Aromatase Inhibitors and Breast Cancer
Aromatase Inhibitors and Breast Cancer
There is mounting evidence that aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant treatment for postmenopausal women with oestrogen receptor positive breast cancer. Nevertheless, tamoxifen still remains a useful and relatively nontoxic treatment, and further work is necessary to determine which patients need an AI. In terms of cost-effectiveness, letrozole has been estimated to be superior to tamoxifen. Anastrozole, letrozole and exemestane have not been compared directly in an adjuvant setting but letrozole proved superior to anastrozole in patients with advanced breast cancer. Although tumour receptor phenotype may be useful in selection for tamoxifen or AI, the evidence is mixed. Optimal sequencing and duration of treatment have yet to be determined. If nationally funded and organised trials could be instigated, these would give timely and reliable data, so that adjuvant endocrine treatment of breast cancer could be tailored to needs of the individual patient.
A casual observer might evince bewilderment as more agents become licensed for niche markets within the adjuvant endocrine treatment of breast cancer. With so many choices, is it possible to set out a structured approach to adjuvant management that takes into account available data on patient and tumour characteristics? Five years ago, the situation was clear: for any woman with an oestrogen receptor positive (ER) tumour, give tamoxifen 20 mg daily for 5 years, then stop. This state of settled certainty was disturbed by the emergence of aromatase inhibitors (AIs) that had jumped from second- or first-line treatment of advanced disease into trials of adjuvant treatment.
Unlike tamoxifen which is effective in both pre- and postmenopausal women, the AIs are active only in the latter group in whom they block biotransformation of adrenal androgens to oestrogens in peripheral fat, resulting in undetectable levels of plasma oestrogens. Tamoxifen is a partial oestrogen agonist, decreasing risk of osteoporosis but giving an increased risk of endometrial cancer and thrombo-embolism in postmenopausal women. In contrast, because they have no oestrogen agonist activity, AIs do not engender endometrial malignancy or thromboembolism but do increase the risk of osteoporosis and can induce bone and joint pain.
The series of adjuvant trials of AIs were almost all funded by the manufacturers, and decisions regarding trial design were based on need to gain approval from regulatory bodies rather than as a concerted effort to establish the most cost-effective AI adjuvant agent and optimal duration of treatment. As a result, we are confronted with results from several trials with different entry criteria testing three different AIs. Trial groups have reported up-dated results at the recent American Society of Clinical Oncologists meeting in Orlando, Florida, St Gallen 2005 and San Antonio Breast Cancer Symposium 2005. Trial designs are summarised in Table 1 .
In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) study, there was a direct comparison of adjuvant tamoxifen and an AI, anastrozole, given as 5 years of adjuvant therapy following primary local treatment. Originally, there was a third arm treated with both tamoxifen and anastrozole, which was closed after the first analysis, because results were no better than with tamoxifen alone. There were 3125 treated with Arimidex (anastrozole) and 3116 who received tamoxifen. After 68 months median follow-up, there was a significant reduction in distant metastases among those given anastrozole (Hazard Ratio (HR) = 0.86, p = 0.94). Furthermore, there was a constant reduction in deaths after relapse in the anastrozole arm during the 5 years of treatment. Within the trial, Duffy et al. analysed gynaecological adverse events (AEs) and reported a significant reduction in the anastrozole arm. In particular, for those women with an intact uterus at the start of therapy, the rate of hysterectomy fell from 115 (5%) to 30 (1%).
Two German and Austrian Cooperative groups recently reported the joint results of two similar trials, ABCSG-8 and ARNO-95 in which after up-front randomisation, postmenopausal women who had taken 2 years of adjuvant tamoxifen either continued tamoxifen or switched to anastrozole 1 mg daily. After 28 months median follow-up, there was a 40% reduction in relapses in the anastrozole group. For patients with ER/PgR tumours, the benefit was even greater (HR = 0.47, p = 0.03). The number of distant relapses in the anastrozole arm was almost halved (HR = 0.54).
The BIG 1-98 trial is examining whether the AI Letrozole is better when used as primary adjuvant treatment or sequentially after tamoxifen. Only preliminary results are available, which give a direct comparison of letrozole and tamoxifen and show a small but significant benefit for women receiving the former agent. Time to distant recurrence was significantly longer in the letrozole arm (HR = 0.73, p = 0.01).
In another major trial, the Intergroup Exemestane Study examined the effect of switching from tamoxifen to the AI exemestane after patients had been taking adjuvant tamoxifen for 2-3 years. After a median follow-up of 31 months, there had been more events in the tamoxifen group (266 vs. 183). There was a 32% reduction of risk of relapse in the exemestane group representing an absolute benefit in disease-free survival of 4.7% at 3 years.
In MA-17, a large double-blind placebo-controlled study with 5187 participants, the effect of letrozole on relapse of breast cancer in postmenopausal women who had received 5 years of adjuvant tamoxifen was examined. Recent results have been reported after median follow-up of 30 months. There had been 127 relapses in the placebo group and 75 in the letrozole group with a 40% reduction in risk of distant metastases. Among node positive patients, there was a significant reduction in overall survival (HR = 0.61). This trial was stopped and those on tamoxifen could switch to letrozole, so that no further interpretable results will be available.
