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Aromasin

  1. #1
    Novice beaf's Avatar
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    Aromasin
    I am trying to find some goood info about Aromasin, why isnīt it listed under "drug profiles"? Can you point me out in the right direction, I canīt find any...

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    Senior Member mvmaxx's Avatar
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    Good point. That needs to be added. Let me see if I can find some info for you.

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    Senior Member mvmaxx's Avatar
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    Ok, you asked for it. Here's more info than you'll ever need or want on Aromasin. Thanks to Zyglamail for finding and posting this info originally.


    Aromasin (exemestane) (post #21)

    1: Am J Health Syst Pharm 2002 Nov 15;59(22):2194-2201; quiz 2202-4 Related Articles, Links


    Exemestane: treatment of breast cancer with selective inactivation of aromatase.

    Higa GM.

    Department of Clinical Pharmacy, Mary Babb Randolph Cancer Center, West Virginia University, 1124 Health Sciences North, P.O. Box 9250, Morgantown, WV 26506-9520, USA. ghiga@hsc.wvu.edu

    The mechanism of action, pharmacology, and clinical efficacy and safety of exemestane in the treatment of metastatic breast cancer are reviewed. Endocrine strategies that deprive tumor cells of estrogens are effective therapeutic modalities for patients with hormone-dependent breast cancer. The efficacy and toxicities associated with tamoxifen and aminoglutethimide have contributed to the development of agents that selectively target aromatase, the enzyme responsible for conversion of androgens to estrogens. Exemestane, an orally active irreversible inhibitor of aromatase, was recently approved as second-line endocrine therapy of advanced hormone-sensitive postmenopausal breast cancer. Compared with megestrol acetate in patients with disease progressing on tamoxifen, a number of clinical endpoints, including a survival advantage, were significantly better in the exemestane-treated group. Preliminary data also indicate that cross-resistance is incomplete between exemestane and the reversible aromatase inhibitors. Even though suppression of aromatase activity is quantitatively similar regardless of the interactive mechanism between drug and enzyme, clinically relevant differences may become apparent with further application of these two types of aromatase inhibitors. Exemestane is effective as a second- or third-line treatment of advanced, estrogen-receptor positive breast cancer in postmenopausal patients.

    PMID: 12455303 [PubMed - in process]

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    2: Eur J Cancer 2002 Nov;38(17):2214-21 Related Articles, Links


    Neoadjuvant endocrine therapy of breast cancer: a surgical perspective.

    Dixon JM, Anderson TJ, Miller WR.

    Edinburgh Breast Unit, Western General Hospital, EH4 2XU, Edinburgh, UK

    Neoadjuvant treatment with chemotherapy or endocrine agents is being used increasingly to downstage locally advanced and large operable breast cancers. Following these treatments, inoperable breast cancer often becomes fully resectable, and initially operable tumours requiring mastectomy may be successfully removed by breast-conserving surgery. Patient selection is important to optimise neoadjuvant endocrine therapy: only patients with oestrogen receptor (ER)-rich breast cancer are candidates, and postmenopausal women are likely to benefit the most. Such patients can expect a high probability of responses over a 3-month treatment period. Response to therapy should be monitored by clinical examination as well as by ultrasound, mammography, or other imaging procedures. Third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen in this treatment setting. In a large randomised trial of neoadjuvant endocrine therapy in postmenopausal women, letrozole achieved significantly higher response rates than tamoxifen, and a correspondingly higher rate of breast-conserving surgery was possible in the letrozole-treated patients. There is some evidence to suggest that the nature of the tumour response is different for preoperative endocrine therapy compared with chemotherapy. This difference may result in a higher rate of complete tumour excisions following breast-conserving surgery after neoadjuvant endocrine treatment. There appears to be a low rate of subsequent local recurrence in patients having breast-conserving therapy after neoadjuvant endocrine therapy.

    PMID: 12441257 [PubMed - in process]

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    3: Cancer 2002 Nov 1;95(9):2006-16 Related Articles, Links


    An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane.

    Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM.

    Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. abuzdar@mdanderson.org

    BACKGROUND: The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS: In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS: At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS: All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated. Copyright 2002 American Cancer Society.

    Publication Types:
    Review
    Review, Academic

    PMID: 12404296 [PubMed - indexed for MEDLINE]

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    4: Int J Clin Oncol 2002 Oct;7(5):279-83 Related Articles, Links


    The evolving role of aromatase inhibitors in breast cancer.

    Mokbel K.

    St George's Hospital and Medical School, London SW17 0QT, UK. kefahmokbel@hotmail.com

    Anti-aromatase agents inhibit the cytochrome p-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues. These drugs can be classified into first-generation (e.g., aminoglutethimide), second-generation (e.g., formestane and fadrazole), and third-generation (e.g., anastrozole, letrozole, and exemestane) agents. Anti-aromatase agents can also be divided into type I and type II inhibitors. Type I inhibitors have a steroidal structure similar to androgens and inactivate the enzyme irreversibly by blocking the substrate-binding site, and are therefore known as aromatase inactivators. Type II inhibitors are nonsteroidal and their action is reversible. This article reviews the recent evidence regarding the role of third-generation aromatase inhibitors in the management of breast cancer. Relevant PubMed listed articles and presentations at recent international symposia were reviewed. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) as first-line and second-line therapy for estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor-positive invasive breast cancer unsuitable for breast-conserving surgery. Furthermore, the preliminary results of the ATAC (Arimidex, Tamoxifen, Alone and in Combination) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), adverse effects, and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. However, longer follow-up is required to assess the long-term effects of these agents on bone mineral density, cognitive function, and overall survival prior to considering their routine use in the adjuvant setting instead of tamoxifen. The potential role of these drugs in the management of ductal carcinoma in situ (DCIS), premenopausal breast cancer, and breast cancer prevention is worth investigating.

    PMID: 12402060 [PubMed - in process]

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    5: Breast Cancer Res Treat 2002 Oct;75 Suppl 1:S27-32; discussion S33-5 Related Articles, Links


    Sequencing of endocrine therapies in breast cancer--integration of recent data.

    Carlson RW.

