TRENDS IN RESEARCH AND TRIAL UPDATES FOR BREAST CANCER DETECTION AND TREATMENT IMPLICATIONS FOR SURGEONS

Late-Breaking Results: Anastrozole and Tamoxifen Alone or in Combination Trial—Expanding Role of Aromatase Inhibitors

Adjuvant hormonal treatment is an important part of treatment of early-stage breast cancer. For women who are postmenopausal and have hormone receptor-rich cancer cells, tamoxifen is the gold standard adjuvant hormonal therapy to prevent recurrence. In women with advanced breast cancer, anastrozole has been shown to be an effective hormonal therapy in postmenopausal women with estrogen receptor-rich tumors. Gershon Y. Locker, MD, Associate Professor of Medicine, Northwestern University Medical School, and Chief, Hematology/ Oncology, Evanston Hospital, Evanston, Illinois, provided an overview of the recently conducted study comparing the use of tamoxifen alone, anastrozole alone, or tamoxifen plus anastrozole as adjuvant hormonal therapy in postmenopausal women with early-stage breast cancer.

Tamoxifen and Anastrozole
Both tamoxifen and anastrozole are commonly used systemic therapies in women with hormone receptor-containing breast cancer. Tamoxifen is indicated for use as a first-line therapy in persons with metastatic breast cancer, as adjuvant therapy to prevent recurrence in women with early-stage invasive breast cancer, as adjuvant therapy to reduce the risk of invasive cancer in women with ductal carcinoma in situ, and to reduce the risk of developing breast cancer for women at high risk for developing the disease. Anastrozole is currently indicated as a first-line therapy in postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer and as second hormonal therapy of advanced breast cancer that has progressed after tamoxifen therapy. Tamoxifen, a selective estrogen receptor modulator, works by binding to estrogen receptors, competing with and blocking estrogen from stimulating breast cancer cell growth, resulting in cancer cell death. In some tissues, however, tamoxifen binding stimulates the receptor mimicking estrogen action. Anastrozole, a highly selective and potent third-generation aromatase inhibitor, works by inhibiting the enzyme aromatase, which converts androgen into estrogen, thus reducing endogenous estrogen levels by 90% in postmenopausal women. Randomized studies have shown anastrozole to be well tolerated and to be more effective than megestrol as a second-line hormonal therapy in postmenopausal women with advanced breast cancer (Buzdar, JCO 1996), and more effective than tamoxifen as a first-line hormonal therapy in postmenopausal women with estrogen receptor-rich tumor (Nabholtz, JCO 2000). In the recently conducted randomized, double-blind Anastrozole or Tamoxifen Alone or in Combination (ATAC) trial, researchers sought to determine: 1) which agent would be more clinically effective as an adjuvant agent and 2) whether the combination therapy would be more effective than either agent alone in postmenopausal women with breast cancer.

The ATAC Trial
After primary therapy for early-stage breast cancer, 9366 women from 380 centers in 21 countries were randomized to receive either tamoxifen (20 mg/day) or anastrozole (1 mg/day) or both agents for 5 years. Patients in the three treatment arms were matched for age, primary treatments received, and prognostic factors. Eighty-three percent of patients had estrogen receptor-positive disease. After a median follow-up period of 33 months, anastrozole was associated with a 17% reduction in total breast cancer events, compared with tamoxifen. Eighty-eight percent of those taking tamoxifen, 88% of those taking the combination, and 90% of those taking anastrozole were free of recurrence. Of the women with hormone receptor-positive disease, anastrozole was associated with a 22% reduced risk in total events over tamoxifen and the combination therapy. No overall survival difference was noted between the groups. Importantly, a significant difference was noted in contralateral breast cancer occurrence. Contralateral breast cancer occurred in 33 patients receiving tamoxifen, 28 receiving the combination, and 14 receiving anastrozole, producing a 58% additional reduction with anastrozole. The results also showed a favorable toxicity profile for anastrozole in terms of hot flashes, vaginal bleeding and discharge, endometrial cancer, and thromboembolic events (stroke, pulmonary embolus, deep vein thrombosis) compared to tamoxifen. Tamoxifen was associated with fewer musculoskeletal disorders and fractures (Table 1).

In closing, Dr. Locker concluded, “Anastrozole showed a favorable toxicity profile and a significantly reduced overall event rate, breast cancer event rate, incidence of contralateral breast cancer, as well as increased recurrence-free survival compared with the tamoxifen and combination treatments”.