Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

Background: The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. Methods: We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptorpositive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2–3 years of tamoxifen then aromatase inhibitor to year 5; and of 2–3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs). Findings: In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors signifi cantly during years 0–1 (RR 0·64, 95% CI 0·52–0·78) and 2–4 (RR 0·80, 0·68–0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75–0·96; 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, 0·62–0·89) 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, 0·81–0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78–1·03; 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, 0·46–0·67) 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 three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments diff ered (RR 0·70, 0·64–0·77), but not significantly thereafter (RR 0·93, 0·86–1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments diff ered (RR 0·79, 0·67–0·92), and subsequently (RR 0·89, 0·81–0·99), and for all periods combined(RR 0·86, 0·80–0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82–0·94; 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, 0·21–0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28–1·57); non-breast-cancer mortality was similar. Interpretation: Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments diff er, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Funding: Cancer Research UK, Medical Research Council.