    Department of Medicine, Stanford University, Palo Alto, CA 94304, USA. rcarlson@SMI.Stanford.EDU

    A wide range of endocrine therapies has demonstrated activity in the treatment of hormone receptor-positive metastatic breast cancer and sequential tumor responses to sequential hormonal therapies are common. However, the optimal sequence of the hormonal therapies has not yet been determined. The selection of endocrine therapies in women with hormone receptor-positive breast cancer is strongly influenced by the menopausal status of the patient. For premenopausal women, tamoxifen alone or combined with ovarian suppression using a luteinizing hormone-releasing hormone (LHRH) agonist - such as goserelin or leuprolide - is an appropriate first-line hormonal therapy. Ovarian ablation or megestrol acetate is an appropriate second-line hormonal therapy for premenopausal women treated with tamoxifen as first-line therapy, or ovarian ablation plus an aromatase inhibitor (AI) or megestrol acetate for women treated with first-line tamoxifen plus an LHRH agonist. For postmenopausal women, the non-steroidal AIs anastrozole and letrozole now represent the preferred first-line hormonal treatment for metastatic breast cancer, based upon both efficacy and toxicity considerations. For second-line therapy in postmenopausal women, a number of options now exist, including tamoxifen, the steroidal Aromatase inhibitor (AI) exemestane, and the new agent fulvestrant. Fulvestrant, a novel estrogen receptor (ER) antagonist that downregulates the ER and has no known agonist effects, has been demonstrated to be at least as effective as anastrozole in postmenopausal women whose tumors progress on tamoxifen. The establishment of the optimal sequence of the endocrine therapies should offer significant benefits to women with hormone-sensitive metastatic breast cancer.

    PMID: 12353821 [PubMed - in process]

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    6: Breast Cancer Res Treat 2002 Oct;75 Suppl 1:S13-7; discussion S33-5 Related Articles, Links


    New generation aromatase inhibitors--from the advanced to the adjuvant setting.

    Buzdar AU.

    Department of Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston 77030-4009, USA. abuzdar@mdanderson.org

    Aromatase inhibitors (AIs) are a class of compounds that inhibit the cytochrome P450 aromatase enzyme that mediates conversion of androgens to estrogen in the adrenal gland. AIs have been approved for second-line and, more recently, first-line treatment of advanced breast cancer in postmenopausal women. The most recent, third generation of AIs are the non-steroidal agents anastrozole ('Arimidex') and letrozole, and the steroidal compound exemestane. As second-line therapy, anastrozole demonstrated a significant survival advantage over megestrol acetate (26.7 months v.s. 22.5 months; p < 0.025). Exemestane also produced better survival than megestrol acetate, although these data were less mature. Letrozole 2.5 mg has not demonstrated a survival advantage versus megestrol acetate in the second-line setting. As first-line therapy, anastrozole has demonstrated significant superiority in response rates with respect to time to progression (TTP) (11.1 months v.s. 5.6 months; p = 0.005) and has also demonstrated significantly greater clinical benefit rates compared with tamoxifen (59.1% v.s. 45.6%; p = 0.0098). Letrozole has also demonstrated significantly longer TTP than tamoxifen in the first-line setting (9.5 months v.s. 6 months; p = 0.0001). Important differences between the pharmacological profiles of these agents have been noted, particularly with respect to their effects on glucocorticoid metabolism; data for individual agents should not be extrapolated from one to another, particularly in the adjuvant setting.

    PMID: 12353818 [PubMed - in process]

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    7: Int J Clin Oncol 2002 Aug;7(4):265-70 Related Articles, Links


    The role of aromatase inactivators in the treatment of breast cancer.

    Lonning PE.

    Department of Oncology, Haukeland Hospital, University of Bergen, N - 5021 Bergen, Norway. plon@haukeland.no

    Third-generation aromatase inhibitors and inactivators have earned their place in the treatment of metastatic breast cancer. The third-generation aromatase inactivator exemestane was found to be superior to megestrol acetate as second-line endocrine therapy in postmenopausal women, with respect to time to progression as well as overall survival, and the results from an ongoing study comparing exemestane with tamoxifen in first-line treatment are promising. The finding that exemestane may also work in patients previously exposed to nonsteroidal aromatase inhibitors reveals lack of complete cross-resistance between the compounds. Currently, exemestane given as monotherapy, or in sequence with tamoxifen (2-3 + 3-2 years of tamoxifen-exemestane or 5 years of tamoxifen followed by 2 years of exemestane) is being compared with tamoxifen 5 years monotherapy in the adjuvant setting. In addition, we are currently addressing the toxicity of exemestane in a placebo-controlled trial in low-risk breast-cancer patients. The results from these studies will outline the potential role of exemestane in adjuvant treatment and, potentially, for breast-cancer prevention in postmenopausal women.

    Publication Types:
    Review
    Review, Academic

    PMID: 12202980 [PubMed - indexed for MEDLINE]

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    8: J Pediatr Endocrinol Metab 2002;15 Suppl 3:897-901 Related Articles, Links


    McCune-Albright syndrome--the German experience.

    Albers N, Jorgens S, Deiss D, Hauffa BP.

    Kinderhospital, Osnabruck Germany. nalbers@kinderhospital.de

    The classical McCune-Albright syndrome (MAS) consists of peripheral precocious puberty (PPP), fibrous bone dysplasia and cafe-au-lait spots. We conducted a survey among pediatric endocrinologists in Germany, Austria and Switzerland, most of them participating in the German Working Group for Pediatric Endocrinology (APE). Thirty-three physicians reported 58 patients. A detailed questionnaire yielded extensive data from 41 patients. Patients (36 females, 5 males) were diagnosed between the 4th week of life and 8 years. Symptoms included precocious puberty (37 patients), cafe-au-lait spots (35), fibrous bone dysplasia (32), hyperthyroidism (5), liver disease (5), phosphate wasting (4), GH hypersecretion (3), anemia in infancy (2), hyperprolactinemia (1), and Cushing's disease (1). Therapy of PPP included testolactone (15), tamoxifen (7), cyproterone acetate (CPA) (5), anastrozole (1) and exemestane (1). Testolactone, tamoxifen and CPA showed varying degrees of clinical remission; none was unanimously effective, but side effects were very rare. New aromatase inhibitors were not well validated in MAS. Eleven children received bisphosphonate therapy (pamidronate i.v. q 3 months) for fibrous bone dysplasia. Pamidronate was well tolerated, and pain improved when present, but data on preventive effects are not yet available. In conclusion, this survey describes a large cohort of patients with MAS, many with severe clinical problems, including major physical handicaps. Our results show that there is no 'gold standard' for the therapy of PPP; tested treatment regimens are not ideal, and new aromatase inhibitors need to be evaluated in controlled studies. Pamidronate was well tolerated, but preventive effects on bone dysplasia have not yet been proven.

    PMID: 12199348 [PubMed - in process]

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    9: Breast Cancer Res Treat 2002 Jul;74(2):177-85 Related Articles, Links


    Overview of the pharmacology of the aromatase inactivator exemestane.

    Brueggemeier RW.

    College of Pharmacy, The Ohio State University, Columbus 43210-1291, USA. Brueggemeier.1@osu.edu

    One third of all breast cancers and two thirds of postmenopausal breast cancers are estrogen dependent. Antiestrogen strategies, such as inhibition of estrogen-receptor binding and estrogen deprivation, are effective for the management of hormone-dependent breast cancer. Although currently available agents are effective, the development of more potent and selective agents continues. Both steroidal and nonsteroidal inhibitors of aromatase have been developed for clinical uses. A novel class of steroidal irreversible antiaromatase agents demonstrates a high degree of specificity for the aromatase enzyme and exhibits a unique pharmacokinetic profile. The ability of these agents to inactivate aromatase may explain their high degree of potency and lengthy duration of action. Exemestane, an orally active aromatase inactivator, has demonstrated excellent selectivity and tolerability and broad-based efficacy in the treatment of postmenopausal breast cancer. Current findings suggest that exemestane will be a valuable alternative for women with breast cancer, not only for those progressing on other hormonal therapies but in earlier stages of the disease and prevention.

