Although tamoxifen is generally well tolerated and relatively nontoxic, it has become clear during the past decade that prolonged use of this agent is associated with significant gynaecological complications, including proliferative endometrial abnormalities in postmenopausal women. An increased incidence of endometrial cancer has been reported in association with tamoxifen treatment  and the level of risk appears to be time and dose dependent. Most studies involving tamoxifen have found the increased relative risk of developing endometrial cancer while taking tamoxifen to be two to three times higher than that of an age-matched population . The incidence and pattern of this increase in endometrial changes suggest that the underlying mechanism may be related to the oestrogenic properties of tamoxifen. Other side effects related to the oestrogenic properties of tamoxifen include the increased risk of thromboembolic disorders .
Most patients who exhibit an initial response to tamoxifen will eventually develop resistance to treatment . Many of these patients, however, respond to both second-line and third-line endocrine therapies, indicating that resistance is not necessarily due to a complete loss of hormone responsiveness. In view of this, alternative agents to tamoxifen are now required to treat breast cancer patients.
The third generation of oral aromatase inhibitors lend themselves ideally as candidates either to enhance the activity of tamoxifen or to replace it entirely in the adjuvant setting.
The ATAC trial in postmenopausal breast cancer patients with early breast cancer is the first report of a new-generation aromatase inhibitor compared with tamoxifen in the early breast cancer setting . An interesting feature of this trial was the inclusion of the combination arm, hence allowing the investigation of any possible additive effects through the use of two drugs with different modes of action. It is possible that anastrozole, by depleting the oestrogen receptor (ER) of its natural ligand while allowing tamoxifen to exert its beneficial effect via saturation of the receptor, could act synergistically in treating early breast cancer.
The ATAC study has been reported in detail  but it is worth reviewing in order to clearly understand the message that might have an immediate impact on clinical practice around the world.
Postmenopausal patients with operable invasive breast cancer, who had completed their primary treatment (which included chemotherapy in about 20% of cases who were judged to be at very high risk of relapse) and who were candidates to receive adjuvant hormonal therapy, were randomized with their informed consent. The patients were randomized to one of three groups: 1.0 mg anastrozole daily plus a placebo for tamoxifen; 20 mg tamoxifen daily plus a placebo for anastrozole; or a combination of the two active agents. A total of 9366 patients from 380 centres in 21 countries were recruited. Five years of treatment were selected for both drugs bearing in mind the optimum duration for tamoxifen and the wish to remain blinded. We of course have no idea of the optimum duration for anastrozole. It also should be noted that the analysis was triggered by a predetermined number of events when the median duration on therapy was only about 2.5 years.
To understand some of the important subgroup findings, it must be emphasized that the chemotherapy involved those with extensive lymph node involvement but also implied a delay in the start of the allocated endocrine therapy by about 6 months. Furthermore, in many parts of Europe for what was a truly global study, the entry criteria included ER status unknown. However, most of the blocks were retrieved and classified by immunohistochemistry to an ER category. This provided an interesting subgroup.
Disease-free survival was significantly prolonged for patients receiving anastrozole alone compared with those who received either tamoxifen alone (hazard ratio [HR] = 0.83, 0.71–0.96; P = 0.013) or the combination (HR = 0.81, 0.70–0.94; P = 0.006). The combination was not significantly different from tamoxifen alone (HR = 1.02, 0.89–1.18; P = 0.8).
When these patients were censored at the time of death, the HR for time to recurrence (including new tumours) was further reduced in the anastrozole arm compared with that of tamoxifen alone (HR = 0.79, 0.67–0.94; P = 0.008). In comparison with the combination treatment, anastrozole alone also showed a greater benefit for this endpoint (HR = 0.75, 0.63–0.89; P = 0.0007). No difference was observed, however, between the arm receiving tamoxifen alone and the combination arm (HR = 1.06, 0.90–1.24; P = 0.5).
As expected, the standard prognostic factors predicted recurrence. The recurrence rate was more than three times higher in hormone receptor-negative women than in those who were hormone receptor-positive.
Two interactions of anastrozole or tamoxifen with potential predictive factors are worthy of comment. The hormone receptor status was close to significance, with the comparison of effects of treatments in the receptor-positive subgroup being predefined in the protocol. In other words, the two drugs were equally ineffective in the ER subgroup.
An interaction, close to significance, within the group receiving chemotherapy first was unexpected and not fully understood. Two possible explanations are being considered: a chance imbalance of key prognostic factors (unlikely), or some unexplained mechanism linked to the delay in starting the endocrine therapy. Alternatively, tamoxifen might be performing better than anticipated because, by the design of the trial, it was provided at the end of chemotherapy rather than concurrently (Intergroup trial 0100 presented at the American Society of Clinical Oncology, Orlando, FL, USA, May 2002; principal investigator Kathy Albain). Nevertheless, as we expect tamoxifen to provide added value to chemotherapy, we can predict that anastrozole and tamoxifen are close to equivalent in this setting. This issue requires further events and longer follow-up before any firm conclusions can be drawn on the relative efficacy of anastrozole and tamoxifen after primary chemotherapy treatment.
A striking reduction in contralateral breast primaries as a first event was found in the anastrozole arm of the trial when compared with that of tamoxifen; the odds were reduced by 58%.
Most of the contralateral breast cancers were invasive (83%). When the analysis was restricted to these invasive events, the difference was somewhat larger (nine patients in the anastrozole arm versus 30 in the tamoxifen arm versus 23 in the combination arm; odds ratio of anastrozole versus tamoxifen = 0.30, 0.14–0.63; P = 0.0014).