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MD ChM FRCS FRCR
Emeritus Professor of Surgery and Visiting Professor of Medical Humanities
University College London
The dramatic fall in mortality from breast cancer over the last 15 years is probably due to the direct or indirect effects of adjuvant hormonal manipulation.
“Medical adrenalectomy”, induced by the interruption of steroidogenesis at the level of the cholesterol-to- pregnenolone conversion, can achieve objective responses in metastatic breast cancer amongst women without ovarian function to a similar extent as a surgical adrenalectomy and, thus, be further applicable to those with poor operative risk.(1)
Aromatase inhibitors (AIs) act by blocking aromatase, the enzyme that catalyses the final and rate-limiting step in the synthesis of oestrogens.(2) Aromatase is expressed in nonovarian tissues, such as muscle and fat, in both pre- and postmenopausal women. These nonovarian tissues become the dominant sources of oestrogen in postmenopausal women. Available AIs fall into two classes: class I inhibitors bind aromatase irreversibly, and the available agents have a steroidal structure (eg, exemestane); class II agents bind aromatase in a reversible manner, and the available agents are nonsteroidal (eg, anastrozole).
The latest class of compound, because of the specificity of its mode of action, is remarkably non-toxic and, therefore, is appropriate in the management of both early and advanced disease. Although the first adjuvant trial to be reported, the ATAC trial (Arimidex, Tamoxifen, Alone or in Combination), started recruitment before publication of trials from the advanced settings, trials with AIs as first-line therapy for metastatic breast cancer will first be briefly mentioned. Both anastrozole and letrozole have now been demonstrated as being superior to megestrol acetate in second-line endocrine therapy after failure with tamoxifen. However, it is important to note that both drugs are superior in efficacy and have better tolerability than tamoxifen in first-line therapy of locally advanced or metastatic disease for postmenopausal women with hormone receptor-positive disease.(3,4) It is now widely accepted that an AI should be the treatment of choice in this particular setting.
Aromatase inhibitors in the adjuvant setting
In the early breast cancer setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive (oestrogen receptor-positive [ER+ve] and/or progesterone receptor-positive [PR+ve]) disease, and the drug shows significant benefits compared with control/placebo.(5–7) Although tamoxifen is generally well tolerated and relatively nontoxic, 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.(8) Other side-effects related to the oestrogenic properties of tamoxifen include increased risk of thromboembolic disorders.(9)
For these reasons, the third generation of oral AIs are ideal candidates for enhancing the activity of tamoxifen or replacing it entirely in the adjuvant setting. A number of trials are currently exploring the role of the steroidal and of the nonsteroidal agents used head-to-head, sequentially or in combination with tamoxifen.
The ATAC trial is the first completed trial for which results have been published.(10,11) The ATAC trial in postmenopausal breast cancer patients with early breast cancer is the first report of a new generation of AIs being compared with tamoxifen in the early breast cancer setting. The unique feature of this trial was the inclusion of the combination arm, which allowed the investigation of any possible additive effects through the use of two drugs with different modes of action. The ATAC trial was the largest adjuvant breast cancer study ever conducted in postmenopausal patients with early breast cancer. In addition to the main trial endpoints, the differing pharmacological effects of the two drugs, alone or in combination, were addressed within a number of subprotocols. These subprotocols included assessment of effects on the endometrium, bone mineral density and bone markers, quality of life and the possible pharmacokinetic and pharmacodynamic interactions when anastrozole was given in combination with tamoxifen.
Postmenopausal patients with operable invasive breast cancer who had completed primary treatment (which included chemotherapy in about 20% of cases considered to be at very high risk of relapse) and who were candidates to receive adjuvant hormonal therapy were randomised, with their informed consent, into the ATAC trial. There were 380 centres recruiting patients into this three-arm trial. Patients were randomised 1:1:1 to receive: active anastrozole (1mg/day) plus tamoxifen placebo; active tamoxifen (20mg/day) plus anastrozole placebo; or active anastrozole (1mg/day) plus active tamoxifen (20mg/day). A total of 9366 patients in 21 countries were recruited into the trial between July 1996 and 2000 and randomised into one of the three treatment arms.
