An RCT 1 with a total of 8 010 postmenopausal women with hormone-receptor-positive breast cancer compared five years of treatment with either letrozole (n=4 003) or tamoxifen (n=4 007). Letrozole significantly reduced the risk of an event ending a period of disease-free survival as compared with tamoxifen (351 vs. 428 events; RR 0.81; 95% confidence interval 0.70 to 0.93; NNT=52), especially the risk of distant recurrence (RR 0.73; 95% CI 0.60 to 0.88). Median follow-up time was 25.8 months. Five-year disease-free survival estimates were 84.0% and 81.4%, respectively. Letrozole group had a higher incidence of skeletal and cardiac events and of hypercholesterolemia. Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group.
In an update of BIG 1-98 trial 2 4 922 women of the 8 028 postmenopausal women randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. At a median follow-up time of 51 months, 352 disease-free survival (DFS) events among 2 463 women receiving letrozole and 418 events among 2 459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio 0.82; 95% CI 0.71 to 0.95; P 0 .007). Adverse events were similar to previous reports.
A meta-analysis 3 included 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer. In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.64, 95% CI 0.52 to 0.78) and 2-4 (RR 0.80, 0.68 to 0.93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12.1% vs 14.2%; RR 0.85, 0.75 to 0.96; 2p=0.009).
In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.74, 0.62 to 0.89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0.90, 0.81 to 0.99; 2p=0.045), though the breast cancer mortality reduction was not significant (RR 0.89, 0.78 to 1.03; 2p=0.11).
In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0.56, 0.46 to 0.67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8.7% vs 10.1%; 2p=0.015).
Aggregating all 3 types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0.70, 0.64 to 0.77), but not significantly thereafter (RR 0.93, 0.86 to 1.01; 2p=0.08). Breast cancer mortality was reduced both while treatments differed (RR 0.79, 0.67 to 0.92), and subsequently (RR 0.89, 0.81 to 0.99), and for all periods combined (RR 0. 86, 0.80 to 0.94; 2p=0.0005). All-cause mortality was also reduced (RR 0.88, 0.82 to 0.94; 2p=0.0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0.4% vs 1.2%; RR 0.33, 0.21 to 0.51) but more bone fractures (5-year risk 8.2% vs 5.5%; RR 1.42, 1.28 to 1.57); non-breast-cancer mortality was similar.
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