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

Mitch Dowsett ,Jf Forbes ,Matti Hakama

doi:10.1016/s0140-6736(15)61074-1

Mitch Dowsett , Jf Forbes + Show 1 more

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https://doi.org/10.1016/s0140-6736(15)61074-1

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Abstract

The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. We undertook meta-analyses of individual data on 31,920 postmenopausal women with oestrogen-receptor-positive 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). 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 0·52-0·78) 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 differed (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 differed (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. Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, 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. Cancer Research UK, Medical Research Council.

Highlights

Treatment for 5 years with the selective oestrogen receptor (ER) modulator tamoxifen reduces recurrence rates in ER-positive early breast cancer by about half during treatment and about one-third in the subsequent 5 years, and reduces breast cancer mortality by almost one-third throughout the first 15 years.[1]
American Society of Clinical Oncology (ASCO) clinical practice guidelines reflect this, recommending that postmenopausal women with early ER-positive breast cancer be offered either tamoxifen for 10 years, an aromatase inhibitor for 5 years, tamoxifen initially for 5 years followed by an aromatase inhibitor for up to a further 5 years, or tamoxifen for [2,3] years followed by an aromatase inhibitor for up to a further 5 years.[5]
Individual patient datasets were provided for nine trials,[8,9,10,11,12,13,14,15,16] including 35 129 (98%) of the 35 718 women randomised between aromatase inhibitor and tamoxifen as part of about 5 years of adjuvant endocrine treatment

Summary

Introduction

Treatment for 5 years with the selective oestrogen receptor (ER) modulator tamoxifen reduces recurrence rates in ER-positive early breast cancer by about half during treatment and about one-third in the subsequent 5 years, and reduces breast cancer mortality by almost one-third throughout the first 15 years.[1]. American Society of Clinical Oncology (ASCO) clinical practice guidelines reflect this, recommending that postmenopausal women with early ER-positive breast cancer be offered either tamoxifen for 10 years, an aromatase inhibitor for 5 years, tamoxifen initially for 5 years followed by an aromatase inhibitor for up to a further 5 years, or tamoxifen for [2,3] years followed by an aromatase inhibitor for up to a further 5 years.[5] To help clarify the relative benefits of aromatase inhibitors and tamoxifen and the effect of different scheduling during 5 years of endocrine therapy, we undertook collaborative meta-analyses of individual patient data from the trials of aromatase inhibitors versus tamoxifen.

Methods

Results

Conclusion