Littérature scientifique sur le sujet « Third-generation aromatase inhibitor »

Following their successful implementation for the treatment of metastatic breast cancer, the ‘third-generation’ aromatase inhibitors (anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancers. These drugs are characterized by potent aromatase inhibition, causing >98% inhibition of estrogen synthesisin vivo. A recent meta-analysis found no difference in anti-tumor efficacy between these three compounds. As of today, aromatase inhibitor monotherapy and sequential treatment using tamoxifen followed by an aromatase inhibitor for a total of 5 years are considered equipotent treatment options. However, current trials are addressing the potential benefit of extending treatment duration beyond 5 years. Regarding side effects, aromatase inhibitors are not found associated with enhanced risk of cardiovascular disease, and enhanced bone loss is prevented by adding bisphosphonates in concert for those at danger of developing osteoporosis. However, arthralgia and carpal tunnel syndrome preclude drug administration among a few patients. While recent findings have questioned the use of aromatase inhibitors among overweight and, in particular, obese patients, this problem seems to focus on premenopausal patients treated with an aromatase inhibitor and an LH-RH analog in concert, questioning the efficacy of LH-RH analogs rather than aromatase inhibitors among overweight patients. Finally, recent findings revealing a benefit from adding the mTOR inhibitor everolimus to endocrine treatment indicate targeted therapy against defined growth factor pathways to be a way forward, by reversing acquired resistance to endocrine therapy.

Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal. Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020. Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal. Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020. Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

The aromatase enzyme catalyses the last step in estrogen biosynthesis. There are two classes of third-generation aromatase inhibitors: irreversible steroidal inhibitors (e.g. exemestane) and reversible non-steroidal inhibitors (e.g. anastrozole, letrozole). All three agents have been found to be equivalent or superior to megestrol acetate as second-line therapy for metastatic breast cancer. In the first-line setting, large phase III trials have shown that all three are equivalent or superior to tamoxifen in women with metastatic disease. Several large trials with varying study designs have been launched to analyse their role in the adjuvant setting. The four that have reported found longer average disease-free survival for women who received an aromatase inhibitor than for those who did not. In addition, one trial, MA.17, has shown a survival advantage associated with the use of an aromatase inhibitor in node-positive patients. Guidelines produced by the American Society of Clinical Oncology suggest that adjuvant therapy for postmenopausal women with hormone-receptor-positive breast cancer should include an aromatase inhibitor. However, the long-term consequences of estrogen deprivation in postmenopausal women remain uncertain, particularly with regard to bone and cardiovascular health. The advantages and disadvantages of different hormonal strategies should therefore be carefully considered in each individual case.

Tamoxifen has long been the standard endocrine therapy for postmenopausal women with hormone-sensitive breast cancer. However, data now suggest that the third-generation aromatase inhibitors have emerged as superior alternatives for advanced disease. In early disease evaluation of initial adjuvant therapy, data from the Arimidex®, Tamoxifen, Alone and in Combination trial has shown that anastrozole is more effective than tamoxifen with a better risk–benefit profile. This trial provides the most mature data of any aromatase inhibitor study and suggests that anastrozole should be considered the preferred initial adjuvant therapy for postmenopausal women with hormone-responsive early breast cancer. The emergence of aromatase inhibitors as an alternative to tamoxifen for the treatment of breast cancer is challenging the management of the disease and influencing the change of regulatory guidelines.

Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

This review provides the current evidence of clinical studies on the effectiveness of endocrine therapy for breast cancer and endometrial cancer, including endometrial stromal sarcoma, by aromatase inhibitor (AI) III generation. The review presents dates from clinical trials comparing the effectiveness of AI and tamoxifen, as well as dates on combination therapy AI with inhibitors of mTOR pathway (BOLERO-2 trial), an antiestrogen (SWOG S0226, FACT, FIRST trials), an inhibitor of CDK4 / 6 (PALOMA -1 trial) and other drugs.

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.

The work described in this thesis is aimed at defining the role of TRPA1 in several painful states induced by the chemotherapeutic agents paclitaxel, bortezomib and third-generation aromatase inhibitors. To this purpose both in vitro and in vivo assays have been used. Calcium imaging experiments were performed in order to explore whether paclitaxel, bortezomib and third-generation aromatase inhibitors were able to directly gate the TRPA1 channel evoking painful states. Furthermore, several animal models of chemotherapy-evoked painful side effects were developed and the involvement of TRPA1 was investigated through the use of Trpa1+/+ and Trpa1-/- mice or via the administration of TRPA1 selective antagonist.