    PMID: 12186378 [PubMed - in process]

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    10: Pathol Oncol Res 2002;8(2):87-92 Related Articles, Links


    The role of aromasin in the hormonal therapy of breast cancer.

    Dank M.

    Department of Diagnostic Radiology and Oncotherapy, Semmelweis University, Budapest, Hungary. dankeradi.sote.hu

    In the last 40 years tamoxifen and progestogens constituted the basis of hormonal therapy. Introduction of the third generation, selective, anti-aromatase agents added effective drugs of good tolerability to the anti-cancer armamentarium. Exemestane, an oral steroidal-type aromatase inhibitor - which irreversibly blocks aromatase - is very effective in the treatment of metastatic breast cancer. As a second line therapy, exemestane is more effective and causes less side effects than megestrol-acetate. Its administration as first line therapy gave promising results. The role of exemestane in adjuvant treatment has not yet been soundly established but trials are ongoing. It may be effective as neoadjuvant treatment in selected groups of patients. Future studies will clarify exemestane's role in chemoprevention and in the treatment of post-menopausal women administered together with cytostatic agents.

    PMID: 12172571 [PubMed - in process]

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    11: J Clin Oncol 2002 Aug 1;20(15):3317-27 Related Articles, Links


    American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002.

    Winer EP, Hudis C, Burstein HJ, Chlebowski RT, Ingle JN, Edge SB, Mamounas EP, Gralow J, Goldstein LJ, Pritchard KI, Braun S, Cobleigh MA, Langer AS, Perotti J, Powles TJ, Whelan TJ, Browman GP.

    Health Services Research Department, American Society of Clinical Oncology, 1900 Duke Street, Suite 200, Alexandria, VA 22314, USA. guidelines@asco.org

    OBJECTIVE: To conduct an evidence-based technology assessment to determine whether the routine use of anastrozole or any of the aromatase inhibitors in the adjuvant breast cancer setting is appropriate for broad-based conventional use in clinical practice. POTENTIAL INTERVENTIONS: Anastrozole, letrozole, and exemestane. OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefit. EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics and is detailed in the text. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO)-prescribed technology assessment procedure was followed. BENEFITS/HARMS: The ASCO panel recognizes that a woman and her physician's decision regarding adjuvant hormonal therapy is complex and will depend on the importance and weight attributed to information regarding both cancer and non-cancer-related risks and benefits. CONCLUSION: The panel was influenced by the compelling, extensive, and long-term data available on tamoxifen. Overall, the panel considers the results of the Arimidex (anastrozole) or Tamoxifen Alone or in Combination (ATAC) trial and the extensive supporting data to be very promising but insufficient to change the standard practice at this time (May 2002). A 5-year course of adjuvant tamoxifen remains the standard therapy for women with hormone receptor-positive breast cancer. The panel recommends that physicians discuss the available information with patients, and, in making a decision, acknowledge that treatment approaches can change over time. Individual health care providers and their patients will need to come to their own conclusions, with careful consideration of all of the available data. (Specific questions addressed by the panel are summarized in Appendix 3.) VALIDATION: The conclusions of the panel were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors.

    Publication Types:
    Review
    Review Literature

    PMID: 12149306 [PubMed - indexed for MEDLINE]

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    12: Drugs Aging 2002;19(6):453-63 Related Articles, Links


    Efficacy and economics of hormonal therapies for advanced breast cancer.

    Simon MS, Ibrahim D, Newman L, Stano M.

    Barbara Ann Karmanos Cancer Institute at Wayne State University, Harper Hospital, Detroit, Michigan 48201, USA.

    Breast cancer is a leading cause of cancer-related mortality among postmenopausal women in the US, and the economic burden of breast cancer care comprises a large percentage of the healthcare budget. Hormonal therapies have a proven place in the management of advanced breast cancer. This type of therapy is more likely to be used in older, compared with younger, women, because tumours in older women are more likely to express estrogen and progesterone receptors. While it is difficult to measure the costs of cancer care because of variation in extent and duration of treatment, treatment-related costs including costs of hormonal agents used for advanced disease account for a relatively small component of the overall costs. Newer hormonal regimens such as the new third generation nonsteroidal (letrozole, anastrozole) and steroidal (exemestane) aromatase inhibitors have shown improved clinical efficacy compared with standard regimens such as megestrol and tamoxifen in the metastatic setting in terms of objective responses or time to tumour progression. In addition the newer agents have improved toxicity profiles. Cost analyses of the newer aromatase inhibitors (anastrozole and letrozole), compared with megestrol, show an optimistic outlook for these agents. Additional work needs to be done looking at a comparison of the efficacy and costs of the aromatase inhibitors relative to the currently recommended hormonal treatments used for women with metastatic breast cancer.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12149051 [PubMed - indexed for MEDLINE]

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    13: Gan To Kagaku Ryoho 2002 Jul;29(7):1211-21 Related Articles, Links


    [Late phase II study of exemestane in postmenopausal patients with breast cancer resistant to anti-estrogenic agents]

    [Article in Japanese]

    Watanabe T, Sano M, Toi M, Saeki T, Kanda K, Miura S, Inaji H, Sono H, Saeki H, Nishimura R, Fujita Y.

    Division of Internal Medicine, National Cancer Center Hospital.

    A multi-center trial of exemestane 25 mg, an oral aromatase irreversible inactivator, was conducted to evaluate its efficacy and safety in 33 postmenopausal patients, and to investigate the pharmacokinetics/serum hormone levels in 16 postmenopausal patients, respectively, with breast cancer and anti-estrogen resistance. Exemestane 25 mg was given once daily for up to 48 weeks (maximum). The objective of this study was to confirm the reproducibility of the results shown in two studies in other countries with similar patients, to investigate the possibility of extrapolating the overseas data to Japanese. The response rate (CR + PR) was 24.2% (8.33%), which exceeded the minimum number (6 cases) required to evaluate efficacy. The response rate in this study was very similar to that observed in the two international open studies. Adverse events (subjective/objective symptoms), in which a causal relationship with exemestane administration could not be excluded, were observed in 26 cases (78.8%). Of these, hot flushes, increased sweating, fatigue, and insomnia occurred in more than 10% of patients, which was similar to that observed in the two international open studies. Abnormal laboratory results occurring in more than 10% of patients, in which a causal relationship with exemestane administration could not be excluded, were as follows: lymphocyte count decrease, alkaline phosphate increase, GOT increase, GPT increase, gamma-GTP increase, triglyceride increase, and inorganic phosphate increase, most of which were either grade 1 or 2. A remarkable decrease in serum hormone concentration was observed only for estrogen. The values of AUC0-infinity at day 1 and AUC0-24 h at day 29 (steady state) were similar, suggesting no accumulative effect of exemestane. These results demonstrate the anti-tumor effect and safety of exemestane in postmenopausal anti-estrogen resistant breast cancer patients. The reproducibility of the results of the two foreign studies was verified in Japanese patients, and it is concluded that the foreign trial data on exemestane can be extrapolated to Japanese.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase II
    Multicenter Study

