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**Department of Surgery
University of Pisa
Many breast cancers are oestrogen-dependent. Oestrogen effects can be selectively blocked at the receptor site by tamoxifen, which acts as a competitive antagonist.(1) For more than 30 years tamoxifen has been the adjuvant endocrine therapy for women with oestrogen-receptor-positive breast cancer.(2,3) The mechanism of action means that treatment can be applied to pre- as well as postmenopausal women, and five years is the optimum duration for treatment(4) since longer therapy seems to confer no extra benefit.(5,6) Oestrogen deprivation is another key therapeutic approach to inhibiting the development and growth of breast tumours.(7) More than a century ago, oophorectomy was shown to cause regression of advanced breast cancer in premenopause.(8) After menopause, residual oestrogen production derives mainly from subcutaneous fat, where oestrogens are synthesised from androgenic substrates by the enzyme aromatase. Aromatase inhibitors (AIs) markedly suppress plasma and tissue oestrogen levels, inhibiting or inactivating the enzyme aromatase.(3) The first aromatase inhibitor to be ï¿½discovered, amino glutethimide, was found to cause adrenal failure; later, a series of successive inhibitors with fewer side-effects were prepared. These preparations are described as first-, second- and third-generation inhibitors, according to the chronological order of their clinical development, and they are further classified as type 1 or type 2 inhibitors according to their mechanism of action.(3) Type 1 inhibitors are steroidal analogues of androstenedione and bind to the same site on the aromatase molecule, but unlike androstenedione they bind irreversibly; they are enzyme inactivators. Type 2 inhibitors are nonsteroidal and bind reversibly to the heme group of the enzyme. The second-generation aromatase inhibitors formestane (type 1) and fadrozole (type 2) have clinical efficacy, but due to some disadvantages (mainly concerning intramuscular injection and aldosterone suppression respectively) they must be used in doses that produce only about 90% inhibition.Third-generation inhibitors, developed in the early 1990s, include anastrozole (Arimidex(R)), letrozole (Femara(R)) and exemestane (Aromasin(R)), which so far have been those commonly used in clinical trials. In contrast to aminoglutethimide and fadrozole, their specificity appears to be nearly complete at clinical doses, with little or no effect on basal levels of cortisol or aldosterone (see Table 1). The main pharmacodynamic characteristics of anastrozole, letrozole and exemestane are shown in Table 2. Due to the favourable results obtained in recent years by the third-generation AIs as first-line salvage hormone treatment in oestrogen-positive postmenopausal patients,(3,9,10) the use of tamoxifen as standard treatment in this population shifted to the adjuvant as well as the metastatic setting.
In recent years, three different kinds of comparison between third-generation AIs and tamoxifen in the adjuvant setting have been made.
Upfront tamoxifen for five years compared with the same interval time on anastrozole or letrozole (ATAC and BIG 1-98 trials respectively)(11,12)
Postmenopausal women were randomised to receive anastrozole or tamoxifen in the ATAC trial (9,366 women), and letrozole or tamoxifen in the BIG 1-98 trial (8,010 women). Both trials showed a significant increase in disease-free survival (DFS), although data from ATAC were more robust due to a longer follow-up (68 vs 25.8 months), Moreover, in the ATAC trial, a greater advantage was seen in time to recurrence in hormone-receptor-positive patients.
Early switching from adjuvant tamoxifen to AIs compared with tamoxifen only for five years
The ABCSG-8, ARNO 95, IES and ITA trials have all been reported on. The ABCSG-8-ARNO 95 combined analysis,(13) carried out at a median follow-up of 28 months, evaluated 3,224 women with early breast ï¿½cancer who, after they had completed two years of adjuvant tamoxifen, were randomised to receive anastrozole or tamoxifen. In the IES and ITA trials,(14,15) after two to three years of tamoxifen, 2,362 and 223 node-positive, oestrogen-receptor-positive patients were randomly assigned to switch to exemestane (IES) or anastrozole (ITA), respectively, while controls continued with tamoxifen. Median follow-up was 30.6 and 36 months. In both ABCSG-8-ARNO 95 combined analysis and the IES and ITA trials, DFS was significantly longer in the AI groups (pâ€‰â€‰<â€‰0.0009, pâ€‰<â€‰0.001 and pâ€‰<â€‰0.001, respectively).
Extended adjuvant treatment with AIs after five years of tamoxifen compared with placebo (delayed switching)
The NCIC CTG MA.(17) and ABCSG-6a trials(16,17) have been reported on. In these two trials, women who had completed five years of adjuvant tamoxifen were randomised to further receive five years of letrozole (5,157 women) and three years of anastrozole (856 women), respectively, or placebo. After a median follow-up of 30 and 60 months, respectively, DFS was statistically better in the further-treated than in the placebo arm (p<0.01 and p<0.047, respectively). Furthermore, in the letrozole arm, overall survival was significantly improved among N+ patients.
Unlike tamoxifen, AIs have no partial oestrogen-agonist activity. The third-generation AIs appear to be very well tolerated, with a remarkably low incidence of serious long-term adverse effects, reflecting the high specificity of their action. Particularly, there is no evidence to suggest an increased risk of uterine carcinoma or venous thromboembolism with AIs; however, the risk of important long-term skeletal problems – fracture or osteoporosis – may increase with the use of AIs.(3) However, this risk may be prevented with concomitant use of bisphosphonates. Table 3 shows the significant differences in adverse effects associated with anastrozole and tamoxifen in the ATAC trial, which is by far the largest trial of adjuvant therapy to date.
Significant DFS increases and a toxicity profile better than that of tamoxifen account for the recent approval of anastrozole and letrozole in the USA and in many European countries, as new adjuvant treatment for postmenopausal oestrogen-positive breast cancer patients.
However, several questions remain to be definitively answered: which of the available AIs – if any – is superior; the time AIs should be given; whether the sequence with tamoxifen and AIs is better than single AI; and what kind of sequence is best. ï¿½Prolonged adjuvant treatment, as for tamoxifen,(18,19) is likely to favour resistance to AIs as well. So far, overall survival has been found to be significantly prolonged only occasionally in subsets with relatively worse prognosis (N+). Although this finding is commonly attributed to the “carryover” effect of tamoxifen, it could also be unfavourably affected by the acquired hormone resistance.
Therefore – as pointed out also by other researchers(3) – it cannot yet be claimed that tamoxifen has definitively been replaced by AIs, at least in most eligible patients in the adjuvant setting. However, we can expect that this important question will be answered by the long-term results of ongoing and further clinical trials.