Breast cancer
Peter Hoskin, Peter Ostler in Clinical Oncology, 2020
Breast cancer is one of the few malignant diseases for which a large randomized trial has shown that chemoprevention is not only feasible but also effective. Tamoxifen 20 mg daily as adjuvant therapy has been conclusively shown to decrease the risk of contralateral breast cancer. This observation has been extrapolated to the prevention setting where a large (15,000 women) placebo-controlled, double-blind, randomized trial has shown this regimen to significantly reduce the risk of developing DCIS and invasive breast cancer. There is an increased risk of thromboembolic disease and endometrial cancer in women receiving tamoxifen. Tamoxifen incidentally reduces cholesterol levels and helps maintain bone mineral density in postmenopausal women, and could therefore have additional health benefits. The osteoporosis-prevention drug raloxifene has also been shown to reduce substantially the risk of developing breast cancer, and has the advantage of not causing hyperstimulation of the endometrium. The aromatase inhibitor anastrozole also reduces the risk of contralateral breast cancer in women receiving the drug as treatment for metastatic breast cancer. Anastrozole could therefore be a promising prevention strategy for postmenopausal women.
Chemoprevention and endocrine therapy of endometrial carcinoma
A. R. Genazzani in Hormone Replacement Therapy and Cancer, 2020
The new non-steroidal aromatase inhibitors anastrozole and letrozole have been recently assessed for breast cancer treatment3,66,67. Letrozole has been shown to be significantly superior to megestrol acetate in overall response rates and time to treatment failures, whereas anastrozole has been found to improve survival in comparison with megestrol acetate66. Moreover, anastrozole showed a significant advantage over tamoxifen in terms of time to progression as first-line therapy for advanced breast cancer in postmenopausal women67. As for endometrial cancer, Rose and colleagues65 achieved an objective response in 9% of 23 patients with advanced or recurrent disease who had received no more than one prior hormone therapy regimen. Median progression-free survival and overall survival were 1 and 6 months, respectively. The National Cancer Institute of Canada is currently carrying out a phase II study on letrozole in women with recurrent or metastatic adenocarcinoma or adenosquamous carcinoma of the endometrium not curable by surgery or radiotherapy68.
Breast Cancer
Pat Price, Karol Sikora in Treatment of Cancer, 2020
A series of adjuvant trials with AIs including over 30,000 women have been completed and have established the place of AIs in the management of postmenopausal women with breast cancer. AIs have been explored (1) as replacement for tamoxifen,100 (2) following 2–3 years of tamoxifen,101 (3) following 5 years of tamoxifen,102 and (4) as an extended therapy over 10 years. Updated results from the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial,103 Breast International Group (BIG) 1-98 Femara-Tamoxifen trial,104 and Intergroup Exemestane Study105 all showed a small but statistically significant improvement in relapse-free survival (and in some cases OS) for the AIs over tamoxifen when administered in the first 5 years. The MA17 trial (testing letrozole 2.5 mg daily after 5 years of tamoxifen) also reported a significantly superior DFS in favor of letrozole (and a significant OS benefit), with the consequence that this option has become standard of care for high-risk patients who have completed 5 years of adjuvant tamoxifen therapy.102 To date, there is limited evidence of the value of extending AI therapy to 10 years. Although extended treatment reduces the rate of disease recurrence and contra-lateral breast cancer, the absolute effect is modest, and the MA.17R trial found no difference in overall survival with the additional treatment.106 In terms of choice of agent, a recent study has reported equivalent efficacy between anastrozole and letrozole.107
Effects of psoralen on the pharmacokinetics of anastrozole in rats
Published in Pharmaceutical Biology, 2018
Yuzhu Zhang, Jingjing Wu, Yue Zhou, Yulian Yin, Hongfeng Chen
Anastrozole is a derivative of benzotriazole marketed as ARIMIDEX® by AstraZeneca Pharmaceuticals LP, and it has an inhibitory action on aromatase, thus blocking the conversion of testosterone into estradiol and androstenedione into estrone (Wilkinson 2004; Ding et al. 2017; Ellis 2017; Nave et al. 2018). Anastrozole has significant effects on breast cancer treatment, and it is currently used as first-line treatment in estrogen receptor (ER)-positive postmenopausal women, particularly to treat locally advanced or metastatic breast cancer (Wellington and Faulds 2002; Sanford and Plosker 2008; Kelly and Buzdar 2010). Anastrozole is oxidized to hydroxyanastrozole mainly by CYP3A4 (Antoniou and Tseng 2005; Kamdem et al. 2010; Abubakar et al. 2014), and the transport of anastrozole is mediated by P-gp, which limited its absorption at the blood–brain barrier and intestine (Miyajima et al. 2013).
Benefit–risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John’s wort in breast cancer patients
Published in Climacteric, 2019
X. Ruan, A. O. Mueck, A.-M. Beer, B. Naser, S. Pickartz
Anastrozole metabolites (triazole, hydroxyanastrozole, hydroxyanastrozole glucuronide, and anastrozole glucuronide) result from N-dealkylation, hydroxylation, and glucuronidation processes (Figure 2)95,96. The main metabolite, triazole, is inactive95. Enzymes involved in anastrozole metabolism have not been completely identified95. In vitro, the formation of hydroxyanastrozole was mainly catalyzed by CYP3A4/5 and, to a lesser extent, by CYP2C8, CYP2D6, and CYP2B6 (Figure 2)95,97. CYP3A4 inducers could possibly increase the production of one of the metabolites (hydroxyanastrozole), but it should be taken into account that anastrozole itself inhibits CYP3A495. No influence of potent CYP inducers on anastrozole metabolism is known, and safety data analyses from clinical studies did not show significant interactions with commonly prescribed drugs95.
Development of an intravaginal ring delivering simultaneously anastrozole and levonorgestrel: a pharmacokinetic perspective
Published in Drug Delivery, 2019
Rüdiger Nave
Endometriosis is a chronic inflammatory disease affecting up to 10% of women of reproductive age (Kennedy et al., 2005; Dunselman et al., 2014). There is a high unmet need for effective medical therapies with favorable safety profiles for the long-term treatment of endometriosis. After discovery of aromatase overexpression in endometriotic lesions, new treatment concepts have emerged that aim to reduce local estrogen production in endometriotic lesions through means such as utilizing aromatase inhibitors (Bulun et al., 2000). However, the aromatase inhibitor anastrozole (ATZ) may cause harm to the fetus as studies in animals have shown reproductive toxicity (Arimidex, 2017). Therefore, effective contraception has to be assured while using ATZ in women of childbearing potential.
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