**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.
- Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer: an early clinical appraisal of ICI46474. Br J Cancer 1971 Jun;25(2):270-5.
- Jordan VC. Studies on the estrogen receptor in breast cancer: 20 years as a target for the treatment and prevention of cancer (Third Annual William L. McGuire Memorial Lecture). Breast Cancer Res Treat 1995;36(3):267-85.
- Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003 12;348(24):2431-42.
- Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998 16;351(9114):1451-67.
- Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph-node- negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001 2;93(9):684-90.
- US National Cancer Institute. Clinical announcement: Adjuvant therapy of breast cancer-tamoxifen update. Bethesda (MD): NCI; Nov 1995.
- Howell A, Dowsett M. Recent advances in endocrine therapy of breast cancer. BMJ 1997 4;315(7112):863-6.
- Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases.Lancet 1896;2:104-7.
- Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19(10):2596-606.
- Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003;21(11):2101-9.
- Thurlimann B, Keshaviah A, Coates AS, et al(Breast International Group 1-98 Collaborative Group).A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.N Engl J Med 2005 29;353(26):2747-57.
- Howell A, Cuzick J, Baum M, et al. (ATAC Trialists’ Group). Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer.Lancet 2005;365(9453):60-2.
- Jakesz R, Jonat W, Gnant M, et al. (ABCSG and GABG). Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366(9484):455-62.
- Coombes RC, Hall E, Gibson LJ, et al (Intergroup Exemestane Study). A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.N Engl J Med 2004;350(11):1081-92.
- Boccardo F, Rubagotti A, Puntoni M, et al.Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 2005;23(22):5138-47.
- Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97(17):1262-71.
- Jakesz R, Samonigg H, Greil R, et al. Extended adjuvant treatment with anastrozole: results from the ABCSG trial 6A. J Clin Oncol 2005;23(16S):527.
- Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer 2003;98(2):229-38.
- Clarke R, Leonessa F, Welch JN, Skaar TC. Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacol Rev 2001;53:25-71.