Abstract
Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara®) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Studies have consistently shown that lifetime exposure to estrogens increases the risk of breast cancer [1]. The degree of risk is increased by persistently elevated blood concentrations of estrogen [2]; clinical indicators of persistently elevated blood estrogen concentrations, for example, age at menarche, first live birth, menopause, alcohol consumption, and obesity [3–5]; and, although still controversial, exposure to exogenous estrogen, for example, some forms of hormone replacement therapy and oral contraceptives [6–12]. The presence of some of these factors also increases the risk of breast cancer being estrogen receptor (ER)-positive [13]. Studies have shown that higher levels of endogenous estrogen and testosterone (which is converted to estrogen by aromatase) increases breast cancer risk, regardless of predicted breast cancer risk [14–16]. These data indicate that estrogen is an important risk factor even in women considered at high risk of developing the disease, for example, those with a family history of breast cancer.
Estrogen is thought to contribute to the initiation and contributes to the promotion and progression of breast cancer via two complementary mechanisms [1], the carcinogenic effects of estrogen metabolites, notably hydroxyl metabolites [3, 17, 18], and stimulation of ER signaling pathways, including those initiated by activation of epidermal growth factors, notably the mitogen-activated phosphoinositide 3 kinase pathway [19–30]. Greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis (aromatase inhibitors [AIs]) [31], the ER (selective ER modulators [SERMs], pure antagonists) [32], and intracellular signaling pathways (signal transduction inhibitors) [33].
Hormone receptor (HR)-positive tumors are defined as those with ER or progesterone receptor (PgR) expression detectable above a pre-set limit [34]. Patients whose ER or PgR expression is below this pre-set limit are considered HR–. Approximately two thirds of breast cancer patients have HR+ tumors [13] and are candidates for treatment strategies designed to counteract the growth effects of estrogen. This review describes the rational development of the potent AI letrozole, which has therapeutic utility in HR+ tumors across the breast cancer continuum.
Mechanism of action of aromatase inhibitors
Aromatase
Aromatase (cytochrome P-450 [CYP] 19) catalyzes the rate-limiting step (conversion of steroidal C-19 androgens to C-18 estrogens) in estrogen biosynthesis [35–37]. Aromatization is the final step in steroid biosynthesis (Fig. 1) [38]; and, therefore, aromatase is an attractive target for selective inhibition [39, 40]. Aromatase is expressed primarily in the ovary and also in central and peripheral tissues, fat, muscle, liver, and breast [41, 42]. With increasing age, as ovarian estrogen production declines [43], the contribution of peripheral production of estrogens increases [44], and in postmenopausal women, peripheral aromatization of androstenedione produced by the adrenal gland (Fig. 1) [38] becomes the main source of endogenous estrogens [45–49]. Of note, normal and malignant breast tissue contributes to the peripheral synthesis of estrogens [14, 50–53]. Thus, expression of aromatase in breast tumors may contribute significantly to the degree of cellular exposure to estrogens [14]; therefore, it is important to target both intra-tumoral and peripheral aromatase [31].
The presence of intracellular aromatase activity could explain why estrogen concentrations are 10–20 times higher in peripheral tissue than blood in postmenopausal but not pre-menopausal women [41, 54–58]. Moreover, estrogen concentrations are higher in tumors than in surrounding non-malignant tissue [41, 54–58]. Recent research has increased understanding of how aromatase is regulated by tissue-specific promoters [59] and how genetic variation may affect the pathophysiology of estrogen-dependent disease [60]. Pharmacogenomics may become an increasingly important tool for individualizing hormonal therapy for patients with breast cancer.
Aromatase inhibitors
Modern third-generation AIs effectively block the production of estrogen without exerting effects on other steroidogenic pathways and have been heralded as a “triumph of translational oncology” [61]. The search for potent and selective inhibitors of aromatase started with the first-generation inhibitor aminoglutethimide [62]. However, aminoglutethimide lacked selectivity for aromatase [63] and inhibited biosynthesis of cortisol, aldosterone, and thyroid hormone [64] as well as aromatase; moreover, aminoglutethimide was also found to induce hepatic enzymes (Fig. 2) [65, 66]. Second-generation AIs included the nonsteroidal inhibitor fadrozole and the steroidal inhibitor formestane (4-hydroxyandrostenedione). Fadrozole was superior to aminoglutethimide in terms of potency, selectivity, and safety [67], but its selectivity was not complete and clinical trials suggested that it was no more effective than tamoxifen [68, 69].
To improve on fadrozole, Novartis synthesized a series of new compounds. Structure-activity relationship studies were then performed to identify the most potent AI from a series of benzyl-azole derivatives of fadrozole [70]. The third-generation AI letrozole (Femara®) was the result of this structure-activity approach to drug design and achieved the research goal of creating a highly potent and totally selective AI [71]. These compounds were also used to design pioneering molecular modeling techniques used to map the active site of aromatase [70, 72]. Other third-generation AIs developed during this period were the nonsteroidal agents vorozole (since discontinued) and anastrozole [73] (Fig. 2) [66] and the steroidal agent exemestane [74]. AIs have been classified as steroidal (type I; for example, exemestane) or nonsteroidal (type II; for example, letrozole and anastrozole) [75]. A comprehensive review of AIs focuses on the pharmacology and clinical development of letrozole [76].