    PMID: 12146002 [PubMed - indexed for MEDLINE]

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    14: Gan To Kagaku Ryoho 2002 Jul;29(7):1199-209 Related Articles, Links


    [Early phase II dose-finding study of exemestane in postmenopausal patients with advanced/recurrent breast cancer]

    [Article in Japanese]

    Tabei T, Ogita M, Hirata K, Satomi S, Kimura M, Abe R, Morishita Y, Kimura M, Andou J, Higashi Y, Yoshino K, Tominaga K, Kajiwara T, Kitajima M, Koyanagi Y, Watanabe T, Yamaguchi S, Watanabe M, Toyama K, Kanda K, Kashiki Y, Miura S, Kobayashi Z, Aoyama H, Miyazaki I, Oka T, Koyama H, Kinoshita H, Monden M, Takai S, Yayoi E, Kobayashi T, Takatsuka Y, Kajiwara T, Sonoo H, Toge T, Takashima S, Nomura Y, Nagao K, Fujita Y.

    Saitama Cancer Center.

    Exemestane was administered orally to postmenopausal women with advanced/recurrent breast cancer at a dose of 10 mg/day or 25 mg/day once daily for more than 8 weeks in order to evaluate the drug's anti-tumor effects and safety in a dose-finding study. The response rate (CR + PR) in the 10 mg and 25 mg group was 25.0% (8/32) and 31.4% (11/35), respectively, demonstrating no significant differences between the two groups, yet a higher efficacy rate was observed in 25 mg group. The efficacy rate in hormone-treatment-resistant patients within the 10 mg and 25 mg groups was 14.3% (3/21) and 26.1% (6/23), respectively, demonstrating more than a 20% response rate in 25 mg group. Incidences of the adverse events of which relevance to the drug could not be excluded were 30.6% (11/36) in the 10 mg group. 13.9% (5/36) in the 25 mg group and 22.2% (16/72) in the total group. The major adverse events were, hot flashes, numbness of the limbs, nausea, headache etc. Abnormal findings in clinical laboratory tests were as follows: ALP increase; GOT increase; GPT increase; gamma-GTP increase; total cholesterol increase; urinary sediment present. Abnormal findings in endocrine function were as follows: aldosterone decrease; testosterone.cortisol.DHEA-S decrease. But discontinuation due to abnormal laboratory findings was not found. No abnormal findings in physical tests were observed. A significant decrease in plasma estrogen concentration at week 4 was observed in both the 10 mg and 25 mg groups compared with baseline. These low levels were maintained throughout the study period. On the basis of these results, the efficacy of exemestane 25 mg/day was verified to be slightly higher than 10 mg/day. In addition the safety profile had no major adverse events to notice. In these patients with advanced/recurrent breast cancer, 25 mg/day was recommended as the most appropriate dose to be used clinically.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase II
    Multicenter Study
    Randomized Controlled Trial

    PMID: 12146001 [PubMed - indexed for MEDLINE]

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    15: Gan To Kagaku Ryoho 2002 Jul;29(7):1189-97 Related Articles, Links


    [Phase I multiple-dose administration study of exemestane in postmenopausal women]

    [Article in Japanese]

    Miura S, Tominaga T, Koyama H, Nomura Y, Tsuboi M.

    Aichi Cancer Center Hospital.

    A multiple-dose administration study of exemestane (0.5-50 mg/day after breakfast for 7 days) was conducted in 32 normal healthy postmenopausal Japanese women using a single-blind, 3-step dose-titration method in order to investigate the safety, effect on serum concentration, amount of urinary estrogen excretion, and pharmacokinetics of the drug. Subjective/objective symptoms, in which a causal relationship with exemestane administration could not be excluded, were as follows: headache (8 cases: 1 each in the 0.5 and 25 mg groups, 2 in the 10 mg group and 4 in the 50 mg group), dizziness (2 cases: 1 each in the 0.5 and 25 mg groups), and fever (1 in the 25 mg group), all of which were mild and disappeared without treatment. The only abnormal laboratory findings were a mild increase in levels of GOT and GPT in 1 case and in the number of basophils in another case. There were no notable abnormal findings in vital signs, body weight or EKG. A dose-dependent decrease in serum estrogen level was observed between doses of 0.5 mg and 25 mg. The decrease was maximal at 25 mg, at which serum estrogen concentrations decreased to 14-27% of those observed at day 0. This decrease was maintained for one week, returning to baseline levels 2 weeks after the completion of drug administration. A similar result was also observed in the suppression of 24-hour urinary estrogen excretion. Exemestane was absorbed immediately after initial administration, reaching Cmax 0.9-2.6 hours post-administration. This was followed by a rapid decrease over the next 4-8 hours followed by a gradual decrease Cmax reached normal steady state values on day 5. Cmax and AUC0-24 values taken between administration of the first and final doses increased proportionally in a dose-dependent manner, suggesting that exemestane has a linear pharmacokinetic profile. Furthermore, results of the comparison of the trough concentrations of the initial dose with those of the final dose suggested no accumulative effects of the study drug.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase I
    Randomized Controlled Trial

    PMID: 12146000 [PubMed - indexed for MEDLINE]

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    16: Gan To Kagaku Ryoho 2002 Jul;29(7):1179-87 Related Articles, Links


    [Phase I single-dose administration study of exemestane in postmenopausal women]

    [Article in Japanese]

    Miura S, Tominaga T, Koyama H, Nomura Y, Tsuboi M.

    Aichi Cancer Center Hospital.

