Based on DFS advantage as described below, aromatase inhibitors have become the first-line adjuvant therapy for postmenopausal women; however, because there is no demonstrated survival advantage to aromatase inhibitors, tamoxifen remains a reasonable alternative.[140,141]
A large, randomized trial of 9,366 patients has compared the use of the aromatase inhibitor anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative and node-positive disease.[142,143] Most (84%) of the patients in the study were hormone-receptor positive. Slightly more than 20% had received chemotherapy. With a median follow-up of 33.3 months, no benefit was observed for the combination arm relative to tamoxifen. Patients on anastrozole, however, had a significantly longer DFS (hazard ratio [HR], 0.83) than those on tamoxifen. In an analysis conducted when all but 8% of the patients had completed protocol therapy at a follow-up of 68 months, the benefit of anastrozole relative to tamoxifen with respect to DFS was slightly less (HR, 0.87; 95% CI, 0.78–0.96; P = .01). A greater benefit was seen in hormone receptor-positive patients (HR, 0.83; 95% CI, .73–0.94; P = .05). There was an improvement in time to recurrence (HR, 0.79; 95% CI, 0.70–0.90; P = .005), distant DFS (HR, 0.86; 95% CI, 0.74–0.99; P = .04) and contralateral breast cancer (42% reduction; P = .01) in patients who received anastrozole.[Level of evidence: 1iDii] No difference was shown in OS (HR, 0.97; 95% CI, 0.85–1.12; P = .7 ). Arthralgia and fractures were reported significantly more often in patients who received anastrozole, whereas hot flushes, vaginal bleeding and discharge, endometrial cancer, ischemic cerebrovascular events, venous thromboembolic and deep venous thromboembolic events were more common in patients who received tamoxifen. An American Society of Clinical Oncology (ASCO) Technology Assessment panel has commented on the implications of these results.[144,145]
Three trials examined the effect of switching to anastrozole to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.[146,147,148] One study, which included 448 patients, demonstrated a statistically significant reduction in DFS (HR, 0.35; 95% CI, 0.18–0.68; P = .001) but no difference in OS.[Level of evidence: 1iiA] The other two trials were reported together. A total of 3,224 patients were randomized after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. After a median follow-up of 78 months, an improvement in all-cause mortality (HR, 0.61; 95% CI, 0.42–0.88; P = .007) was observed.