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-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, stratiﬁ ed by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen ﬁ rst-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-signiﬁ cantly 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 signiﬁ cantly 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 signiﬁ cant (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 signiﬁ cantly 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 signiﬁ cantly 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 diﬀ ered 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.


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 fi rst 15 years. 1 Further reductions in breast cancer mortality during years 10-14 are achieved by extending tamoxifen treatment to 10 years. 2,3 In postmenopausal women only, aromatase inhibitors can greatly reduce oestrogen concentrations, hence avoiding stimulation of ER-positive breast cancer cells. Aromatase inhibitors, given either for 5 years or for 2-3 years after 2-3 years of tamoxifen, produce greater reductions in recurrence than 5 years of tamoxifen alone, 4 but the eff ect on breast cancer mortality, and the optimal way to schedule aromatase inhibitors and tamoxifen in the treatment of early breast cancer, remain uncertain.
American Society of Clinical Oncology (ASCO) clinical practice guidelines refl ect this, recom mending that postmenopausal women with early ER-positive breast cancer be off ered 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 benefi ts of aromatase inhibitors and tamoxifen and the eff ect of diff erent scheduling during 5 years of endocrine therapy, we undertook collaborative meta-analyses of individual patient data from the trials of aromatase inhibitors versus tamoxifen.

Identifi cation of studies and collection of data
Trial identifi cation, data checking, analysis, and involvement of trialists are as described in previous Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reports. 1,6,7 Eligible trials began by 2005 and randomised postmenopausal women with ER-positive early breast cancer between 5 years of an aromatase inhibitor versus 5 years of tamoxifen (comparison A); 5 years of aromatase inhibitor versus 2-3 years of tamoxifen, then aromatase inhibitor to year 5 (comparison B); 2-3 years of tamoxifen, then aromatase inhibitor to year 5 versus 5 years of tamoxifen (comparison C); 5 years of aromatase inhibitor versus 2 years of aromatase inhibitor, then tamoxifen to year 5 (comparison D); or 2 years of aromatase inhibitor, then tamoxifen to year 5 versus 5 years of tamoxifen (comparison E). Separate analyses are provided for each of these comparisons (A-E), then results from some of them are combined.
Information was sought during 2012-14 for each individual patient on randomisation date, allocated treatment, age, menopausal status, body-mass index (BMI), tumour diameter, grade, spread to locoregional lymph nodes, ER, progesterone receptor (PR), and HER2 receptor status, and dates of any locoregional, contralateral, or distant breast cancer recurrence, other second primary cancer, bone fractures, death, and cause of death.

Outcomes
The primary outcomes were any recurrence of breast cancer (distant, locoregional, or new primary in the contralateral breast); breast cancer mortality; death without recurrence; and all-cause mortality. Secondary outcomes were incidence and site of second primary cancers, and bone fracture. Prespecifi ed primary subgroup investigations were of site of recurrence, age, nodal status, PR status, histological grade, and follow-up period.

Statistical analyses
Statistical methods (stratifi ed log-rank statistics, Kaplan-Meier graphs) are described elsewhere. 1,6,7 Time-to-event analyses were stratifi ed by age, nodal status, and trial.
Within each stratum, they compared all those allocated aromatase inhibitor versus all those allocated tamoxifen, regardless of treatment compliance (yielding intention-totreat analyses). Log-rank statistics were used to assess the eff ects (aromatase inhibitor vs tamoxifen) on various outcomes, and, for each, to estimate fi rst-event-rate ratios (RRs) and their CIs. If a log-rank statistic (o -e) has variance v, then, defi ning z=(o -e)/√v and b=(o -e)/v, b has variance 1/v and the event RR (newer treatment vs control) is estimated as exp(b) with SE=(RR -1)/z. CIs for RR are derived from those for b (by normal approximations). 2p indicates two-sided signifi cance. The breast cancer mortality rate in each year is the overall mortality rate among all women minus that among women of similar age without recurrence. Breast cancer mortality RRs are estimated from the corresponding log-rank analyses of mortality with recurrence (obtained by subtracting log-rank analyses of mortality without recurrence [ie, censored at recurrence] from those of overall mortality). Analyses used EBCTCG Fortran programs. The policy on data sharing from this study is available online.