    A single-dose administration study of a new type of aromatase inactivator, exemestane, was performed in normal healthy postmenopausal Japanese women. The study was conducted to investigate the safety, effect on serum and urinary estrogen concentrations, and pharmacokinetics of exemestane at 25 or 50 mg. A crossover study using a single dose (25 mg) was also conducted in order to study the effect of meals on these parameters. Adverse events, in which a causal relationship with the study drug could not be excluded, were as follows: hot flushes (2/4), sleepiness (1/4), and glycogeusia (1/4), all of which were mild and transient. There were no clinically significant laboratory test or physical finding abnormalities with either dose, except for one patient in the 50 mg group who had an increase in levels of GPT, ALP and gamma-GTP. Maximal suppression of serum estrogen concentration (22-37% suppression) was achieved 3-4 days after single-dose administration of exemestane (25 mg or 50 mg), and almost no suppression was observed 2 weeks later. A significant decrease in the amount of urinary estrogen excretion occurred on day 4 and day 8 after exemestane administration. The level of urinary estrogen excretion almost returned to baseline levels in the 25 mg group and returned to 65% of baseline levels in the 50 mg group 2 weeks after drug administration. Both serum estrogen concentration and the amount of urinary estrogen excreted decreased in a similar fashion under both fasting and fed conditions, suggesting no effect of meals on the suppression of estrogen concentrations. Exemestane was adsorbed immediately after single-dose administration, and this was followed by a gradual decrease in serum concentrations in a multiphase pattern. An increase in Cmax and AUC0-tz values was observed after meals compared with those values obtained under fasting conditions, yet the increase was not statistically significant, suggesting that the increase was not clinically relevant. The results of this study verified the safety and the estrogen suppressive effects on serum and urinary concentrations of estrogen of a single dose of exemestane up to 50 mg. Furthermore, results suggest that the suppression of serum and urinary estrogen concentrations and pharmacokinetics of exemestane were not affected by food.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase I

    PMID: 12145999 [PubMed - indexed for MEDLINE]

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    17: Semin Oncol 2002 Jun;29(3 Suppl 11):120-8 Related Articles, Links


    Recent advances in aromatase inhibitor therapy for breast cancer.

    Assikis VJ, Buzdar A.

    Divisions of Cancer Medicine and Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

    Third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) have emerged as an alternative first-line endocrine treatment for postmenopausal breast cancer patients with hormone-responsive disease. Their clinical efficacy, excellent tolerability, and safety profile compare favorably with that of tamoxifen, which has been the cornerstone of endocrine therapy for years. This review will discuss the findings of recently published randomized clinical trials comparing this new class of drugs with tamoxifen as first-line treatment for advanced disease. We will also present the design and rationale of ongoing trials looking into the use of third-generation aromatase inhibitors in the adjuvant setting and review data regarding their possible role in premenopausal women. Copyright 2002, Elsevier Science (USA). All rights reserved.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12138406 [PubMed - indexed for MEDLINE]

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    18: Clin Ther 2002;24 Suppl C:C43-57 Related Articles, Links


    Sequencing of hormonal therapy in postmenopausal women with metastatic breast cancer.

    Parker LM.

    Department of Medicine, Harvard Medical School, The Dana-Farber Cancer Institute, Boston, Massachusetts 02115-6013, USA. leroy_parker@dfci.harvard.edu

    BACKGROUND: Hormonal therapy (HT) is an important consideration in the management of postmenopausal women with metastatic breast cancer. Despite the fact that the advanced-stage disease is virtually incurable, HTs can offer patients disease control equivalent to that of chemotherapy, but with improved quality of life (QOL). Knowledge of the estrogen and progesterone receptor status, as well as other clinical factors, allows for selection of patients who are most likely to benefit from HT. Disease that becomes refractory to an initial HT may respond to another agent or class of HTs. Thus, HTs are generally administered sequentially, delaying the need for cytotoxic chemotherapy, which often reduces QOL. Optimal sequencing is thus one of the more important facets of HT. Prior to the release of a number of newer agents, tamoxifen had been considered as initial HT. At present, more agents exist, including the aromatase inhibitors, progestins, and the estrogen receptor antagonist fulvestrant. OBJECTIVE: This article reviews key trials evaluating the use of sequential HTs. METHODS: Articles were identified for inclusion in this manuscript through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780. RESULTS: Results of Phase III studies have shown many of these agents to be equivalent or superior to tamoxifen and can be used initially to treat patients who either have failed tamoxifen therapy or may be unable to tolerate some of the toxicities associated with tamoxifen. For example, the aromatase inhibitors have been shown to be highly active and tolerable in postmenopausal women with breast cancer who have failed tamoxifen therapy or who are naive to HT. Other clinical trials have demonstrated the efficacy of fulvestrant in patients with metastatic breast cancer who are tamoxifen-resistant, and have shown fulvestrant to be at least as effective as anastrozole in tamoxifen-resistant patients. CONCLUSIONS: Although the optimum sequence of HTs remains controversial, using the newer agents as initial or subsequent therapy should improve QOL and may improve overall survival.

    PMID: 12117075 [PubMed - in process]

    --------------------------------------------------------------------------------


    19: Clin Ther 2002;24 Suppl C:C3-25 Related Articles, Links


    Evolving uses of hormonal agents for breast cancer therapy.

    Cummings FJ.

    University Medical Group-Roger Williams Medical Center, Providence, Rhode Island 02908, USA.

    BACKGROUND: During the past decade, a number of new hormonal therapies (HTs) have been developed, including the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and estrogen receptor (ER) antagonists. Their uses in breast cancer are continually evolving as new clinical trial results become available. Although tamoxifen, the most widely used HT for breast cancer, was originally approved for and used in the treatment of metastatic breast cancer (MBC), its effectiveness as MBC therapy led to its subsequent assessment and use as adjuvant and risk-reduction therapy for breast cancer. However, tamoxifen is not universally effective in these settings and is associated with infrequent known toxicities such as increased risk of thromboembolism and endometrial cancer; therefore, a search for more effective and more tolerable HTs has evolved. OBJECTIVE: This article reviews the data supporting the use of newer HTs as initial treatment of MBC and their potential use as adjuvant, neoadjuvant, and chemopreventive therapies. METHODS: Articles for inclusion in this manuscript were identified through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, breast cancer guidelines, hormonal therapies, tamoxifen, toremifine, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780. RESULTS: Recent studies have focused on newer agents as initial and subsequent treatment of MBC, adjuvant or neoadjuvant treatments of breast cancer, and chemopreventive agents in both healthy women and women with a history of ductal carcinoma in situ (DCIS). Results of clinical trials comparing AIs with tamoxifen as first-line MBC treatment show that AIs are as effective as, or more effective than, tamoxifen and are associated with fewer serious adverse events. Tamoxifen remains the gold standard for adjuvant therapy. However, preliminary results of ongoing clinical trials comparing tamoxifen with anastrozole suggest that anastrozole may be the superior agent. Both tamoxifen and the AIs have been shown to be active in the neoadjuvant treatment of breast cancer. Trial results have shown that tamoxifen is effective for breast cancer prevention in patients at high risk of developing breast cancer but who are otherwise healthy, patients with a history of DCIS, and patients with lobular carcinoma in situ. CONCLUSIONS: Although tamoxifen has been the gold standard of HT for breast cancer, results of ongoing trials assessing the newer HTs as initial, neoadjuvant, adjuvant, and chemopreventive therapies may substantially change our current clinical practice patterns.

    PMID: 12117074 [PubMed - in process]

    --------------------------------------------------------------------------------


    20: Clin Ther 2002;24 Suppl C:C26-42 Related Articles, Links


    The impact of hormonal treatments on quality of life of patients with metastatic breast cancer.