Letrozole pharmacodynamics and pharmacokinetics
Potency
The chemical structure of letrozole (4,4′-[(1H-1,2,4-triazol-1-yl) methylene] bis-benzonitrile) is compared with other AIs in Fig. 3 [77]. The nitrogen-containing structures like the imidazoles and the triazoles bind to the iron in the heme moiety of CYP-450, whereas the cyanobenzyl moiety present in the nonsteroidal AIs such as letrozole partially mimics the steroid backbone of the enzyme’s natural substrate androstenedione. Furthermore, the triazole compound letrozole was found to be superior to other derivatives of fadrozole in terms of in vivo inhibition of aromatase [70].
Letrozole is a highly potent inhibitor of aromatase in vitro, in vivo in animals, and in humans. The relative potencies of letrozole, anastrozole, and fadrozole were determined in a variety of model cellular endocrine and tumor systems containing aromatase (hamster ovarian tissue fragments, adipose tissue fibroblasts from normal human breast, the MCF-7Ca human breast cancer cell line transfected with the human aromatase gene, and the JEG-3 human choriocarcinoma cell line) [31]. These studies showed that although letrozole and anastrozole are approximately equipotent in a cell-free aromatase system (human placental microsomes), letrozole is 10–30 times more potent than anastrozole in inhibiting intracellular aromatase in intact rodent cells, normal human adipose fibroblasts, and human cancer cell lines (Fig. 4) [31]. In several other studies, letrozole has consistently demonstrated greater potency compared with anastrozole, exemestane, formestane, and aminoglutethimide (Table 1) [31, 71, 75, 78–82].
The degree of aromatase inhibition can be determined in vivo by measuring uterine weight after treatment with a standard dose of androstenedione in immature female rats [71]. Using this assay, it was found that the in vivo potency of letrozole is more than four orders of magnitude greater than aminoglutethimide (50% effective dose [ED50], 1–3 μg/kg vs. 30 mg/kg, respectively) [71]. It has also been shown that neoadjuvant letrozole profoundly inhibits in situ aromatase activity and reduces endogenous estrogens within the breast in postmenopausal women with large primary breast cancers [75].
In postmenopausal women, letrozole achieves significantly greater plasma estrogen suppression of estrogens and greater inhibition of in vivo aromatization than anastrozole [83]. In the study, levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole (mean percentage inhibition in the whole group, 97.3%) but in none of the 12 patients during treatment with letrozole (>99.1% suppression in all patients; Wilcoxon, P = 0.0022, comparing the two drug regimens). Suppression of estrone and estrone sulfate was found to be significantly greater during treatment with letrozole compared with anastrozole (P = 0.019 and 0.0037, respectively). Another study conducted in 54 postmenopausal women with invasive breast cancer showed that more complete inhibition of aromatase was achieved with 2.5 mg of letrozole than 1 mg of anastrozole, resulting in significantly greater suppression of estradiol (P < 0.0001), the most bioactive estrogen [84]. This recent study confirms previous observations showing that letrozole produces near complete inhibition of aromatase in peripheral tissues, associated with greater suppression of estrogen than achieved with other AIs [78, 85–90].
Selectivity
Letrozole is highly selective for aromatase and unlike first- and second-generation AIs does not significantly affect cortisol, aldosterone, or thyroxine [77]. In vitro studies showed that letrozole was more than three orders of magnitude more selective than aminoglutethimide in its effects on progesterone and corticosterone production, and more than 300-fold more selective against aldosterone than fadrozole [71, 78]. In vivo adrenocorticotrophic hormone (ACTH) stimulation tests in rats showed that letrozole had no significant effect on either aldosterone or corticosterone levels, even at a dose 1,000 times greater than that required for inhibition of aromatase [71].
The selectivity of letrozole has been demonstrated in clinical studies in postmenopausal women. These studies showed that letrozole has no effect on the plasma levels of 17α-OH progesterone, thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), or androstenedione and does not affect normal urine electrolyte excretion or thyroid function [86, 91–93]. Of note, the vast majority of patients treated with letrozole have a normal response to synthetic ACTH [86].
Anti-tumor activity in vivo
The potent anti-tumor effects of letrozole have been demonstrated in several animal models [77, 78, 94]. Letrozole induced complete regression of estrogen-dependent, 9,10-dimethylbenz-a-anthracene (DMBA)-induced mammary tumors in adult female rats [95]. The ED50 for letrozole was determined to be 10–30 μg/kg/day.
