Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials

Abstract

Background: As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen.

Methods: We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment.

Findings: In oestrogen receptor (ER)-positive disease (n=10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0-4 and RR 0·68 [0·06] during years 5-9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10-14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10-19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0-4, 0·66 [0·05] during years 5-9, and 0·68 [0·08] during years 10-14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality.

Interpretation: 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen.

Funding: Cancer Research UK, British Heart Foundation, and Medical Research Council.

Figure 1

Relevance of measured ER and PR status to the effects of about 5 years of tamoxifen on the 10-year probability of recurrence Outcome by allocated treatment in trials of about 5 years of adjuvant tamoxifen. Event rate ratio (RR) is from summed log-rank statistics for all time periods. Gain (and its SE) is absolute difference between ends of graphs. ER=oestrogen receptor. PR=progesterone receptor. O–E=observed minus expected, with variance V.

Figure 2

Relevance of quantitative ER and PR measurement (fmol/mg cytosol protein) to the tamoxifen versus control recurrence rate ratio Outcome by allocated treatment in trials of about 5 years of adjuvant tamoxifen. Other ER poor includes ER-negative by immunohistochemistry and ER unspecified, but less than 10 fmol/mg. ER=oestrogen receptor. PR=progesterone receptor. O–E=observed minus expected.

Figure 3

Relevance of nodal status and of background chemotherapy to the effects of tamoxifen on the 10-year probability of recurrence, for ER-positive disease Outcome by allocated treatment in trials of about 5 years of adjuvant tamoxifen. Event rate ratio (RR) is from summed log-rank statistics for all time periods. Gain (and its SE) is absolute difference between ends of graphs. ER=oestrogen receptor. PR=progesterone receptor. O–E=observed minus expected, with variance V.

Figure 4

Subgroup analyses of the tamoxifen versus control recurrence rate ratio, for ER-positive disease Outcome by allocated treatment in trials of about 5 years of adjuvant tamoxifen. ER=oestrogen receptor. O–E=observed minus expected, with variance V.

Figure 5

Effects of about 5 years of tamoxifen on the 15-year probabilities of recurrence and of breast cancer mortality, for ER-positive disease Outcome by allocated treatment in trials of about 5 years of adjuvant tamoxifen. Event rate ratio (RR) is from summed log-rank statistics for all time periods. Gain (and its SE) is absolute difference between ends of graphs. ER=oestrogen receptor. O–E=observed minus expected, with variance V.

Figure 6

Relevance of intercurrent mortality in women younger than 45 years and 55–69 years of age to the absolute effects of tamoxifen on 15-year mortality, for ER-positive disease Outcome by allocated treatment in trials of about 5 years of adjuvant tamoxifen. Event rate ratio (RR) is from summed log-rank statistics for all time periods. Gain (and its SE) is absolute difference between ends of graphs. ER=oestrogen receptor. O–E=observed minus expected, with variance V.