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MB ChB(Hons) MRCS MD
Nigel J Bundred
Professor in Surgical Oncology
South Manchester University Hospital
Over the past 30 years tamoxifen has been used to prevent recurrence after early breast cancer treatment in postmenopausal women with oestrogen-receptor-positive disease.(1) Aromatase inhibitors (AIs) inhibit aromatase, an enzyme of the cytochrome P450 family responsible for the conversion of androgens (produced by the adrenal glands in postmenopausal women) to oestrone and oestradiol. In postmenopausal women aromatase is found in the ovary and breast (including breast cancer tissues) and is an important source of circulating oestrogen as the AIs reduce circulating oestrogen levels tenfold in postmenopausal women.
Third-generation AIs can be divided into: (a) nonsteroidal AIs (anastrozole and letrozole), which bind reversibly to the haeme group of the enzyme; and (b) steroidal agents (exemestane), which bind irreversibly to the aromatase molecule.
Upfront or primary adjuvant AI therapy
Two trials have reported on arimidex or letrozole used after surgery versus tamoxifen for five years. Both studies have additional arms and will provide updates in the future. The ATAC trial, which also included the combined anastrazole and tamoxifen therapy results, showed an overall 3.1% benefit from the use of anastrazole compared with tamoxifen at five years, and the combination was not better than tamoxifen alone and was dropped.(2,3)
After 68 months of median follow-up, anastrazole prolonged disease-free survival (HR 0.87, 95% CI 0.78-0.97) and time-to-recurrence (HR 0.79, CI 0.70-0.90). No overall survival benefit has yet been shown, but time to distant recurrence was significantly prolonged. There was an excess of bone fractures (11% for anastrozole vs 7.7% for tamoxifen) compared with tamoxifen, but there were significantly fewer venous thromboembolic events or endometrial cancers.
The Breast International Group (BIG) 1-98 trial compared five years of adjuvant letrozole with tamoxifen and incorporated two further arms whereby after two years of tamoxifen or letrozole, the patients swapped to three years of the other agent. At 25.8 months follow-up, letrozole significantly prolonged disease-free survival (HR 0.81, 95% CI 0.70-0.93), including a reduction in the risk of distant recurrence.(4)
Although the BIG 1-98 trial suggested that letrozole was more efficacious in women who had received chemotherapy or who had involved axillary lymph nodes, there are generally similarities between both trials, with an overall approximate 20% reduction risk of relapse with upfront AI therapy.
The first reported trial which switched to anastrazole from tamoxifen after two to three years or continued tamoxifen until five years of total treatment was the Italian Tamoxifen Anastrozole Trial (ITA), which showed significantly increased disease-free survival on switching (HR 0.76, 95% CI 0.66�0.88).(5) Subsequent trials in Austria (ABCSG 8) and Germany (ARNO 95, with Arimidex/Novadex) showed an improvement in disease-free survival on swapping to anastrazole (HR 0.6, 95% CI 0.44-0.81).(6) Recent combined analysis including all three trials indicated improvements with switching to anastrazole in terms of disease-free survival, time to recurrence and overall survival (HR 0.71, p = 0.038). However, this meta-analysis has limitations, as there were different study designs, different primary endpoints and variable times on tamoxifen, but essentially the sequencing/switching trials show approximately 30�40% reduction in risk of relapse by switching to an AI.
Exemestane has also been studied in a switching trial after two years on tamoxifen. The IES trial reported increased disease-free survival (HR 0.70, 95% CI 0.62�0.86) after 58 months for patients switched to exemestane, with a reduction in incidence of contralateral breast cancer, and on the �latest analysis an overall survival advantage (HR 0.83, 95% CI 0.69-1) for oestrogen-receptor-positive breast cancer.
The overall benefit from all sequencing trials is greater than when AIs are used upfront. Only 5% of patients relapse on tamoxifen in the first two years after surgery, and these are mostly confined to grade three tumours of a size greater than 2.5 cm, involving more than four nodes. In addition, bone morbidity (in terms of fractures) as well as tamoxifen side-effects are reduced by switching; therefore, a swap strategy would be the ideal for most postmenopausal women with breast cancer, except for those at high risk of recurrence with two years of surgery on tamoxifen.
Extended adjuvant letrozole trial
The MA-17 trial looked at the effect of switching to letrozole 2.5 mg or placebo after five years of adjuvant tamoxifen.(7) The trial was stopped after 2.4 years median follow-up because of a highly significant reduction in the number of breast cancer events in women receiving letrozole. Subsequent follow-up of these women has confirmed this advantage for letrozole, and indeed continued use of letrozole, even in those who had a long period of placebo, has shown a significant survival advantage. Although these data are nonrandomised they strongly suggest that use of AIs after five years of tamoxifen has advantages, particularly in node-positive patients. This trial was the first to report an overall survival benefit in women who were node-positive at the time of presentation with breast cancer.
AI therapy causes loss of bone mineral density, which is a problem for those women who are either osteoporotic at the time of starting therapy (about 5% of the population) or osteopenic (about 20% of the population). Thus, there is a need for bone mineral density monitoring at the time of starting an AI, although it is not necessary to repeat this if patients have normal bone mineral density at the commencement of therapy, particularly in those groups of patients who switch.
AIs are also associated with increased incidence of musculoskeletal complaints and arthralgia. However, there is a reduction in incidence of endometrial hyperplasia, in the need for hysterectomy and in incidence of venous thromboembolism.
Current clinical practice
Apart from women in high-risk groups, the majority of postmenopausal women who are oestrogen- or progesterone-receptor-positive should receive tamoxifen initially and be considered for a switch strategy either after two to three years or after five years of tamoxifen treatment. Women who develop severe side-effects of tamoxifen (venous thromboembolism, endometrial cancer) should be swapped to an AI, although side-effects such as hot flushes are similar on both treatments. It is claimed that cancers expressing the Her2 onco‑protein require AI therapy, but these patients will have chemotherapy and 12 months of herceptin, and there is no evidence to suggest that patients should not take tamoxifen for two years before swapping over to AIs.
The BIG 1-98 trial will report on whether the swap from tamoxifen to letrozole is better than the swap from letrozole to tamoxifen after two years, and how this compares with upfront aromatase �inhibitor therapy. The TEAM study will compare the same question for exemestane. The future will almost certainly be tailored treatment, personalised for an individual woman according to her risk of relapse. The use of aromatase inhibitors is now an integral part of breast cancer treatment for all patients with this condition.