    Costantino J.

    National Surgical Adjuvant Breast and Bowel Project Biostatistical Center, and Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania 15261, USA. costan@nsabp.pitt.edu

    BACKGROUND: The concept of quality of life (QOL) increasingly has been used to assess health-related outcomes associated with a specific disease or its treatment, especially in patients with incurable tumors, such as metastatic breast cancer (MBC). Hormonal therapy (HT) is often used to treat hormone receptor-positive MBC, with the primary treatment goal of reducing both disease burden and patient suffering. OBJECTIVE: This article reviews the instruments used to assess QOL in patients with breast cancer, the adverse effects of HTs, and the clinical trials that assess QOL in patients with MBC receiving various HTs. METHODS: Articles were identified for inclusion in this manuscript through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstacts (2001 and 2002). The following search terms were used: quality of life, breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, and megestrol acetate. CONCLUSIONS: QOL assessment following MBC treatment has become an important indicator of treatment effectiveness, and numerous clinical trials have studied the impact of HT on QOL. In general, the older HTs, such as the progestins and selective estrogen receptor modulators (SERMs), produce more adverse effects than do the newer HTs, such as the aromatase inhibitors (AIs) and estrogen receptor (ER) antagonists. QOL data regarding tamoxifen, a SERM associated with a high incidence of vasomotor symptoms and vaginal discharge, are limited, although tamoxifen has not been associated with significant psychological distress when administered as a chemopreventive or adjuvant MBC therapy in clinical trials. QOL studies comparing the third-generation AIs with tamoxifen or megestrol acetate show that the AIs produce a more favorable QOL, probably because these agents target the aromatase enzyme, which results in a lower incidence of thromboembolism and vaginal bleeding. Although QOL studies of the ER antagonist fulvestrant have not been conducted, several attributes of this new HT may contribute to the retention of a good QOL in patients with MBC. A variety of QOL-assessment tools to measure the impact of HTs on patients with MBC are available. Clinical trial data regarding QOL in patients with MBC receiving HT will be useful for both clinicians and patients in evaluating treatment options and developing treatment strategies.

    PMID: 12117073 [PubMed - in process]

    --------------------------------------------------------------------------------


    21: Expert Rev Anticancer Ther 2002 Apr;2(2):181-91 Related Articles, Links


    Aromatase inhibitors in breast cancer therapy.

    Brueggemeier RW.

    Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. Brueggemeier.1@osu.edu

    Estrogens are involved in numerous physiological processes and have crucial roles in certain disease states, such as mammary carcinomas. Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in breast tissue and the importance of intratumoral aromatase and local estrogen production is being unraveled. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. Steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy for the treatment of breast cancer. The initial nonselective nature of nonsteroidal inhibitors, such as aminoglutethimide, has been greatly reduced in the later generations of inhibitors, anastrozole and letrozole. Mechanism-based steroidal inhibitors, such as 4-hydroxyandrostenedione and exemestane produce potent aromatase inhibition in patients. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole and exemestane, are approved for clinical use as first-line endocrine therapy in postmenopausal women with metastatic hormone-dependent breast cancer and as second-line endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12113240 [PubMed - indexed for MEDLINE]

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    22: Expert Rev Anticancer Ther 2002 Jun;2(3):267-75 Related Articles, Links


    Exemestane: a potent irreversible aromatase inactivator and a promising advance in breast cancer treatment.

    Dixon JM.

    Edinburgh Breast Unit, Western General Hospital, Edinburgh, EH4 2XU Scottland, UK. jmd@wght.demon.co.uk

    With the introduction of orally-active, potent and selective third-generation aromatase inhibitors and inactivators--anastrozole, letrozole and exemestane--approaches to the treatment of advanced breast cancer are undergoing re-evaluation. In advanced breast cancer, aromatase inhibitors and inactivators are likely to become established as the primary choice over tamoxifen in postmenopausal female breast cancer patients when hormonal therapy is indicated in the first-line setting. The current evaluation of exemestane, an oral steroidal irreversible aromatase inactivator, for primary and adjuvant therapy and the potential role of potent estrogen-deprivation therapy in prevention of postmenopausal breast cancer may extend the use of antiaromatase therapy as an increasingly valuable palliative treatment option, conferring survival benefit and possible preventive outcomes across several treatment settings in the management of breast cancer.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12113050 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    23: Expert Rev Anticancer Ther 2002 Jun;2(3):249-60 Related Articles, Links


    Letrozole for the management of breast cancer.

    Goss PE, Smith RE.

    Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Avenue, 5-303, Toronto, Ontario, M5G 2M9, Canada. pegoss@interlog.com

    Letrozole, a third-generation aromatase inhibitor, has been the only aromatase inhibitor to date to show unequivocal superiority to tamoxifen as first-line treatment of metastatic postmenopausal breast cancer. The superiority of letrozole compared with tamoxifen was also reflected in the neoadjuvant setting, in both estrogen receptor-positive and estrogen receptor-unknown patients with differing HER-2 status. Currently, studies are being performed in the adjuvant setting, which will provide important data on the long-term safety of letrozole and help determine its suitability as a chemopreventive agent in healthy women at risk of developing breast cancer. Nevertheless, the superior clinical efficacy and survival data of letrozole suggest that it has the potential to displace tamoxifen as the gold standard in breast cancer treatment in the coming years.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12113048 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    24: Biochim Biophys Acta 2002 Jul 18;1587(2-3):326-37 Related Articles, Links


    Exemestane, a new steroidal aromatase inhibitor of clinical relevance.

    Lombardi P.

    Biopharmascience, Executive Consultants in Research and Development, 20020 Cesate, Italy. lombardi@maganet.net

    Breast cancer is the leading cause of death among women and the contribution of circulating oestrogens to the growth of some mammary tumours has been recognized. Consequently, suppression of oestrogen action by inhibition of their biosynthesis at the androstenedione-oestrone aromatization step, by means of selective inhibitors of the enzyme aromatase, has become an effective therapeutic option for the treatment of hormone-dependent breast cancer. Exemestane (6-methylenandrosta-1,4-diene-3,17-dione) is a novel steroidal irreversible aromatase inhibitor recently approved and introduced into the global market under the name Aromasin. The design, laboratory and viable syntheses of exemestane, starting from a variety of steroidal precursors, are presented and discussed. Data from biochemical and pharmacological studies as well as the clinical impact of the compound are briefly reviewed. The drug is an orally active and well-tolerated hormonal therapy for postmenopausal patients with advanced breast cancer that has become refractory to standard current hormonal therapies.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12084475 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    25: Magy Onkol 2000 Apr 1;44(1):91-94 Related Articles, Links


    [Aromatase inhibitors and inactivators in the treatment of advanced breast cancer]

    [Article in Hungarian]

    Dank M, Mako E.

    Radiologiai es Onkoterapias Klinika, Semmelweis Egyetem, Budapest, H1082, Hungary.