Role of the funding source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The secretariat had full access to all data and the writing committee had fi nal responsibility for the decision to submit for publication.
In comparison B (5 years of aromatase inhibitor vs 2-3 years of tamoxifen then aromatase inhibitor to year 5: three trials, n=12 779), recurrence was signifi cantly reduced only during years 0-1 (RR 0·74, 95% CI 0·62-0·89; 2p=0·002), ie, when the treatments diff ered, and was similar during years 2-4 (RR 0·99, 0·85-1·15), when both groups were receiving an aromatase inhibitor (fi gure 2). There was no signifi cant further eff ect after year 5, but little follow-up beyond year 7. Perhaps because the period during which the treatments diff ered lasted only half as long as in comparison A, the absolute reductions in recurrence and mortality appeared smaller. The total numbers with recurrence were 705 in the aromatase inhibitor group versus 765 in the tamoxifen group (2p=0·045). Although breast cancer mortality appeared somewhat reduced (RR 0·89, 95% CI 0·78-1·03; 2p=0·11), this was not signifi cant, and nor were the eff ects on other mortality or all-cause mortality.
The recurrence results already described for comparisons A-C are summarised in the appendix, using black squares for periods when the treatments diff ered (aromatase inhibitor in one group vs tamoxifen in the other) and open squares for periods when they did not. It also gives the comparisons D and E, which both derive from BIG 1-98. 8 Comparison D was restricted to the 2558 women who were recurrence free and still on treatment after 2 years of aromatase inhibitor. Although they suggest no apparent gain from continuing to take an aromatase inhibitor rather than switching to tamoxifen after 2 years, the CIs were wide. Comparison E included 3060 women; the proportional recurrence reduction during years 0-1 (when the treatments diff ered) was similar to that in earlier comparisons, and the apparent fl uctuations in the recurrence RR during the period when the treatments no longer diff ered could well be chance.
To enhance statistical power, the main subgroup analyses of recurrence are restricted to the periods when aromatase inhibitor was directly compared with tamoxifen (fi gure 5). The fi rst such analyses compare the six components from previous fi gures that contribute to this: the recurrence RRs during years 0-1 were, as expected, similar in comparisons A, B, and E, but the recurrence RRs during years 2-4 appeared somewhat more extreme after 2-3 years of previous tamoxifen (RR 0·56, 95% CI 0·46-0·67) than after 2-3 years of aromatase inhibitor versus tamoxifen (RR 0·83, 0·69-1·00), or after 2 years of aromatase inhibitor (RR 1·08, 0·70-1·68). Figure 5 subdivides the aggregated result from the periods when treatments diff ered by aromatase inhibitor drug, site of fi rst recurrence, entry age, BMI, and tumour characteristics: PR status, nodal status, tumour diameter, tumour grade, and HER2 status (available for only one-third of patients). The recurrence RRs were similar with diff erent aromatase inhibitors (each p<0·0001), with local recurrence, contralateral Death rates (%/year: total rate minus rate in women without recurrence) and log-rank statistics Allocation AI Tamoxifen Rate ratio (95% CI)  breast cancer, and distant recur rence all substantially reduced by aromatase inhibitor compared with tamoxifen. In the aggregated data, the RRs while treatments diff ered appeared similar in every subgroup, suggesting that age, BMI, and tumour characteristics cannot usefully predict the RR.   Tumour characteristics were, however, importantly predictive of the absolute risk of recurrence, and hence of the absolute eff ect on breast cancer outcomes of giving an aromatase inhibitor rather than tamoxifen (appendix). For example, in the aggregate of the trials that contribute to the black squares in fi gure 4, the   overall Kaplan-Meier estimate of the 5-year recurrence risk was reduced by 2·5% (7·3% vs 9·8%, appendix). But, in this same data set, the 5-year recurrence risks for women with N0, N1-3, and N4+ disease were reduced by 1·2%, 3·7%, and 6·4%, respectively. Similar sets of subgroup analyses for each separate category of comparisons A-E are in the appendix, but with so many subgroup analyses the apparent fi ndings should be interpreted cautiously, as striking false-positive and false-negative results can easily arise just by chance. For example, the hypothesis from ATAC 15 of a more extreme recurrence RR in ER-positive PR-negative than in ER-positive PR-positive disease is not supported by evidence from other trials (fi gure 5, appendix). Likewise, the hypothesis from comparison C of equivalent effi cacy of aromatase inhibitors and tamoxifen in node-negative disease is not supported by evidence from the other comparisons. Such patterns might be due mainly to chance.

Death rate/year (%), events/woman-years and log-rank statistics
Results for cause-specifi c mortality, second cancer incidence, and bone fracture before any breast cancer recurrence are in the appendix. There was a signifi cant reduction in mortality without recurrence in comparison C (tamoxifen then aromatase inhibitor vs tamoxifen alone) that was not explained by any particular cause and is unlikely to be due to misclassifi ed breast cancer deaths (partly because the non-breast-cancer mortality rates were sharply agerelated whereas breast cancer mortality rates were similar in all age groups).

