Elsevier

The Lancet

Volume 351, Issue 9114, 16 May 1998, Pages 1451-1467
The Lancet

Articles
Tamoxifen for early breast cancer: an overview of the randomised trials

https://doi.org/10.1016/S0140-6736(97)11423-4Get rights and content

Summary

Background

There have been many randomised trials of adjuvant tamoxifen among women with early breast cancer, and an updated overview of their results is presented.

Methods

In 1995, information was sought on each woman in any randomised trial that began before 1990 of adjuvant tamoxifen versus no tamoxifen before recurrence. Information was obtained and analysed centrally on each of 37 000 women in 55 such trials, comprising about 87% of the worldwide evidence. Compared with the previous such overview, this approximately doubles the amount of evidence from trials of about 5 years of tamoxifen and, taking all trials together, on events occurring more than 5 years after randomisation.

Findings

Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18 000 with ER-positive tumours, plus nearly 12 000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30 000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment21=52·0, 2p<0·00001). The corresponding proportional mortality reductions were 12% (SD 3), 17% (SD 3), and 26% (SD 4), respectively, and again the test for trend was significant (χ21= 8·8, 2p=0·003). The absolute improvement in recurrence was greater during the first 5 years, whereas the improvement in survival grew steadily larger throughout the first 10 years. The proportional mortality reductions were similar for women with node-positive and node-negative disease, but the absolute mortality reductions were greater in node-positive women. In the trials of about 5 years of adjuvant tamoxifen the absolute improvements in 10-year survival were 10·9% (SD 2·5) for node-positive (61·4% vs 50·5% survival, 2p<0·00001) and 5·6% (SD 1·3) for node-negative (78·9% vs 73·3% survival, 2p<0·00001). These benefits appeared to be largely irrespective of age, menopausal status, daily tamoxifen dose (which was generally 20 mg), and of whether chemotherapy had been given to both groups. In terms of other outcomes among all women studied (ie, including those with "ER-poor" tumours), the proportional reductions in contralateral breast cancer were 13% (SD 13), 26% (SD 9), and 47% (SD 9) in the trials of 1, 2, or about 5 years of adjuvant tamoxifen. The incidence of endometrial cancer was approximately doubled in trials of 1 or 2 years of tamoxifen and approximately quadrupled in trials of 5 years of tamoxifen (although the number of cases was small and these ratios were not significantly different from each other). The absolute decrease in contralateral breast cancer was about twice as large as the absolute increase in the incidence of endometrial cancer. Tamoxifen had no apparent effect on the incidence of colorectal cancer or, after exclusion of deaths from breast or endometrial cancer, on any of the other main categories of cause of death (total nearly 2000 such deaths; overall relative risk 0·99 [SD 0·05]).

Interpretation

For women with tumours that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research. However, some years of adjuvant tamoxifen treatment substantially improves the 10-year survival of women with ER-positive tumours and of women whose tumours are of unknown ER status, with the proportional reductions in breast cancer recurrence and in mortality appearing to be largely unaffected by other patient characteristics or treatments.

Introduction

In women with “early” breast cancer, all detectable cancer is, by definition, restricted to the breast (and, in the case of node-positive patients, the local lymph nodes) and can be removed surgically. But undetected micrometastatic deposits of the disease may remain that, perhaps after a delay of several years, develop into a clinically detectable recurrence that eventually causes death. It has been shown previously that the use of adjuvant tamoxifen significantly improves the 10-year survival for such women,1, 2, 3 but uncertainty has remained about who should be treated and for how long treatment should usually continue. Many randomised trials have assessed the effects of 1 or 2 years of adjuvant tamoxifen, and others have assessed the effects of about 5 years of treatment. Some more recent trials have directly compared 5 years of treatment with either shorter or longer durations, but results from these are generally not yet available (or, where available, are not yet based on sufficiently long follow-up). This overview is therefore restricted to the trials of adjuvant tamoxifen versus no adjuvant tamoxifen (control). Many of these trials allowed or encouraged the use of tamoxifen for any women in the control group who relapsed. So, although they provide a direct assessment of the effects of adjuvant tamoxifen on recurrence rates, for mortality they involve the comparison of adjuvant tamoxifen versus no tamoxifen until relapse (ie, many of these trials actually compare the effects on survival of two different ways of using tamoxifen).

Section snippets

Methods

Every 5 years since 1984-85, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has undertaken systematic overviews (meta-analyses) of all randomised trials of any aspect of the treatment of early (ie, apparently resectable) breast cancer.1, 2, 3, 4, 5 This report is based on data collected and finalised in 1995–96. Trial identification and data-checking procedures have been described previously.1, 2, 3 For the analyses presented here, data were sought for all randomised trials

Data on each individual patient

Information was sought for each woman on her age and menopausal status at randomisation, on whether or not there had been evidence of tumour spread to the axillary or other local lymph nodes (node-positive or node-negative disease, respectively), and on the results of any oestrogen-receptor (ER) or progesterone-receptor (PR) measurements on the primary tumour. Information was also sought on the date of randomisation, the allocated treatment, and the dates of first subsequent occurrence of any

Statistical methods

The statistical methods have been described in detail elsewhere,1, 2, 3 with comparisons based on the intention-to-treat principle. First each trial was analysed separately, and then the resulting log-rank statistics, one per trial, were combined to give an overall estimate of the effect of tamoxifen. When information from different trials is combined in this way, women in one trial are compared directly only with other women in the same trial, and not with women in another trial. The

