Effects of ovarian ablation or suppression on breast cancer recurrence and survival: patient-level meta-analysis of 15 000 women in 23 randomised trials

BACKGROUND: For premenopausal women with oestrogen receptor (ER)-positive early breast cancer, the additional protective effect of ovarian function suppression (OFS, by ablation or drugs) may depend on menopausal status after any chemotherapy, and tamoxifen usage. We assess the effects of OFS on breast cancer outcomes among premenopausal women and how they vary by patient or tumour characteristics and receipt of other treatments. METHODS: We conducted a meta-analysis of individual participant data from the randomised trials comparing OFS versus no OFS, in women with ER-positive or ER-unknown early breast cancer who were premenopausal at randomisation and younger than 55 years. Trials were categorised by whether premenopausal status was or was not confirmed after chemotherapy (if given), and by allocation to tamoxifen. Primary outcomes were invasive breast cancer recurrence, breast cancer mortality, other mortality, and all-cause mortality. ER-weighted log-rank methods estimated event rate ratios (RRs) for ER-positive disease. FINDINGS: Datasets were provided for 23 of 25 identified eligible trials, comprising 18 851 (98·9%) of 19 053 randomly assigned women. Among 15 075 premenopausal women with ER-positive or ER-unknown tumours, allocation to OFS significantly reduced recurrence rates (RR 0·82, 95% CI 0·77-0·87; p<0·00001), with larger reductions in women who were confirmed premenopausal after chemotherapy (or who did not receive chemotherapy) than in those with unconfirmed premenopausal status after chemotherapy; heterogeneity p=0·0004. Among confirmed premenopausal women, recurrence reductions were larger in older trials without tamoxifen (RR 0·61, 0·52-0·71; p<0·0001) than in more recent trials of OFS plus tamoxifen versus tamoxifen (RR 0·79, 0·70-0·91; p=0·0008). In these more recent trials, the additional recurrence reduction with OFS appeared larger in women younger than 45 years than in women aged 45-54 years (RR 0·73, 0·63-0·86 vs RR 0·95, 0·75-1·21; p=0·072); in those younger than 45 years, breast cancer mortality was similarly improved (RR 0·74, 0·58-0·94; p=0·012). There was no increase in deaths without recurrence. Findings did not differ significantly by OFS method or other recorded patient or tumour characteristics. INTERPRETATION: For premenopausal women with ER-positive early breast cancer, even if chemotherapy or tamoxifen are given, OFS significantly reduces the 15-year risk of recurrence and death. FUNDING: Nuffield Department of Population Health, University of Oxford; Cancer Research UK; the Breast Cancer Research Foundation; and the UK Medical Research Council.