The use of MCF-7 cells transfected with human aromatase gene (MCF-7Ca) and implanted into athymic nude mice has proved to be an effective in vivo model for predicting clinical results with AIs [61, 96, 97]. Using this model, it has been shown that letrozole produces dose-dependent inhibition of tumor growth, resulting in complete inhibition at a daily dose of 10 μg/animal/day [94, 98]. Comparative studies using the MCF-7Ca model have shown that letrozole is more effective at suppressing tumor growth than the pure anti-estrogen fulvestrant and the SERM tamoxifen [99]. While anastrozole was also better than fulvestrant and tamoxifen in suppressing tumor growth, only letrozole was shown to induce tumor regression [99].
Another study, also using the MCF-7Ca model, demonstrated that letrozole potently inhibits mammary tumor growth but does not have the estrogenic effects of tamoxifen, as measured by its uterotrophic effects [100]. The observation that tamoxifen has an agonist effect even when estrogen synthesis is inhibited by letrozole suggests that there may be a degree of antagonism between these compounds [100]. Interestingly, studies in the MCF-7Ca model showed that letrozole is more effective as monotherapy than when combined with tamoxifen [80, 101]. In the study reported by Long et al. [101] tumor volume doubling times were 3–4 weeks in controls, 16 weeks with tamoxifen alone, 18 weeks with tamoxifen plus letrozole, and 34 weeks with letrozole alone. First-line treatment with letrozole was shown to be significantly superior to treatment with tamoxifen alone or with the two drugs combined (at week 16, both P < 0.001). Tumors that progressed during treatment with tamoxifen remained sensitive to second-line letrozole therapy, whereas tumors that progressed on letrozole did not respond to second-line treatment with tamoxifen or fulvestrant. In another series of experiments conducted by the same group using the MCF-7Ca model, letrozole was even effective as third-line therapy for a limited period when administered after treatment with tamoxifen and exemestane [102]. The studies showed that although exemestane was more effective than tamoxifen in controlling tumor growth, letrozole as first-line therapy was the most effective treatment overall, both in terms of the degree of tumor suppression and the length of effectiveness of treatment [102].
The potential of letrozole as a chemopreventive agent was investigated in an in vivo model using aromatase-transgenic female mice [103]. The model provided evidence to show that aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes that can be completely abrogated by treatment with letrozole. Carcinogenicity studies have also found that letrozole decreases the incidence of spontaneous mammary tumors and granular cell tumors in rats [104].
Pharmacokinetics of letrozole
Clinical pharmacokinetic studies of letrozole have been conducted in healthy volunteers [105–107] and in patients with breast cancer [108, 109]. Following oral administration, letrozole is rapidly and completely absorbed (mean absolute bioavailability of 99.9%) and extensively distributed to tissues. It has a large apparent volume of distribution at steady state (1.87 l/kg [range, 1.47–3.24]), and approximately 60% is bound to plasma proteins, mainly to albumin (55%). The terminal half-life (T1/2) of letrozole is 42 h. The terminal T1/2 was observed to be longer and area under the curve (AUC) greater in patients with breast cancer than in healthy volunteers, possibly due to reduction in metabolic clearance [109]. The major route of elimination of letrozole is metabolism by CYP-450 isoenzymes (CYP 3A4 and CYP 2A6) into an inactive carbinol metabolite. Systemic exposure to metabolites is, therefore, low. Steady-state concentrations of letrozole are reached after 2–6 weeks and maintained for long periods with no evidence of drug accumulation.
In marked contrast to the first-generation AI aminoglutethimide, no significant drug interactions have been reported for letrozole; however, when combined with tamoxifen, letrozole plasma concentrations are reduced by between 35% and 40% [110]. Age does not have an effect on the pharmacokinetics of letrozole. Exposure to letrozole, measured by AUC, is increased in renally impaired subjects but remains in the range seen in subjects without impaired function. However, hepatic impairment can markedly increase the T1/2 of letrozole, and caution is required in such patients.
Differences in pharmacokinetics, including uptake rates, elimination T1/2, and metabolism and clearance exist between AIs and have been reviewed by Lønning et al. [111]. The clinical significance of such differences is not known.
Clinical development of letrozole
Letrozole entered clinical trials on the basis of its high potency and selectivity for aromatase, the demonstration of unsurpassed anti-tumor effects in models of human breast cancer, and the development of a convenient oral formulation. Daily doses of 0.1–5 mg have been shown to suppress estradiol, estrone, and estrone sulfate plasma concentrations by 75–95% from baseline, while doses >0.5 mg suppress estrogens to below limit of detection [92, 112, 113]. Based on pharmacokinetic and pharmacodynamic studies, the recommended dose of letrozole is one 2.5 mg tablet once daily.
Preclinical models [97, 101] successfully predicted that letrozole would be superior to tamoxifen, the previous gold standard in the treatment of breast cancer. An extensive program of clinical trials has been conducted with letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women. The first randomized controlled trials demonstrated consistent superiority for letrozole compared with megestrol acetate, aminoglutethimide, and tamoxifen in patients with advanced breast cancer [114–118]. The clinical efficacy of letrozole in advanced breast cancer is described in a review by Dr. Mouridsen in this supplement.
