Tamoxifen, when used in combination with cytotoxic chemotherapy, improves survival in women with positive axillary lymph nodes and tumor estrogen receptor expression (108). In patients with node-negative, estrogen receptor–positive disease, the addition of tamoxifen to chemotherapy improved disease-free survival rates after 5 years of follow-up (109). In NSABP study B-14, 2,644 patients with estrogen receptor–positive tumors and no axillary metastases were randomized to either tamoxifen (10 mg orally twice daily for 5 years) or a placebo control. After a 4-year median follow-up, the disease-free survival rate for the 1,318 patients treated with tamoxifen was 82% compared with 77% for the 1,326 patients treated with placebo (p = .00001), again regardless of menopausal status.
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) performed a meta-analysis of adjuvant systemic therapy for breast cancer. They analyzed randomized trials involving adjuvant systemic hormonal, cytotoxic, or immune therapy administered to more than 75,000 women with stage I or II carcinoma. The investigators concluded that for post-menopausal women with estrogen receptor–positive tumors, tamoxifen daily for at least 2 years had a significant beneficial effect on disease-free survival rates, with these effects lasting up to 10 years. The incidence of both carcinoma in the contralateral breast and death rate from heart disease decreased.
In addition to tamoxifen, aromatase inhibitors have been approved for use in the adjuvant treatment of patients with estrogen receptor–positive cancers. Aromatase inhibitors act by inhibiting the aromatase enzyme, thus blocking the conversion of androgens into estrogens. These drugs should be used only in postmenopausal patients or premenopausal women who have undergone chemical ovarian suppression or oophorectomy. Although aromatase inhibitors cause fewer episodes of thrombotic events, hot ﬂashes, and endometrial cancers, musculoskeletal symptoms and osteoporosis are more commonly encountered among aromatase inhibitor users than those taking tamoxifen. Results from the anastrozole (Arimidex), tamoxifen, Alone or in Combination (ATAC) trial showed overall lower recurrence rates, as well as fewer contralateral tumors, among women treated with anastrozole alone after 68 months of follow-up (110). A meta-analysis confirmed that aromatase inhibitor therapy alone conferred a 2.9% absolute decrease in recurrence; aromatase inhibitor therapy after 2 to 3 years of tamoxifen conferred a 3.1% reduction in recurrence, as well as a 0.7% decrease in mortality at 5-year follow-up, although additional long-term follow-up is needed (111). Based on these results, aromatase inhibitors are now often offered as a first-line treatment option for adjuvant therapy. Research suggests that conversion of patients from tamoxifen to an aromatase inhibitor, such as letrozole (Femara), after 2.5 or 5 years may improve survival, although concurrent use of the two agents offers no benefit (110,112).