    Advanced breast cancer remains incurable. For these patients, durable response and minimal toxicity are the main goals of current therapy. The antiestrogen tamoxifen has proved to be a significant advance in the treatment of breast cancer. Due to its partial estrogen activity, long term medication with tamoxifen has been found to cause endometrium proliferation wich can result in cancer in some patients. Reduction of estrogen production identified the aromatase inhibitors. Both steroidal substrate analog, type I inactivator, wich inactivate the enzyme and non-steroidal competitive reversible, type II inhibitors, are now avaiable. Two new 3(rd) generation aromatase inactivators have recently completed phase III evaluation (anastrozole and letrozole) and we have some results investigating one of the new 3(rd) generation aromatase inhibitors (exemestane). The 3(rd) generation aromatase inhibitors and inactivators are better tolerated and more effective than each of our current standard 2(nd) line endocrin therapies. These agents are being directly compared with standard adjuvant medication, tamoxifen, or are being evaluated in different sequences.

    PMID: 12050773 [PubMed - as supplied by publisher]

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    26: Minerva Ginecol 2002 Apr;54(2):115-31 Related Articles, Links


    [The role of aromatase inhibitors in the treatment of breast neoplasms. An evaluation of clinical efficacy and the tolerability profile]

    [Article in Italian]

    Porpiglia M, Genta F, Vicelli R, De Nicola B, Ferraris F, Piccinno R, Benedetto C.

    Dipartimento di Discipline Ginecologiche, Universita degli Studi, Turin, Italy.

    Constant acquisitions regarding endocrine pathogenesis and the biology of breast neoplasms have led to the evolution of hormone manipulation as a therapeutic option in patients suffering from this disease. There has been a shift from ablative surgical procedures to the use of drugs offering greater clinical efficacy and an improved tolerability profile. Since the late 1970s tamoxifen has been regarded as the gold standard for hormone treatment in hormone-responsive breast neoplasm, but promising new endocrine agents are now being compared in random trials. Of these, the latest generation of aromatase inhibitors appears to gather the widest consensus on the basis of the results published to date. This article aims to review this new category of drugs, illustrating their rationale of use, the results obtained in the treatment of breast neoplasm and the main studies in which they are currently being investigated.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12032450 [PubMed - indexed for MEDLINE]

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    27: Clin Breast Cancer 2002 Apr;3(1):33-42 Related Articles, Links


    Antiaromatase agents: evolving role in adjuvant therapy.

    Jones SE.

    Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA. steve.jones@usoncology.com

    The goal of adjuvant hormonal therapy is to prevent breast cancer recurrence. Standard therapy with tamoxifen has shown great value in the adjuvant setting; however, its tolerability profile can render it unsuitable for some patients. The aromatase inactivator, exemestane, and the 2 aromatase inhibitors, letrozole and anastrozole, have been shown to be equivalent or superior to tamoxifen with respect to multiple endpoints in patients with metastatic breast cancer. With tolerability profiles that are similar to, and in many cases, more acceptable than that of tamoxifen, and efficacy potentially superior to tamoxifen, studies using the antiaromatase agents as adjuvant therapy are currently ongoing. These trials will answer some important questions, such as the order in which adjuvant hormonal therapies are selected to maximize efficacy, whether the antiaromatase agents show improved tolerability, and whether combination therapy is more effective than monotherapy.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12020394 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    28: Int J Oncol 2002 Jun;20(6):1283-8 Related Articles, Links


    Current status and future potential role of exemestane in the treatment of early and advanced breast cancer (Review).

    Crucitta E, Fornier MN, Locopo N, Silvestris N, Lorusso V, De Lena M.

    Operative Unit of Medical Oncology, Oncology Institute of Bari, Italy. enricocrucitta@yahoo.it

    Exemestane is a new oral steroidal aromatase inactivator, active in postmenopausal women with hormonal sensitive breast carcinoma. This drug, at a dosage of 25 mg once daily, was shown to suppress in vivo aromatase activity by 97.9%, with a subsequent reduction superior to 85% of circulating oestrogen level. It exhibits definite antitumor activity at a relatively low daily dose, and is highly potent, highly selective, and well-tolerated. Moreover, for postmenopausal women with metastatic breast cancer, exemestane demonstrated a higher activity and lower toxicity profile when compared to megestrol acetate and tamoxifen in second- and first-line therapy, respectively. New data on exemestane are forthcoming both in the adjuvant and neoadjuvant setting, which could improve the management of early breast cancer in the future.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 12012011 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    29: Clin Breast Cancer 2000 Sep;1 Suppl 1:S9-S14 Related Articles, Links


    Antiaromatase agents: preclinical data and neoadjuvant therapy.

    Miller WR, Dixon JM.

    Breast Research Unit, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK;e-mail: wrmiller@ed.ac.uk

    Novel drugs such as exemestane are highly potent and specific inactivators of aromatase activity in test systems such as placental microsomes, breast cancer homogenates, and cultures of mammary fibroblasts, with IC50 values in the nmol range. When given in daily milligram amounts to postmenopausal women, exemestane almost totally blocks peripheral aromatase and reduces circulating estrogens to levels that are at the limit of detection of current assays. Additionally, exemestane profoundly inhibits in situ aromatase activity both in breast cancers and surrounding nonmalignant breast. In postmenopausal women with large estrogen receptor-rich cancers, these endocrine influences translate into antitumor effects, and, for example, following exemestane treatment in the neoadjuvant setting, tumor resolution may be observed on mammography. In conclusion, the ability to block estrogen biosynthesis peripherally and locally within the breast provides new options for the treatment of hormone-sensitive breast cancers in postmenopausal women

    PMID: 11970756 [PubMed - in process]

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    30: Clin Breast Cancer 2000 Sep;1 Suppl 1:S68-73 Related Articles, Links


    Comparison of in vitro exemestane activity versus other antiaromatase agents.

    Soudon J.

    Pharmacell, Paris, France; pharm2@jupiter.chu-stlouis.fr

    Anastrozole, letrozole, and exemestane are the most selective and potent oral antiaromatase agents currently available. However, in vitro and in vivo studies comparing these agents are lacking. Anastrozole and letrozole are reversible, competitive nonsteroidal type II inhibitors, whereas exemestane is an irreversible steroidal type I inactivator. The study was conducted to determine the impact of this characteristic on in vitro residual aromatase activity and protein levels after incubation of JEG-3 cells with aminoglutethimide (a type II inhibitor), anastrozole, exemestane, or letrozole. Aromatase activity was measured after various incubation times with each antiaromatase agent at a concentration 10 times higher than IC50 (concentration giving 50% inhibition). Only exemestane induced a residual inhibition of aromatase activity after its removal, without any change in the aromatase protein level. Aromatase activity increased after preincubation of JEG-3 cells with either aminoglutethimide or anastrozole without any change in the aromatase protein level. The aromatase protein level increased rapidly when cells were incubated with letrozole and aromatase activity inhibition disappeared immediately after removal of the drug. The breakthrough effects in aromatase activity or protein levels observed after treatment with reversible inhibitors may be a factor in therapeutic failure with these agents. These results suggest a possible advantage for exemestane because it is the only clinically available oral irreversible aromatase inactivator.