Preclinical MCF-7Ca models have also predicted that letrozole should be clinically more effective than other less potent third-generation AIs [99, 102]. Letrozole (2.5 mg/day) and anastrozole (1 mg/day) were directly compared in a randomized, open-label phase IIIb/IV study involving 713 postmenopausal women with advanced breast cancer previously treated with an anti-estrogen [119]. While there was no difference between the treatment arms in the time to progression, letrozole produced a significantly higher overall response rate than anastrozole (19.1 vs. 12.3%, P = 0.013). Letrozole and anastrozole are currently being compared in a large randomized head-to-head trial in early breast cancer (ClinicalTrials.gov identifier NCT00248170) [120]. A review by O’Shaughnessy in this supplement provides the rationale for this trial and a description of its design.
The clinical benefits of letrozole in early breast cancer have already been demonstrated in landmark randomized clinical trials. MA.17 was the first trial to show improved clinical outcomes with extended adjuvant hormone therapy [121]. In this trial, letrozole given after initial adjuvant therapy with tamoxifen significantly improved disease-free survival compared with placebo [121, 122]. Full details of this trial are provided in a review by Dr. Goss in this supplement.
Subsequently, the Breast International Group 1-98 trial provided high-level evidence for the superiority of letrozole over tamoxifen as initial adjuvant therapy [123]. A detailed description of this ongoing trial, which will also help to define the optimal sequence for hormone therapies in hormone-responsive early breast cancer, is provided in a review by Dr. Thürlimann in this supplement. Letrozole has also demonstrated superior efficacy compared with tamoxifen when used as neoadjuvant therapy [124]. This treatment setting is particularly interesting in terms of drug development because the effects of hormone therapy on breast tumors can be detected early and may be predictive of long-term outcome [125].
Conclusions
Letrozole is a highly potent and selective AI that inhibits the enzyme activity of intracellular aromatase at the major sites where it is found, resulting in almost complete suppression of whole body aromatization. By effectively blocking estrogen synthesis, letrozole inhibits the growth or induces the regression of hormone-responsive breast tumors in vivo. Estrogen is implicated as a major risk factor in the majority of breast cancers; therefore, use of the most potent AI is a logical treatment strategy.
Studies conducted using in vitro and in vivo models have demonstrated that letrozole is the most potent of the third-generation AIs. Preclinical data obtained from MCF-7Ca xenograft models suggest that the greater potency of letrozole compared with anastrozole and exemestane may translate into clinically meaningful differences in postmenopausal women with hormone-responsive breast cancer. These models accurately predicted that letrozole would be more effective than tamoxifen in the clinical setting. The superiority of letrozole over tamoxifen has been consistently demonstrated in advanced and early breast cancer [118, 123]. Outstanding clinical questions, including what is the most effective AI and what is the optimal sequence for adjuvant hormonal therapy, will be answered by the results of ongoing trials involving letrozole.
In conclusion, experimental data indicating that letrozole efficiently inhibits aromatase activity have been confirmed clinically, leading to approved indications across the spectrum of breast cancer. The broad range of indications for letrozole in unique clinical settings is reshaping the management of hormone-sensitive breast cancer.
References
Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282
Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, Stanczyk FZ, Stephenson HE Jr, Falk RT, Miller R, Schatzkin A, Allen DS, Fentiman IS, Key TJ, Wang DY, Dowsett M, Thomas HV, Hankinson SE, Toniolo P, Akhmedkhanov A, Koenig K, Shore RE, Zeleniuch-Jacquotte A, Berrino F, Muti P, Micheli A, Krogh V, Sieri S, Pala V, Venturelli E, Secreto G, Barrett-Connor E, Laughlin GA, Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE, Cauley JA, Kuller LH, Cummings SR, Helzlsouer KJ, Alberg AJ, Bush TL, Comstock GW, Gordon GB, Miller SR, Longcope C; Endogenous Hormones Breast Cancer Collaborative Group (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226
Yue W, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL (2003) Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. J Steroid Biochem Mol Biol 86:477–486
Clemons M, Goss P (2001) Estrogen and the risk of breast cancer. N Engl J Med 344:276–285. Erratum in: N Engl J Med (2001) 344:1804
Key T, Appleby P, Barnes I, Reeves G; Endogenous Hormones, Breast Cancer Collaborative Group (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94:606–616
Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047–1059. Erratum in: Lancet (1997) 350:1484
Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R (2000) Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283:485–491. Erratum in: JAMA (2000) 284:2597
Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F (2005) Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 114:448–454
Beral V; Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419–427. Erratum in: Lancet (2003) 362:1160
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S; Women’s Health Initiative Steering Committee (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712
Collaborative Group on Hormonal Factors in Breast Cancer (1996) Breast cancer and hormonal contraceptives: further results. Contraception 54(Suppl 3):1S–106S
Huang WY, Newman B, Millikan RC, Schell MJ, Hulka BS, Moorman PG (2000) Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am J Epidemiol 151:703–714
Miller WR, Forrest AP (1974) Oestradiol synthesis by a human breast carcinoma. Lancet 2:866–868
Miller WR, Telford J, Dixon JM, Hawkins RA (1985) Androgen receptor activity in human breast cancer and its relationship with oestrogen and progestogen receptor activity. Eur J Cancer Clin Oncol 21:539–542
Miller WR, O’Neill J (1987) The importance of local synthesis of estrogen within the breast. Steroids 50:537–548
Devanesan P, Santen RJ, Bocchinfuso WP, Korach KS, Rogan EG, Cavalieri E (2001) Catechol estrogen metabolites and conjugates in mammary tumors and hyperplastic tissue from estrogen receptor-alpha knock-out (ERKO)/Wnt-1 mice: implications for initiation of mammary tumors. Carcinogenesis 22:1573–1576
Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, Johansson SL, Patil KD, Gross ML, Gooden JK, Ramanathan R, Cerny RL, Rogan EG (1997) Molecular origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci USA 94:10937–10942
Santen RJ, Lobenhofer EK, Afshari CA, Bao Y, Song RX (2005) Adaptation of estrogen-regulated genes in long-term estradiol deprived MCF-7 breast cancer cells. Breast Cancer Res Treat 94:213–223
Webb P, Nguyen P, Valentine C, Lopez GN, Kwok GR, McInerney E, Katzenellenbogen BS, Enmark E, Gustafsson JA, Nilsson S, Kushner PJ (1999) The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 13:1672–1685
Sabbah M, Courilleau D, Mester J, Redeuilh G (1999) Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc Natl Acad Sci USA 96:11217–11222
Levin ER (2003) Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 17:309–317
Stoica GE, Franke TF, Moroni M, Mueller S, Morgan E, Iann MC, Winder AD, Reiter R, Wellstein A, Martin MB, Stoica A (2003) Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene 22:7998–8011
Sekeris CE (1990) The mitochondrial genome: a possible primary site of action of steroid hormones. In vivo 4:317–320
Liao JK (2003) Cross-coupling between the oestrogen receptor and phosphoinositide 3-kinase. Biochem Soc Trans 31:66–70
Aronica SM, Kraus WL, Katzenellenbogen BS (1994) Estrogen action via the cAMP signalling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 91:8517–8521
Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F (1996) Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J 15:1292–1300
Song RX-D, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ (2002) Linkage of rapid estrogen action to MAPK activation by ERα-Shc association and Shc pathway activation. Mol Endocrinol 16:116–127
Razandi M, Pedram A, Greene GL, Levin ER (1999) Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol 13:307–319
Razandi M, Pedram A, Levin ER (2000) Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer. Mol Endocrinol 14:1434–1447
Bhatnagar AS, Brodie AMH, Long BJ, Evans DB, Miller WR (2001) Intracellular aromatase and its relevance to the pharmacological efficacy of aromatase inhibitors. J Steroid Biochem Mol Biol 76:199–202
Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, McCue BL, Wakeling AE, McClelland RA, Manning DL, Nicholson RI (1995) Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 87:746–750
Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, Schiff R, Osborne CK, Dowsett M (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23:2469–2476
Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ; Panel members (2005) Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569–1583
Ryan KJ (1959) Biological aromatization of steroids. J Biol Chem 234:268–272
Meigs RA, Ryan KJ (1968) Cytochrome P-450 and steroid biosynthesis in the human placenta. Biochim Biophys Acta 165:476–482
Fishman J, Raju MS (1981) Mechanism of estrogen biosynthesis. Stereochemistry of C-1 hydrogen elimination in the aromatization of 2 beta-hydroxy-19-oxoandrostenedione. J Biol Chem 256:4472–4477
Lønning PE (2004) Aromatase inhibitors in breast cancer. Endocr Relat Cancer 11:179–189
Brodie AM, Schwarzel WC, Shaikh AA, Brodie HJ (1977) The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen-dependent processes in reproduction and breast cancer. Endocrinology 100:1684–1695
Brodie AM, Brodie HJ, Garrett WM, Hendrickson JR, Marsh DA, Tsai-Morris CH (1982) Effect of an aromatase inhibitor, 1,4,6-androstatriene-3,17-dione, on 7,12-dimethylbenz[a]anthracene-induced mammary tumors in the rat and its mechanism of action in vivo. Biochem Pharmacol 31:2017–2023
