A meta-analysis of these three studies showed that patients who switched to anastrozole had significant improvements in DFS (HR, 0.59; 95% CI, 0.48–0.74; P < .001), EFS (HR, 0.55; 95% CI, 0.42–0.71; P < .001), distant DFS (HR, 0.61; 95% CI, 0.45–0.83; P = .002), and OS (HR, 0.71; 95% CI, 0.52–0.98; P = .04) compared with the patients who remained on tamoxifen.
A large double-blinded randomized trial of 8,010 postmenopausal women with hormone receptor-positive breast cancer compared the use of letrozole versus tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years. In an updated analysis from the Breast International Group (IBCSG-1-98) including only the 4,922 women who received tamoxifen or letrozole for 5 years, at a median follow-up time of 51 months, DFS was significantly superior in patients treated with letrozole (HR, 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS = 84.0% vs. 81.1%).[Level of evidence: 1iDii] OS was not significantly different (HR, 0.91; 95% CI, 0.75–1.11; P = .35). Patients on letrozole had significantly fewer thromboembolic events, endometrial pathology, hot flashes, night sweating, and less vaginal bleeding. Patients on tamoxifen had significantly fewer bone fractures, arthralgia, hypercholesterolemia, and cardiac events other than ischemic heart disease and cardiac failures.
A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 (4.5–6.0) years. After the first planned interim analysis, when median follow-up for patients on study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR, 0.57) favoring the letrozole arm.[Level of evidence: 1iDii] After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Women on letrozole had significantly more hot flashes, arthritis, arthralgia and myalgia, but less vaginal bleeding. New diagnoses of osteoporosis were more frequent on letrozole (5.8% vs. 4.5%), though the difference was not statistically significant (P = .07). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.[153,154] An updated analysis including all events prior to unblinding confirmed the results of the interim analysis. In addition, a statistically significant improvement in distant DFS was found for patients on letrozole (HR, 0.60; 95% CI, 0.43–0.84; P = .002). Although no significant difference was found in the total study population, the node-positive patients on letrozole also experienced a statistically significant improvement in OS (HR, 0.61; 95% CI, 0.38–0.98; P = .04), though the P value was not corrected for multiple comparisons. An ASCO Technology Assessment panel has commented on the implications of these results.[144,145]