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Head of Department
Department of Obstetrics and Gynaecology and Breast Cancer Centre
Klinikum Offenbach GmbH
Breast cancer is the most common cause of cancer-related mortality in women worldwide, and over a million new cases are diagnosed amongst women each year.(1,2) Approximately 75% of breast cancers are oestrogen-responsive1 and proliferate through the stimulus of endogenous oestrogens. For the last 30 years, the partial anti-oestrogen tamoxifen has been used as adjuvant therapy following surgery. However, tamoxifen is associated with a number of potentially serious side-effects, including thromboembolic events and endometrial cancer.(3) In addition, tumours can develop resistance to tamoxifen, leading to recurrence.(3) The past five years have seen an increasingly prominent role for the aromatase inhibitors (AIs), which proved to be more effective than tamoxifen for the treatment of advanced disease in postmenopausal women(4-6) and have subsequently demonstrated superior efficacy to tamoxifen in the adjuvant setting.
The main source of endogenous oestrogens in postmenopausal women is the aromatisation of androgens by the aromatase enzyme in peripheral tissue. By inhibiting the action of this enzyme, AIs effectively starve oestrogen-dependent tumours of growth stimulus. Each of the third-generation AIs has slight differences in structure; anastrozole and letrozole are nonsteroidal AIs, whereas the structure of exemestane includes a steroid ring. Although small differences in aromatase suppression have been recorded, they are unlikely to influence clinical efficacy. However, other pharmacokinetic/pharmacodynamic differences raise questions as to the potential for differences in tolerability profiles for anastrozole, letrozole and exemestane.(7)
Efficacy of AIs in the adjuvant setting
Adjuvant trials schemes of an AI in the adjuvant setting are shown in Figure 1. In two separate trials, anastrozole and letrozole have been compared with tamoxifen as primary adjuvant therapy in newly diagnosed patients. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial has the longest median follow-up to date and showed that five years of treatment with ï¿½anastrozole significantly improved disease-free survival (hazard ratio [HR] 0.87; 95% confidence intervals [CI] 0.78ï¿½0.97; p=0.01) and time to recurrence (HR 0.79; 95% CI 0.70ï¿½0.90; p=0.0005) compared with five years of tamoxifen. A greater advantage was seen in these parameters in hormone receptor-positive patients (see Figure 2).(8) Similarly, the latest data from the Breast International Group (BIG) 1-98 trial in an entirely hormone receptor-positive group revealed a benefit for the AI letrozole over tamoxifen in disease-free survival (HR 0.82; 95% CI 0.71ï¿½0.95; p=0.007) (see Figure 2).(9,10)
A number of “switching” trials have been conducted to assess the advantages of switching patients who are partway through a course of tamoxifen to an AI. Postmenopausal patients who had received and tolerated two to three years of tamoxifen without disease progression were enrolled into switching trials and then randomised either to continue receiving tamoxifen for the remainder of the five years or to have their treatment switched to an AI (anastrozole or exemestane).(11-13) Impressive reductions in recurrence rates were demonstrated in those patients who changed treatment to an AI, compared with those who continued to receive tamoxifen.
There are currently no data directly comparing five years of primary adjuvant AI treatment with a strategy of initiating tamoxifen therapy then switching to an AI after two to three years. Indirect intertrial comparisons must be interpreted carefully, as “switching” trials enrol enriched populations of women who are proven responders and tolerant to endocrine therapy. Two arms of the BIG 1-98 trial (as yet unreported) will provide the first data on prospectively sequencing an AI and tamoxifen compared with five years of primary adjuvant AI therapy.
Patients who have completed an adjuvant course of five years of tamoxifen may also benefit from between three and five years of an AI. The MA 17 trial investigated extending adjuvant therapy beyond five years with letrozole compared with placebo; letrozole significantly improved disease-free survival.(14,15) Similar results were recorded in a trial comparing three years of extended adjuvant anastrozole with no further treatment.(16)
Tolerability of AIs and tamoxifen in the adjuvant setting
Differing modes of action give rise to differing adverse event profiles for tamoxifen and AIs. Tamoxifen has a partial agonist effect, which can encourage endometrial proliferation, increasing the risk of endometrial cancer and other gynaecological events, such as vaginal bleeding and discharge and endometrial polyps and fibroids.(3,17) Compared with AIs, long-term tamoxifen therapy is also associated with an increased risk of cerebrovascular events and thromboembolic events.(8,10)
Due to the suppression of endogenous oestrogens, the AIs are predominantly associated with increased fracture risk and joint pain/arthralgia.(8,10) It is possible to identify patients at increased risk of fracture by bone mineral density measurement, and prophylactic bisphosphonate therapy can be used to manage the effects in patients at increased risk.(9,18,19)
As it is not yet certain whether the AIs have comparable tolerability profiles, safety data for anastrozole, letrozole and exemestane should not be viewed as interchangeable. In practice, the AI that has been studied in the setting most closely approximating each patient’s clinical circumstance should be prescribed.
Given the increased efficacy and preferable tolerability profile of the AIs compared with tamoxifen, the risk:benefit ratio is consistently in favour of the AIs for postmenopausal women with early breast cancer.(20) Postmenopausal women with oestrogen-responsive breast cancer receive increased benefit from an AI compared with tamoxifen, whether newly diagnosed or after an initial course of adjuvant tamoxifen.
Following the completion of five years of adjuvant tamoxifen, extended adjuvant treatment with an AI is an option in high-risk patients. This stance is echoed in current American Society of Clinical Oncology (ASCO) guidelines, which recommend that optimal adjuvant endocrine therapy should include an AI.(21)