Longcope C, Pratt JH, Schneider SH, Fineberg SE (1978) Aromatization of androgens by muscle and adipose tissue in vivo. J Clin Endocrinol Metab 46:146–152
Miller WR (1991) Aromatase activity in breast tissue. J Steroid Biochem Mol Biol 39:783–790
Couzinet B, Meduri G, Lecce MG, Young J, Brailly S, Loosfelt H, Milgrom E, Schaison G (2001) The postmenopausal ovary is not a major androgen-producing gland. J Clin Endocrinol Metab 86:5060–5066
Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC (1974) Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab 38:476–479
Schweikert HU, Milewich L, Wilson JD (1976) Aromatization of androstenedione by cultured human fibroblasts. J Clin Endocrinol Metab 43:785–795
Smuk M, Schwers J (1977) Aromatization of androstenedione by human adult liver in vitro. J Clin Endocrinol Metab 45:1009–1012
Perel E, Killinger DW (1979) The interconversion and aromatization of androgens by human adipose tissue. J Steroid Biochem 10:623–627
Frisch RE, Canick JA, Tulchinsky D (1980) Human fatty marrow aromatizes androgen to estrogen. J Clin Endocrinol Metab 51:394–396
Matsumine H, Hirato K, Yanaihara T, Tamada T, Yoshida M (1986) Aromatization by skeletal muscle. J Clin Endocrinol Metab 63:717–720
Perel E, Wilkins D, Killinger DW (1980) The conversion of androstenedione to estrone, estradiol, and testosterone in breast tissue. J Steroid Biochem 13:89–94
Reed MJ, Owen AM, Lai LC, Coldham NG, Ghilchik MW, Shaikh NA, James VH (1989) In situ oestrone synthesis in normal breast and breast tumour tissues: effect of treatment with 4-hydroxyandrostenedione. Int J Cancer 44:233–237
Miller WR, Anderson TJ, Jack WJ (1990) Relationship between tumour aromatase activity, tumour characteristics and response to therapy. J Steroid Biochem Mol Biol 37:1055–1059
Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER (1993) A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 77:1622–1628. Erratum in: J Clin Endocrinol Metab (1994) 78:494
Edery M, Goussard J, Dehennin L, Scholler R, Reiffsteck J, Drosdowsky MA (1981) Endogenous oestradiol-17beta concentration in breast tumours determined by mass fragmentography and by radioimmunoassay: relationship to receptor content. Eur J Cancer 17:115–120
Miller WR, Hawkins RA, Forrest AP (1981) Steroid metabolism and oestrogen receptors in human breast carcinomas. Eur J Cancer Clin Oncol 17:913–917
van Landeghem AAI, Poortman J, Nabuurs M, Thijssen JHH (1985) Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res 45:2900–2906
Vermeulen A, Deslypere JP, Paridaens R, Leclercq G, Roy F, Heuson JC (1986) Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women. Eur J Cancer Clin Oncol 22:515–525
Geisler J, Detre S, Berntsen H, Ottestad L, Lindtjørn B, Dowsett M, Lønning PE (2001) Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels and proliferation markers in patients with locally advanced breast cancer. Clin Cancer Res 7:1230–1236
Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, Deb S (2005) Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57:359–383
Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L, Eckloff BW, Schaid D, Wieben ED, Adjei AA, Weinshilboum RM (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65:11071–11082
Swain SM (2005) Aromatase inhibitors—a triumph of translational oncology. N Engl J Med 353:2807–2809
Santen RJ, Santner S, Davis B, Veldhuis J, Samojlik E, Ruby E (1978) Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J Clin Endocrinol Metab 47:1257–1265
Hausler A, Schenkel L, Krahenbuhl C, Monnet G, Bhatnagar AS (1989) An in vitro method to determine the selective inhibition of estrogen biosynthesis by aromatase inhibitors. J Steroid Biochem 33:125–131
Pittman JA, Brown RW (1966) Antithyroid and antiadrenocortical activity of aminoglutethimide. J Clin Endocrinol Metab 26:1014–1016
Murray M, Cantrill E, Farrell GC (1993) Induction of cytochrome P450 2B1 in rat liver by the aromatase inhibitor aminoglutethimide. J Pharmacol Exp Ther 265:477–481
Santen RJ, Harvey HA (1999) Use of aromatase inhibitors in breast carcinoma. Endocr Relat Cancer 6:75–92
Santen RJ, Demers LM, Lynch J, Harvey H, Lipton A, Mulagha M, Hanagan J, Garber JE, Henderson IC, Navari RM, Miller AA (1991) Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor. J Clin Endocrinol Metab 73:99–106
Falkson CI, Falkson HC (1996) A randomised study of CGS 16949A (fadrozole) versus tamoxifen in previously untreated postmenopausal patients with metastatic breast cancer. Ann Oncol 7:465–469
Thürlimann B, Beretta K, Bacchi M, Castiglione-Gertsch M, Goldhirsch A, Jungi WF, Cavalli F, Senn H-J, Fey M, Löhnert T (1996) First-line fadrozole HCI (CGS 16949A) versus tamoxifen in postmenopausal women with advanced breast cancer. Prospective randomised trial of the Swiss Group for Clinical Cancer Research SAKK 20/88. Ann Oncol 7:471–479
Lang M, Batzl C, Furet P, Bowman R, Häusler A, Bhatnagar AS (1993) Structure-activity relationships and binding model of novel aromatase inhibitors. J Steroid Biochem Mol Biol 44:421–428