Proportional benefits and absolute benefits

Throughout this report, the effects of treatment are described either as proportional benefits (eg, as a 25% reduction in the death rate) or as absolute benefits. (Terminology: a proportional reduction of a quarter in the annual odds of death might equivalently be described as an odds ratio of 0·75, a hazard ratio of 0·75, an odds reduction of 25%, or a 25% reduction in the death rate. Similarly, in the tables, a ratio of rates of 0·75 corresponds to a 25% reduction in the rate.) For a given

Numbers available

63 randomised controlled trials of adjuvant tamoxifen versus no adjuvant tamoxifen that began before 1990 were identified, involving a total of more than 42 000 women (table 1). This total is substantially more than in the previous cycle of this collaboration,3 because some trials were then still recruiting, some were unavailable, and those that began in 1985–89 were not eligible. Of the 63 trials, some scheduled no adjuvant chemotherapy for either group, but others randomised tamoxifen plus

Results

The general structure of each figure is similar: the left-hand side describes recurrence rates and the right-hand side describes mortality rates, while the upper, middle, and lower parts describe the trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, respectively. Figure 1 and figure 2 include all women with relevant data (as do the tables). Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 exclude women recorded as having had ER-poor tumours.

Overall findings

Figure 1 shows the results from each of the 55 trials, irrespective of duration of follow-up, with subtotals for the trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen. The totals at the bottom of figure 1 show that, both for recurrence as a first event and for mortality, allocation to tamoxifen produces highly statistically significant (2p<0·00001) benefits after a median of about 10 years of follow-up. However, comparisons of the subtotals suggest that the proportional risk

Hormone receptors

Figure 2 subdivides the overall results by what is known about the ER status of the primary cancer. For each tamoxifen duration, the proportional reduction in recurrence appears to be greater for patients with ER-positive tumours than for patients with ER-poor tumours, and this heterogeneity in therapeutic effect is most definite in the trials of about 5 years of tamoxifen (χ21 for heterogeneity=26·5, 2p<0·00001). Likewise, for each tamoxifen duration, the proportional reduction in mortality

Effects on recurrence and mortality after exclusion of women with ER-poor tumours

Even though there may be some benefit among some of the women classified as having ER-poor tumours, the subsequent analyses of recurrence or of total mortality include only the 18 000 women with confirmed ER-positive tumours and the 12 000 women with tumours of unrecorded ER status (of which about 8000 would be expected to have been ER-positive), among whom there is clear evidence of substantial benefit. Figure 2 shows that further restriction to just those with tumours that were known to be

Effects of tamoxifen on other outcomes

Table 2 describes the effects of tamoxifen on various other outcomes: incidence of contralateral breast cancer (which has also been included in all previous analyses of recurrences, accounting for 8% of them), incidence of colorectal and endometrial cancer (including both fatal and non-fatal cases, as long as there had been no previous recurrence of breast cancer), and death from endometrial cancer or from a cause other than breast or endometrial cancer (among women with no previous recurrence

Discussion

This collaboration has now continued for over 10 years, accumulating more randomised evidence on tamoxifen than is available on any other anticancer drug, and these updated results are essentially complete (table 1). What is new is the growing evidence for the importance of the hormone-receptor measurement as a determinant of the response to treatment, the widening range of patients for whom some years of adjuvant tamoxifen is now known to be protective (including those aged under 50), the

Hormone receptors

ER-positive (or ER status unknown)—The apparent benefits of tamoxifen for women whose tumours were classified as ER-positive are still about as great as in the previous cycle of this collaboration.3 Figure 2 shows that, for all tamoxifen durations taken together, the recurrence reduction among women with known ER-positive tumours is now 34% (SD 3) compared with 32% (SD 3) previously, and the mortality reduction is now 20% (SD 3) compared with 21% (SD 3) previously. There was no evidence in

Duration of adjuvant tamoxifen

5 years versus shorter—After exclusion of women considered to have ER-poor tumours in these trials, the difference between the recurrence reductions associated with 5 years and with only 1 or 2 years of adjuvant tamoxifen was large, and did not appear to be accounted for by differences in nodal status, tamoxifen dose, concurrent chemotherapy, age, or menopausal status (figure 3, figure 6, and figure 7). This finding therefore strongly suggests that about 5 years of adjuvant tamoxifen produces a

Age

The lack of definite benefit among younger women in the previous overviews1, 2, 3 may have been due partly to the play of chance (which, particularly in trials of only 1 or 2 years of treatment, could obscure any real benefits) and partly to the higher prevalence of ER-negative disease in younger women. With the larger numbers now available, it is clear that about 5 years of adjuvant tamoxifen has a substantial effect on recurrence and on long-term survival not only in older women but also in

Addition of tamoxifen to chemotherapy

Irrespective of whether—in comparison with the trials of tamoxifen on its own—there were greater or lesser treatment effects in the trials of tamoxifen plus chemotherapy versus chemotherapy alone, the addition of tamoxifen to chemotherapy certainly produced some additional benefits. In particular, chemotherapy plus about 5 years of tamoxifen was substantially better than the same chemotherapy alone. (The assessment of whether chemotherapy adds to the benefits of tamoxifen in different settings

Conclusions

The fundamental question when assessing the proportional risk reduction that a woman can expect from a few years of adjuvant tamoxifen is whether her tumour is completely ER-negative—and not whether she is young or old, with or without nodal involvement, or receiving chemotherapy. If the tumour is shown by reliable assays to be completely ER-negative, although adjuvant tamoxifen might produce some small but still clinically meaningful benefit (figure 2), it might well not do so: further

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