There is mounting evidence that aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant treatment for postmenopausal women with oestrogen receptor positive breast cancer. Nevertheless, tamoxifen still remains a useful and relatively nontoxic treatment, and further work is necessary to determine which patients need an AI. In terms of cost-effectiveness, letrozole has been estimated to be superior to tamoxifen. Anastrozole, letrozole and exemestane have not been compared directly in an adjuvant setting but letrozole proved superior to anastrozole in patients with advanced breast cancer. Although tumour receptor phenotype may be useful in selection for tamoxifen or AI, the evidence is mixed. Optimal sequencing and duration of treatment have yet to be determined. If nationally funded and organised trials could be instigated, these would give timely and reliable data, so that adjuvant endocrine treatment of breast cancer could be tailored to needs of the individual patient.
A casual observer might evince bewilderment as more agents become licensed for niche markets within the adjuvant endocrine treatment of breast cancer. With so many choices, is it possible to set out a structured approach to adjuvant management that takes into account available data on patient and tumour characteristics? Five years ago, the situation was clear: for any woman with an oestrogen receptor positive (ER) tumour, give tamoxifen 20 mg daily for 5 years, then stop. This state of settled certainty was disturbed by the emergence of aromatase inhibitors (AIs) that had jumped from second- or first-line treatment of advanced disease into trials of adjuvant treatment.
Unlike tamoxifen which is effective in both pre- and postmenopausal women, the AIs are active only in the latter group in whom they block biotransformation of adrenal androgens to oestrogens in peripheral fat, resulting in undetectable levels of plasma oestrogens. Tamoxifen is a partial oestrogen agonist, decreasing risk of osteoporosis but giving an increased risk of endometrial cancer and thrombo-embolism in postmenopausal women. In contrast, because they have no oestrogen agonist activity, AIs do not engender endometrial malignancy or thromboembolism but do increase the risk of osteoporosis and can induce bone and joint pain.
The series of adjuvant trials of AIs were almost all funded by the manufacturers, and decisions regarding trial design were based on need to gain approval from regulatory bodies rather than as a concerted effort to establish the most cost-effective AI adjuvant agent and optimal duration of treatment. As a result, we are confronted with results from several trials with different entry criteria testing three different AIs. Trial groups have reported up-dated results at the recent American Society of Clinical Oncologists meeting in Orlando, Florida, St Gallen 2005 and San Antonio Breast Cancer Symposium 2005. Trial designs are summarised in Table 1 .
In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) study, there was a direct comparison of adjuvant tamoxifen and an AI, anastrozole, given as 5 years of adjuvant therapy following primary local treatment. Originally, there was a third arm treated with both tamoxifen and anastrozole, which was closed after the first analysis, because results were no better than with tamoxifen alone. There were 3125 treated with Arimidex (anastrozole) and 3116 who received tamoxifen. After 68 months median follow-up, there was a significant reduction in distant metastases among those given anastrozole (Hazard Ratio (HR) = 0.86, p = 0.94). Furthermore, there was a constant reduction in deaths after relapse in the anastrozole arm during the 5 years of treatment. Within the trial, Duffy et al. analysed gynaecological adverse events (AEs) and reported a significant reduction in the anastrozole arm. In particular, for those women with an intact uterus at the start of therapy, the rate of hysterectomy fell from 115 (5%) to 30 (1%).
Two German and Austrian Cooperative groups recently reported the joint results of two similar trials, ABCSG-8 and ARNO-95 in which after up-front randomisation, postmenopausal women who had taken 2 years of adjuvant tamoxifen either continued tamoxifen or switched to anastrozole 1 mg daily. After 28 months median follow-up, there was a 40% reduction in relapses in the anastrozole group. For patients with ER/PgR tumours, the benefit was even greater (HR = 0.47, p = 0.03). The number of distant relapses in the anastrozole arm was almost halved (HR = 0.54).
The BIG 1-98 trial is examining whether the AI Letrozole is better when used as primary adjuvant treatment or sequentially after tamoxifen. Only preliminary results are available, which give a direct comparison of letrozole and tamoxifen and show a small but significant benefit for women receiving the former agent. Time to distant recurrence was significantly longer in the letrozole arm (HR = 0.73, p = 0.01).
In another major trial, the Intergroup Exemestane Study examined the effect of switching from tamoxifen to the AI exemestane after patients had been taking adjuvant tamoxifen for 2-3 years. After a median follow-up of 31 months, there had been more events in the tamoxifen group (266 vs. 183). There was a 32% reduction of risk of relapse in the exemestane group representing an absolute benefit in disease-free survival of 4.7% at 3 years.
In MA-17, a large double-blind placebo-controlled study with 5187 participants, the effect of letrozole on relapse of breast cancer in postmenopausal women who had received 5 years of adjuvant tamoxifen was examined. Recent results have been reported after median follow-up of 30 months. There had been 127 relapses in the placebo group and 75 in the letrozole group with a 40% reduction in risk of distant metastases. Among node positive patients, there was a significant reduction in overall survival (HR = 0.61). This trial was stopped and those on tamoxifen could switch to letrozole, so that no further interpretable results will be available.