Bhatnagar AS, Häusler A, Schieweck K, Lang M, Bowman R (1990) Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol 37:1021–1027
Furet P, Batzl C, Bhatnagar A, Francotte E, Rihs G, Lang M (1993) Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds. J Med Chem 36:1393–1400
Plourde PV, Dyroff M, Dukes M (1994) Arimidex: a potent and selective fourth-generation aromatase inhibitor. Breast Cancer Res Treat 30:103–111
Giudici D, Ornati G, Briatico G, Buzzetti F, Lombardi P, di Salle E (1988) 6-Methylenandrosta-1,4-diene-3,17-dione (FCE 24304): a new irreversible aromatase inhibitor. J Steroid Biochem 30:391–394
Miller WR (1999) Biology of aromatase inhibitors: pharmacology/endocrinology within the breast. Endocr Relat Cancer 6:187–195
Njar VC, Brodie AM (1999) Comprehensive pharmacology and clinical efficacy of aromatase inhibitors. Drugs 58:233–255
Haynes BP, Dowsett M, Miller WR, Dixon JM, Bhatnagar AS (2003) The pharmacology of letrozole. J Steroid Biochem Mol Biol 87:35–45
Bhatnagar AS, Batzl C, Hausler A, Schieweck K, Lang M, Trunet PF (1996) Pharmacology of non-steroidal aromatase inhibitors. In: Pasqualini JR, Katzenellenbogen BS (eds) Hormone-dependent cancer. Marcel Dekker, New York, pp 155–168
Long BJ, Tilghman SL, Yue W, Thiantanawat A, Grigoryev DN, Brodie AM (1998) The steroidal antiestrogen ICI 182,780 is an inhibitor of cellular aromatase activity. J Steroid Biochem Mol Biol 67:293–304
Lu Q, Liu Y, Long BJ, Grigoryev D, Gimbel M, Brodie A (1999) The effect of combining aromatase inhibitors with antiestrogens on tumor growth in a nude mouse model for breast cancer. Breast Cancer Res Treat 57:183–192
Odum J, Ashby J (2002) Detection of aromatase inhibitors in vitro using rat ovary microsomes. Toxicol Lett 129:119–122
Kao YC, Cam LL, Laughton CA, Zhou D, Chen S (1996) Binding characteristics of seven inhibitors of human aromatase: a site-directed mutagenesis study. Cancer Res 56:3451–3460
Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE (2002) Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20:751–757
Dixon JM, Renshaw L, Young O, Murray J, Macaskill EJ, McHugh M, Folkerd E, Cameron D, Dowsett M (2006) Letrozole suppresses plasma oestradiol (E2) levels more completely than anastrozole in postmenopausal women with breast cancer [abstract]. J Clin Oncol 24(Suppl 18):552
Demers LM, Lipton A, Harvey HA, Kambic KB, Grossberg H, Brady C, Santen RJ (1993) The efficacy of CGS 20267 in suppressing estrogen biosynthesis in women with advanced stage breast cancer. J Steroid Biochem Mol Biol 44:687–691
Demers LM (1994) Effects of fadrozole (CGS 16949A) and letrozole (CGS 20267) on the inhibition of aromatase activity in breast cancer patients. Breast Cancer Res Treat 30:95–102
Dowsett M, Jones A, Johnston SRD, Jacobs S, Trunet P, Smith IE (1995) In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1:1511–1515
Geisler J, King N, Dowsett M, Ottestad L, Lundgren S, Walton P, Kormeset PO, Lønning PE (1996) Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer 74:1286–1291
Geisler J, King N, Anker G, Ornati G, Di Salle E, Lønning PE, Dowsett M (1998) In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res 4:2089–2093
Bernardi A, Zamagni C, Di Fabio F, Piana E, Martoni A, Vecchi F (2002) Randomized comparative study on estrogen suppression induced by 3 different aromatase inhibitors in postmenopausal patients with advanced breast cancer [abstract]. Proc Am Soc Clin Oncol 21:217
Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M (1993) Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women. J Clin Endocrinol Metab 77:324–331
Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M (1993) Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res 53:266–270
Bajetta E, Zilembo N, Dowsett M, Guillevin L, Di Leo A, Celio L, Martinetti A, Marchiano A, Pozzi P, Stani S, Bichisao E (1999) Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer 35:208–213
Brodie A, Lu Q, Liu Y, Long B (1999) Aromatase inhibitors and their antitumor effects in model systems. Endocr Relat Cancer 6:205–210
Schieweck K, Bhatnagar AS, Batzl C, Lang M (1993) Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol 44:633–636
Yue W, Brodie A (1993) MCF-7 human breast carcinomas in nude mice as a model for evaluating aromatase inhibitors. J Steroid Biochem Mol Biol 44:671–673
Yue W, Zhou D, Chen S, Brodie A (1994) A new nude mouse model for postmenopausal breast cancer using MCF-7 cells transfected with the human aromatase gene. Cancer Res 54:5092–5095
Jelovac D, Macedo L, Goloubeva OG, Handratta V, Brodie AMH (2005) Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res 65:5439–5444
Lu Q, Yue W, Wang J, Liu Y, Long B, Brodie A (1998) The effects of aromatase inhibitors and antiestrogens in the nude mouse model. Breast Cancer Res Treat 50:63–71
Yue W, Wang J, Savinov A, Brodie A (1995) Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model. Cancer Res 55:3073–3077
Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N, Ragaz J, Goloubeva OG, Brodie AM (2004) Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model. J Natl Cancer Inst 96:456–465
Jelovac D, Macedo L, Handratta V, Long BJ, Goloubeva OG, Ingle JN, Brodie AMH (2004) Effects of exemestane and tamoxifen in a postmenopausal breast cancer model. Clin Cancer Res 10:7375–7381
Tekmal RR, Kirma N, Gill K, Fowler K (1999) Aromatase overexpression and breast hyperplasia, an in vivo model—continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands. Endocr Relat Cancer 6:307–314
Markovits JE, Sahota PS (2000) Aromatase inhibitors prevent spontaneous granular cell tumors in the distal female reproductive tract of Sprague-Dawley rats. Toxicol Pathol 28:799–801
Sioufi A, Gauducheau N, Pineau V, Marfil F, Jaouen A, Cardot JM, Godbillon J, Czendlik C, Howald H, Pfister C, Vreeland F (1997a) Absolute bioavailability of letrozole in healthy postmenopausal women. Biopharm Drug Dispos 18:779–789
Sioufi A, Sandrenan N, Godbillon J, Trunet P, Czendlik C, Howald H, Pfister C, Ezzet F (1997b) Comparative bioavailability of letrozole under fed and fasting conditions in 12 healthy subjects after a 2.5 mg single oral administration. Biopharm Drug Dispos 18:489–497
Colussi DM, Parisot CY, Lefèvre GY (1998) Plasma protein binding of letrozole, a new nonsteroidal aromatase enzyme inhibitor. J Clin Pharmacol 38:727–735
Dowsett M, Pfister C, Johnston SRD, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE (1999) Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res 5:2338–2343
Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, Duval M, Hornberger U (2001) Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara®) in breast cancer patients. Biopharm Drug Dispos 22:191–197
Dowsett M, Pfister CU, Johnston SRD, Houston SJ, Miles DW, Verbeek JA, Smith IE (1997) Pharmacokinetic interaction between letrozole and tamoxifen in postmenopausal patients with advanced breast cancer. The Breast 6:245
Lønning P, Pfister C, Martoni A, Zamagni C (2003) Pharmacokinetics of third-generation aromatase inhibitors. Semin Oncol 30(Suppl 14):23–32
Femara prescribing information (2005) Novartis
Trunet PF, Mueller P, Bhatnagar AS, Dickes I, Monnet G, White G (1993) Open dose-finding study of a new potent and selective nonsteroidal aromatase inhibitor, CGS 20 267, in healthy male subjects. J Clin Endocrinol Metab 77:319–323
Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz J, Xiang X, Brady C (2001) Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19:3357–3366
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U, Trunet PF (1998) Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16:453–461
Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi F, Bodrogi I, Ludwig H, Reichardt P, O’Higgins N, Romieu G, Friederich P, Lassus M; for the Letrozole International Trial Group (AR/BC3) (1998) Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 9:639–645
Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M (2001) Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:2596–2606. Erratum in: J Clin Oncol (2001) 19:3302
Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21:2101–2109
Rose C, Vtoraya O, Pluzanska A, Davidson N, Gershanovich M, Thomas R, Johnson S, Caicedo JJ, Gervasio H, Manikhas G, Ben Ayed F, Burdette-Radoux S, Chaudri-Ross HA, Lang R (2003) An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer 39:2318–2327
DeBoer R, Burris H, Monnier A, Mouridsen H, O’Shaughnessy J, McIntyre K, Pritchard K, Smith I, Yardley D, on behalf of the H2H trial steering committee (2006) The head to head trial: letrozole vs anastrozole as adjuvant treatment of postmenopausal patients with node positive breast cancer [abstract]. J Clin Oncol 24(18S):582s. Abstract 10672
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Eng J Med 349:1793–1802
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271
Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardly A, Price KN, Goldhirsch A; Breast International Group (BIG) 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757
Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Jänicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M (2001) Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 19:3808–3816
Dowsett M, A’Hern R, Smith I; on behalf of the IMPACT Trialists (2005) Ki67 after 2 weeks endocrine treatment predicts relapse-free survival (RFS) in the IMPACT trial [abstract]. Breast Cancer Res Treat 94(Suppl 1):45
Author information
Authors and Affiliations
Corresponding author
Additional information
An erratum to this article can be found at http://dx.doi.org/10.1007/s10549-007-9857-4
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 2.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this licence, visit https://creativecommons.org/licenses/by-nc/2.0/.
About this article
Cite this article
Bhatnagar, A.S. The discovery and mechanism of action of letrozole. Breast Cancer Res Treat 105 (Suppl 1), 7–17 (2007). https://doi.org/10.1007/s10549-007-9696-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-007-9696-3