At this early stage of follow-up, anastrozole (A) shows superior efficacy to tamoxifen (T), with a 17% relative risk reduction in disease-free survival (DFS) in the intention-to-treat population, and a 19% improvement compared with the combination arm (C). The result is even more impressive in the subgroup known to be hormone receptor-positive, where the relative risk reduction for A against T is 27% (the target population in future therapeutic decisions for adjuvant endocrine therapy). It is too early to describe outcomes in terms of all-causes and cause-specific mortality, although it is worth noting that an exploratory analysis of “breast cancer-related deaths”, having censored deaths from unrelated causes, shows a significant advantage of A against T.
The most surprising result was perhaps that the results of C were not better than those of T and were significantly worse than those of A. One explanation is that, in an oestrogen-deprived environment, tamoxifen is “seen” as an agonist, whereas in a normal oestrogen-rich environment tamoxifen can exert its usual antioestrogen effect.
Perhaps the most impressive result at this stage is the near-50% reduction in the incidence of contralateral invasive cancers for A compared with T. Yet, T has been known since 1985 to be associated with a significant reduction in contralateral disease, compared with a control population. In the latest overview, five years ago, T was associated with a 50% reduction in the contralateral breast cancer.(7) If these trends are confirmed, A has the potential to prevent (or delay) up to 75% of all cancers.
Tolerability and side-effects
The ATAC trial was carried out to demonstrate “equivalence”, on the basis that A demonstrates a better tolerability profile than T in the advanced setting.(3) It could therefore be argued that if this is the case in the adjuvant setting, then A could become the treatment of choice, with A having already demonstrated greater efficacy than T at a relatively short period of follow-up and probably also having better tolerability. Amongst the predetermined adverse events analysed, A is significantly less likely to contribute to hot flushes, vaginal discharge, vaginal bleeding, endometrial cancer, strokes and thromboembolic disease. Although a rare event, the fear of endometrial cancer, associated with exposure to T, means that most women with gynaecological symptoms might have been subjected to invasive investigations. This advantage for A could, in the long term, save unnecessary anxiety and health service costs.
The disadvantages of A compared with T are found in the contrast between women with chronic oestrogen deprivation and women on a drug with weak agonist effect. Before mentioning the problem of bone mineral metabolism, it is worth pointing out that women on A are more likely to suffer from musculoskeletal problems, particularly polyarthralgia, which seems to be a specific side-effect of this class of compounds. The mechanism of this disease is obscure but might be related to aromatase inhibition in the small muscles of the distal limbs. A significant excess of fractures has also already been observed in the A group. Whether this is the result of the protective effect of T on bone compared with an untreated population or whether this is due to oestrogen deprivation because of aromatase inhibition is still unknown. This is the subject of intense scrutiny in another subprotocol, which has been prospectively studying bone mineral metabolism in a sample population of the main study. In pragmatic terms, understanding this mechanism is not important, as women will have to make an informed choice between one drug or the other. Nevertheless, this side-effect could be managed if anticipated. Clinicians opting to treat women with A should request a baseline bone density scan, which should perhaps be repeated at 12-month intervals. Women whose bone density starts to fall into the osteopenic range could be considered for a variety of options. The drug treatment could be stopped if women have been treated, for example, for more than three years; alternatively, the patient could be given a bisphosphonate, which, in addition to protecting the skeleton, might also reduce the risk of skeletal metastases.
Finally, a recent publication has generated a lot of interest and controversy.(12) The NCIC MA-17 trial examined women who were alive and symptom-free after completing 5 years of tamoxifen. They were then randomised to placebo or 5 years of letrozole. The trial was aborted prematurely because of a significant improvement in disease-free survival favouring the letrozole group. Patients on placebo were then offered letrozole. In my opinion, this is a great pity, for although it is of scientific interest to note that the natural history of the disease can be perturbed after 5 years of tamoxifen, this study will never address the issue of clinical utility in overall survival or give an accurate harm–benefit analysis.
What type of treatment should be given to newly diagnosed patients? There is now a choice of adjuvant endocrine therapy for postmenopausal hormone-receptor-positive patients. For example, if T is specifically contraindicated, maybe because of a previous history of thromboembolic disease, then A could be considered. However, I consider that it is too early for an accurate risk–benefit analysis to be calculated, as overall survival results (which should become available in the third quarter of 2004) should be included. The balance of benefits versus harm may allow a selective approach based on age prognostic factors and biological predictive measurements.