Discussion
Individual trials have already shown reduced recurrence rates with aromatase inhibitor compared with tamoxifen but none has shown in intention-to-treat analyses that breast cancer mortality is reduced, nor did previous meta-analyses. 4 Now, with longer follow-up, the present meta-analyses establish that breast cancer mortality and all-cause mortality are also reduced, better characterise time-dependent eff ects on recurrence, and allow informative investigation of diff erential effi cacy within subgroups and of uncommon adverse events.
There was a fairly consistent pattern of substantial recurrence reductions during periods when one group was receiving an aromatase inhibitor and the other tamoxifen, but little further reduction during subsequent periods when both groups were receiving the same endocrine treatment or after scheduled endocrine treatment had ended in both groups. However, this fi nding should not be interpreted as aromatase inhibitors not having the carry-over benefi ts of tamoxifen, 1 rather that 5 years of endocrine therapy that includes an aromatase inhibitor reduces recurrence by about one-third during years 5-9, as does 5 years of tamoxifen.
The most extreme recurrence reduction appeared to be in comparison C in which, after 2 years of tamoxifen, an aromatase inhibitor was compared with tamoxifen during years 2-4. This result is not explained by diff erences in effi cacy between diff erent aromatase inhibitors, as indirect comparisons in fi gure 5, and direct randomised comparisons, 16 show little diff erence between drugs. It has been hypothesised that the superiority of aromatase inhibitors over tamoxifen is greater after previous exposure to tamoxifen, 17 and the larger recurrence reductions reported in years 5-9 in trials of aromatase inhibitor versus no further treatment 18-20 after 5 years of tamoxifen than in trials of 10 versus 5 years of tamoxifen 2,3 provide some support for this. However, the directly randomised fi ndings in comparison B do not show any eff ect of the type of endocrine therapy during years 0-1 on the effi cacy of treatment during years 2-4, so the apparent heterogeneity of benefi t from indirect comparisons could be largely chance.
In comparison E, after an initial 2-3 years of an aromatase inhibitor there appeared to be no benefi t from continuing an aromatase inhibitor to 5 years rather than switching to tamoxifen, but this result was based on one trial with few events. Hence, it remains uncertain whether, after 2-3 years of an aromatase inhibitor, any loss of benefi t occurs from switching to tamoxifen-reassuringly for women who do not tolerate aromatase inhibitors. Results of ongoing trials comparing diff erent durations of aromatase inhibitor treatment will determine whether, as with tamoxifen, longer is better. 2,3,21 The reduction in breast cancer mortality with aromatase inhibitor compared with tamoxifen is only slight, as expected in an already relatively good-prognosis population, but persists during years 0-4 and 5-9, signifi cantly reducing 10-year breast cancer mortality. Overall 10-year mortality was also signifi cantly reduced, even though about half the deaths were not due to breast cancer. Non-breast cancer death rates were similar with aromatase inhibitor and tamoxifen except that, after 2-3 years of tamoxifen, there appeared to be fewer such deaths with an aromatase inhibitor than with continuing tamoxifen. This fi nding was unexpected, not explained by any one cause, and not replicated in the other comparisons. Though likely to be a chance fi nding, it is reassuring for the safety of aromatase inhibitors.
Bone fractures are a concern with aromatase inhibitors, though the absolute excess of about 0·5% per year might be partly explained by a bone-protective eff ect of RR (95% CI) p value RR (95% CI) p value RR (95% CI) p value
Among the postmenopausal women in these trials there were no signifi cant diff erences in the RR by age. Trials of aromatase inhibitors versus tamoxifen in premenopausal women treated with an ovarian suppressant 25,26 were not included. Although age is not an independent correlate of distant recurrence or treatment effi cacy, it is a major determinant of the life expectancy gain from avoiding distant recurrence. As subgroup analyses pooling data from all trials did not identify any patient or tumour characteristic that strongly predicted the RR, the key quantitative fi ndings likely to be generalisable to future patients 27 are the proportional risk reductions of around 30% in recurrence during the aromatase inhibitor versus tamoxifen comparison periods, and the proportional reduction of about 15% in the breast cancer mortality rate during the fi rst decade.
We can infer from the present results the proportional reductions that would be achieved with 5 years of aromatase inhibitor compared with no adjuvant endocrine therapy (table). Treatment with tamoxifen for 5 years reduces recurrence by about half during years 0-4 and one-third during years 5-9, and reduces the breast cancer mortality rate by about 30% throughout the fi rst decade and beyond. 1 Therefore, 5 years of an aromatase inhibitor compared with no endocrine therapy would reduce breast cancer recurrence by about two-thirds during treatment and by about one-third during years 5-9, and would reduce the breast cancer mortality rate by around 40% throughout the fi rst decade, and perhaps beyond. Though these proportional reductions in risk are approximately independent of nodal status, tumour grade, diameter, PR, and HER2 status, these prognostic factors substantially aff ect the absolute risk with no endocrine treatment, and hence substantially aff ect the absolute reduction in that risk produced by aromatase inhibitors.
Finally, the trials that involve starting endocrine treatment with an aromatase inhibitor rather than with tamoxifen collectively show a highly signifi cant 30% recurrence reduction during years 0-1. The trials comparing 5 years of aromatase inhibitor with a switching strategy of 2-3 years of tamoxifen then aromatase inhibitor to year 5 provide no indication that this recurrence reduction during years 0-1 will later be lost, and it is likely that it would eventually translate into a slight survival improvement. However, in the 2014 ASCO guidelines on endocrine treatment of postmenopausal women with ER-positive early breast cancer, three of the four recommended options start with tamoxifen; 5 a review seems appropriate.