A randomised study of the effects of letrozole and anastrozole on oestrogen receptor positive breast cancers in postmenopausal women. Breast Cancer Res Treat

Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 04/2008; 114(3):495-501. DOI: 10.1007/s10549-008-0027-0
Source: PubMed


Changes in proliferation as measured by Ki67 occur within 14 days of starting treatment with an aromatase inhibitor and these changes have been shown to be predictors of long term outcome. This study aimed to compare changes in proliferation following 14 days of treatment with anastrozole and letrozole.
Two hundred and six women with 209 estrogen receptor (ER) positive operable breast cancers (three bilateral) were randomly allocated to receive either 14 days treatment with 2.5 mg of letrozole or 1 mg of anastrozole prior to surgery. Changes in expression of estrogen (ER) and progesterone receptors (PgR) as assessed by ALLRED scores and proliferation as assessed by Ki67 were analysed. The HER2 status of each tumour was also assessed using a combination of the Hercept test and FISH.
Both letrozole and anastrozole reduced ER expression (ALLRED score) by a mean of 0.32 (0.20-0.44), P<0.001 and PgR fell by a mean of 2.54 (2.20-2.89) P<0.0001. Letrozole reduced proliferation from a geometric mean of 6.37% to 0.81%, P<0.0001 and anastrozole reduced proliferation from 5.81% to 0.77%, P<0.0001. There was no differences between drugs in the fall in ER, PgR or proliferation. Both letrozole and anastrozole produced significant falls in proliferation in both HER2 positive and HER2 negative cancers, all P<0.001.
14 days of both letrozole and anastrozole reduces proliferation, ER and PgR expression. No significant difference between these two drugs was identified.

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    • "Increasing evidence suggests that non-steroid AIs40 are highly specific, potent and have less adverse effects during breast cancer treatment. These AIs such as anastrozole and letrozole41,42, by non-covalently binding to the aromatase enzyme heme moiety and preventing androgen binding by saturating the binding site, are a successful alternative to tamoxifen as a first-line therapy in postmenopausal women. However, several clinical trials in postmenopausal breast cancer patients and healthy postmenopausal women treated with AIs evaluated the risks of bone fractures. "
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    ABSTRACT: Aim: Aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). Methods: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. Results: The Z′ value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 μmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 μmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein. Conclusion: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.
    Acta Pharmacologica Sinica 07/2014; 35(8). DOI:10.1038/aps.2014.53 · 2.91 Impact Factor
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    ABSTRACT: Background: Epidemiological studies have reported positive asso-ciations between anthropometric measures and risk for developing breast cancers that express hormone receptors and associated mor-tality. However, the impact of nutritional status on the molecular response to endocrine therapy has yet to be described.
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    ABSTRACT: Letrozole (Femara) is a third-generation, nonsteroidal aromatase inhibitor. Adjuvant therapy with letrozole is more effective than tamoxifen in postmenopausal women with hormone-responsive early breast cancer, and extended adjuvant therapy with letrozole after the completion of adjuvant tamoxifen therapy is more effective than placebo in this patient population; letrozole is generally well tolerated. Ongoing trials will help answer outstanding questions regarding the optimal duration of letrozole therapy in early breast cancer and its efficacy compared with other third-generation aromatase inhibitors such as anastrozole. In the meantime, letrozole should be considered a valuable option in the treatment of postmenopausal women with hormone-responsive early breast cancer, both as adjuvant and extended adjuvant therapy.
    Drugs 02/2009; 69(12):1681-705. DOI:10.2165/10482340-000000000-00000 · 4.34 Impact Factor
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