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

Gershanovich, M.; Chaudri, H. A.; Ayres-de-Campos, Diogo; Lurie, H.; Bonaventura, Antonino; Jeffrey, M.; Buzzi, Franco; Bodrogi, I.; Ludwig, H; Reichardt, Peter; O’Higgins, N.; Romieu, Gilles; Friederich, Philip W.; Lassus, M.

doi:10.1023/a:1008226721932

Cited by 235 publications

(105 citation statements)

References 26 publications

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“…greater than 99% suppression) and activity was barely detectable in the other two. Very little difference was apparent between the 0.5 mg and 2.5 mg/day doses of letrozole, although it is of interest that substantial differences have been noted in the clinical activity of these doses (Dombernowsky et al 1998, Gershanovich et al 1998.…”

Section: Aromatase Inhibitionmentioning

confidence: 99%

“…As a result of this pharmacokinetic interaction, the plasma concentrations of letrozole are equivalent to those predicted to be achieved by 1.5-2.0 mg/day when given alone. It is possible that this may be of clinical importance because, as mentioned above, there is a dose-response relationship between letrozole 0.5 mg/day and 2.5 mg/day (Dombernowsky et al 1998, Gershanovich et al 1998. Thus, with the combination, the complete additive efficacy of letrozole may not be achieved.…”

Section: Pharmacokinetic Interactionsmentioning

confidence: 99%

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Drug and hormone interactions of aromatase inhibitors.

Dowsett¹

1999

Endocrine-Related Cancer

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The clinical development of aromatase inhibitors has been largely confined to postmenopausal breast cancer patients and strongly guided by pharmacological data. Comparative oestrogen suppression has been helpful in circumstances in which at least one of the comparitors has caused substantially non-maximal aromatase inhibition. However, the triazole inhibitors, letrozole and anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition. Comparisons between these drugs therefore require more sensitive approaches such as the direct measurement of enzyme activity by isotopic means. None of these three agents has significant effects on other endocrine pathways at its clinically applied doses. Pharmacokinetic analyses of the combination of tamoxifen and letrozole have revealed that these drugs interact, resulting in letrozole concentrations approximately 35-40% lower than when Endocrine-Related Cancer (1999) 6 181-185 letrozole is used alone.

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Section: Aromatase Inhibitionmentioning

confidence: 99%

Section: Pharmacokinetic Interactionsmentioning

confidence: 99%

Drug and hormone interactions of aromatase inhibitors.

Dowsett¹

1999

Endocrine-Related Cancer

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“…For the purposes of the study, we used letrozole (Femara), an active, nonsteroidal, nitrogen-containing compound which selectively inhibits cytochrome P450 aromatase by binding its heme iron. Letrozole has no estrogenic, anti-estrogenic or antiandrogenic properties at doses required to inhibit estrogen synthesis (Gershanovich et al 1998). It is therefore useful for the study of the cellular mechanisms in the mice growth plate and for comparison of the action of testosterone and estrogen.…”

Section: Introductionmentioning

confidence: 99%

The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice

Eshet

Maor²,

Ari³

et al. 2004

Journal of Endocrinology

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Sex hormones may influence longitudinal growth, either indirectly, by affecting the growth-hormone-insulin-like growth factor I (IGF-I) axis, or directly, by affecting changes within the epiphyseal growth plate (EGP). The aim of the present study was to investigate the effects of letrozole, an aromatase inhibitor, on longitudinal growth and changes in the EGP in vivo. Eighteen peripubertal male mice were divided into three groups. The first group was killed at baseline, the second was injected with letrozole (Femara) s.c., 2 mg/kg body weight/day, for 10 days, and the third was injected with the vehicle alone. Serum testosterone levels were found to be significantly higher in the treated group than in the controls. Letrozole induced a significant increase in body weight, tail length and serum growth hormone level, but had no significant effect on the level of serum IGF-I. On histomorphometric study, there was a significant increase (12%) in EGP height in the treated animals compared with controls. Immunohistochemistry showed a 3·4-fold letrozole-induced increase in the proliferation of the EGP chondrocytes, as estimated by the number of proliferation cell nuclear antigen-stained cells, and a decrease in the differentiation of the EGP chondrocytes, as estimated by type X collagen staining. Letrozole did not interfere with type II collagen levels. The study group also showed a twofold increase in the number of IGF-I receptor-positive cells compared with controls. In conclusion, the aromatase inhibitor, letrozole, appears to increase the linear growth potential of the EGP in mice.

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“…In an early, open-label, randomized, comparative trial of letrozole (n = 185, 2.5 mg letrozole; n = 192, 0.5 mg letrozole) with aminoglutethimide (n = 178) in women with advanced breast cancer, letrozole at 2.5 or 0.5 mg resulted in an objective response rate (ORR) of 19.5% and 16.7%, respectively, versus only 12.4% for aminoglutethimide, and there was a significantly better time to progression (RR 0.72; 95% CI: 0.57-0.92; P = 0.008), time to treatment failure (RR 0.70; 95% CI: 0.55-0.88; P = 0.003), and OS (RR 0.64; 95% CI: 0.49-0.85; P = 0.002) for letrozole 2.5 mg versus aminoglutethimide. 33 Another study of advanced breast cancer patients compared letrozole (n = 356) with anastrozole (n = 357) as second-line therapy. 34 In this study, median time to progression, the primary endpoint, was identical for the two drugs (5.7 months).…”

Section: Binding and Potency Of Anastrozole And Letrozolementioning

confidence: 99%

FACE: the barefaced facts of AI potency

Monnier¹

2010

CMAR

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Abstract:The use of third-generation aromatase inhibitors (AIs), such as anastrozole and letrozole, as initial adjuvant hormonal therapy in postmenopausal women (PMW) with hormone receptor-positive (HR+) breast cancer offers a significant benefit over tamoxifen for reducing recurrence risk. Clinical studies, including the Arimidex Tamoxifen Alone or in Combination (ATAC) and the Breast International Group (BIG) 1-98 trials, have proven that both anastrozole and letrozole are, respectively, superior to tamoxifen in improving disease-free survival. Although differing in design, objectives, and follow-up time, these trials offer some insight into the comparative clinical efficacy of these two nonsteroidal AIs. In particular, results from BIG 1-98 show that letrozole significantly reduces early distant metastatic (DM) events, which constitute the majority of early recurrence events. Subsequently, there is a beneficial overall survival effect emerging in the trial, whereas survival is unchanged with anastrozole after 100 months of follow-up in ATAC. Significant differences in the potency of these two drugs, vis-à-vis their degree of aromatase inhibition, have been observed in comparative trials and show that letrozole causes a more complete suppression of estrogen levels than does anastrozole. Whether this difference in potency is relevant to reductions in DM events during adjuvant therapy remains unclear. The Femara Anastrozole Clinical Evaluation trial is addressing this issue in a more unequivocal manner by comparing initial adjuvant treatment with anastrozole or letrozole in a population of breast cancer patients at high risk of recurrence: PMW with HR+ disease and axillary lymph node involvement.

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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

Abstract: Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-oestrogens.

Cited by 235 publications

References 26 publications

Drug and hormone interactions of aromatase inhibitors.

Drug and hormone interactions of aromatase inhibitors.

The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice

FACE: the barefaced facts of AI potency

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