the basis of both improved efficacy and superior side effect profiles, anastrozole and letrozole have now been approved for use as first-line treatment for women at first relapse of their disease. These data are reviewed in detail elsewhere in this journal issue (18, 19). Although useful in the treatment of advanced disease, the real benefits of tamoxifen have been seen in its ability to reduce mortality by as much as one-third for up to 15 years after primary surgery in women given 5 years of adjuvant treatment. 4 This makes tamoxifen one of the most successful anticancer therapeutics ever developed in terms of "number of years of life saved." The recently demonstrated superiority of the aromatase inhibitors over tamoxifen in the advanced disease setting is, therefore, a significant finding. Consequently, they are currently being tested in the adjuvant setting in women with early-stage breast cancer, and the results promise to alter the current treatment paradigm of the disease. The trials that are ongoing and their companion studies are briefly described. R a t i o n a l e a n d Des ign of O n g o i n g A d j u v a n t T r i a l s Biological and Pharmacological Concepts: Disease " R e s i s tance" Mechanisms. After initially responding to tamoxifen, metastatic breast cancer inevitably begins to progress de1 Presented at the First International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer, June 21-23, 2001, Cambridge, MA. z To whom requests for reprints should be addressed, at Princess Margaret Hospital, 610 University Avenue, Toronto, ON M5G 2M9, Canada. Phone: (416) 946-4501, extension 5103; Fax: (416) 946-2983; E-mail: [email protected]. 3 SERM, selective ER modulator; ER, estrogen receptor; BMD, bone mineral density; NSABP, National Surgical Adjuvant Breast and Bowel Project; NCIC, National Cancer Institute of Canada; CTG, Clinical Trials Group; ATAC, Arimidex and Tamoxifen, Alone or in Combination (trial). 4 R. Peto, Oxford ECTG meta-analysis. Presented at Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer, February 21-24, 2001, St. Gallen, Switzerland. Unpublished data. 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