Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.726465
Title: A comparison of the third-generation aromatase inhibitors and their effects on postmenopausal women with early hormone sensitive breast cancer
Author: McCaig, Fiona M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2012
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Abstract:
Breast cancer is the most common malignancy and the second highest cause of cancer death in women. Many of these tumours are oestrogen dependent and can be treated using compounds which are themselves antioestrogenic or reduce the production of oestrogen. Until recently, the selective oestrogen receptor modulator (SERM) tamoxifen was prescribed as standard adjuvant therapy for postmenopausal women with hormone sensitive tumours. Several studies have shown that in postmenopausal women, the newer aromatase inhibitors (AIs) are effective at suppressing plasma oestrogen levels and are more efficacious than tamoxifen. Although their use is increasing there remain concerns about their side-effects. There are two classes of AIs: type 1 which are irreversible, steroidal inhibitors and include the drug exemestane; type II that are reversible, non-steroidal inhibitors and include the drugs letrozole and anastrozole. Each has similar but different levels of oestrogen suppression and it remains to be determined whether these differences in suppression of aromatase translate into differences in clinical benefits and side-effects. The purpose of the following studies was to assess the pharmacodynamic differences between the AIs anastrozole, letrozole and exemestane in postmenopausal women with early hormone sensitive breast cancer. The oestrogen-depriving effects of AIs have been reported to be associated with an increased risk of osteoporosis and cardiovascular disease alongside a potential reduction in the risk of thromboembolic events. These studies therefore investigated the differential effects of the more commonly used AIs, anastrozole, letrozole and exemestane on bone turnover markers, lipid profiles, coagulation parameters and quality of life (QOL). ALIQUOT (Anastrozole vs Letrozole, an Investigation of Quality of Life and Tolerability) was an open randomised pharmacodynamic study in which 185 patients were randomised to receive either 3 months s of letrozole followed by 3 months of anastrozole or 3 months of anastrozole followed by 3 months of letrozole. 39 patients had received prior tamoxifen therapy. Blood and urine samples were collected at baseline and after 3 months of each drug. Hormone naive (i.e. those who did not receive prior tamoxifen) patients were switched to tamoxifen after 6 months and further samples obtained after an additional 3 months. Validated QOL questionnaires were collected during treatment. ALEX (a randomised study of the effects of Anastrozole, Letrozole and Exemestane on bone turnover, lipid metabolism and coagulation) was an open randomised pharmacodynamic study in which 120 patients were randomised to receive 4 months of either drug and then switched to tamoxifen. Similar blood and urine samples were collected at baseline, after 3, 4 and 12 months. Results demonstrated that each AI increased bone turnover markers. The non-steroidal AI exemestane showed a greater increase in markers of bone turnover compared with the non-steroidal AIs. Significant changes in bone turnover were observed when tamoxifen was withdrawn and a non-steroidal AI commenced. The data from these studies suggest that any benefit from tamoxifen in increasing bone density is likely to be lost in the months and years after treatment is stopped. Patients who take anastrozole or letrozole following tamoxifen need the same bone monitoring as any patient taking anastrozole or letrozole alone. The non-steroidal AIs had different effects on lipid profiles compared to the steroidal group. Exemestane caused an increase in atherogenic ratios and a decrease in the cardioprotective high density lipoprotein (HDL) compared to the non-steroidal AIs. This supports studies suggesting that exemestane may have a negative impact on lipid levels and may increase the risk of cardiovascular disease (CVD). There were no significant differences between coagulation parameters in the patients treated with non-steroidal AIs. However exemestane caused a significant reduction in several anticoagulants predisposing to a potential increased risk of thromboembolic disease. Data presented in this thesis indicate that steroidal and non-steroidal AIs have different metabolic effects on bone, lipids and coagulation and suggest each will have different side effect and morbidity profiles. These observations have important implications when considering which AI to use in the clinical setting and how patients on different drugs should be monitored.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.726465  DOI: Not available
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