    PMID: 11970753 [PubMed - in process]

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    31: Clin Breast Cancer 2000 Sep;1 Suppl 1:S28-33 Related Articles, Links


    Exemestane in breast cancer: current status and future directions.

    Lonning PE.

    Section of Oncology, Department of Medicine, Haukeland University Hospital, Bergen, Norway; plon@haukeland.no

    Exemestane is a novel, potent, and specific third-generation aromatase inactivator developed for breast can-cer therapy. The drug is effective in patients with metastatic disease failing tamoxifen alone or tamoxifen followed by megestrol acetate or a nonsteroidal aromatase inhibitor. In a phase III study, exemestane was superior to megestrol acetate in overall survival, time to tumor progression, and time to treatment failure in women with metastatic disease who experienced failure of tamoxifen. Preliminary evidence suggests activity to exemestane exceeds that obtained with tamoxifen as first-line treatment. Two studies are comparing sequential treatment with tamoxifen followed by exemestane to tamoxifen monotherapy in the adjuvant set-ting. A third study is comparing the toxicity profile of exemestane with that of placebo in patients with early breast cancer who are at low risk of relapse. The findings from these studies will determine the role of exemestane in early breast cancer and lay the foundation for assessing its potential role in breast cancer prevention.

    PMID: 11970747 [PubMed - in process]

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    32: Clin Breast Cancer 2000 Sep;1 Suppl 1:S22-7 Related Articles, Links


    Antiaromatase agents after adjuvant tamoxifen: rationale and clinical implications.

    Mamounas EP.

    Aultman Cancer Center, Canton, OH; e-mail: epmamounas@aol.com

    Although tamoxifen is considered standard adjuvant hormonal therapy in receptor-positive, stage I and II breast cancer, information on its optimal duration of administration has only been reported recently and, for many, the subject is still a matter of scientific debate. Data suggest that there is a time period beyond which, if tamoxifen is continued, it may become ineffective or even detrimental to the patient. Tamoxifen is usually discontinued after approximately 5 years of therapy, at which time most patients are thought to be disease free; however, some patients may harbor residual micrometastases. A fraction of these patients will have micrometastatic tumor cells that are still responsive to tamoxifen, and tamoxifen discontinuation could result in cancer cell growth. The preponderance of clinical data, however, indicate that a greater fraction of patients will have micrometastatic tumor cells that have become progressively resistant to tamoxifen. In fact, tumor cell growth could be stimulated by continued therapy with the drug. Although in some patients the micrometastatic tumor cells may have become hormonally unresponsive, in most cases (tamoxifen-responsive or tamoxifen-stimulated micrometastases), the tumor remains hormonally responsive. Therefore, the use of anti-aromatase agents to reduce the level of estrogenic stimulation and, as a result, the risk of recurrence may prove to be a valuable approach at the time of tamoxifen discontinuation. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is in the final stages of developing a clinical trial (NSABP B-33) to evaluate the effect of administering 2 years of therapy with the aromatase inactivator exemestane to postmenopausal, receptor-positive patients who have completed 5 years of tamoxifen therapy and are disease free at the time of tamoxifen discontinuation.

    PMID: 11970746 [PubMed - in process]

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    33: Clin Breast Cancer 2000 Sep;1 Suppl 1:S19-21 Related Articles, Links


    Promising Results with Exemestane in the First-Line Treatment of Metastatic Breast Cancer: A Randomized Phase II EORTC Trial with a Tamoxifen Control.

    Paridaens R, Dirix L, Beex L, Nooij MN, Cufer T, Lohrisch C, Biganzoli L, Van Hoorebeeck I, Duchateau L, Lobelle JP, Piccart M.

    Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; Robert.Paridaens@uz.kuleuven.ac.be

    Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicenter, randomized, open-label, TAM-controlled (20 mg/day), phase II trial, we examined the activity and tolerability of EXE 25 mg/day for the first-line treatment of MBC in postmenopausal women. Exemestane was well tolerated and demonstrated substantial first-line antitumor activity based on intent-to-treat analysis of peer-reviewed responses. In the EXE arm, values for complete, partial, and objective response, clinical benefit, and time to tumor progression (TTP) exceeded those reported for TAM although no statistical comparison was made. Based on these encouraging results, a phase III trial will compare EXE and TAM.

    PMID: 11970745 [PubMed - in process]

    --------------------------------------------------------------------------------


    34: Clin Breast Cancer 2000 Sep;1 Suppl 1:S15-8 Related Articles, Links


    Exemestane Improves Survival in Metastatic Breast Cancer: Results of a Phase III Randomized Study.

    Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, Salle E, Arkhipov A, Piscitelli G, Miller LL, Massimini G.

    Universitatsklinik, Frankfurt, Germany.

    We compared the efficacy and safety of the oral aromatase inactivator exemestane (EXE) with megestrol acetate (MA) in women with metastatic breast cancer. This phase III randomized, double-blind, multicenter study was conducted in 769 postmenopausal women who had experienced tamoxifen failure. Treatment arms consisted of EXE 25 mg once daily (n = 366) or MA 40 mg four times daily (160 mg daily; n = 403). Peer-reviewed, intent-to-treat analyses demonstrated that EXE induced a trend toward higher rates of complete re-sponse (CR) + partial response (PR) (15.0% vs. 12.4%) and of CR + PR + stable disease (SD) = 24 weeks (37.4% vs. 34.6%), but differences were not statistically significant. Statistically significant differences favoring EXE were seen in median duration of CR + PR + SD = 24 weeks (60.1 vs. 49.1 weeks; P = 0.025), time to tumor progression (20.3 vs. 16.6 weeks; P = 0.037), time to treatment failure (16.3 vs. 15.7 weeks; P = 0.042), and overall survival (not reached vs. 123.4 weeks; P = 0.039). Both treatments were well tolerated, but MA was associated with more grade 3 or 4 weight gain (8% vs. 17%, P = 0.001); the pain score was sim-ilar in both groups. There was a trend toward superiority in treatment-related signs and symptoms (TRSS) with EXE. There was greater improvement in the pain score and TRSS in patients achieving an objective response with EXE vs. MA. Quality of life improved or was similar for EXE in most domains. Exemestane offers an important new treatment option for postmenopausal women with hormone-responsive breast cancer.

    PMID: 11970744 [PubMed - in process]

    --------------------------------------------------------------------------------


    35: Cancer Control 2002 Mar-Apr;9(2 Suppl):9-15 Related Articles, Links


    Endocrine and clinical endpoints of exemestane as neoadjuvant therapy.

    Miller WR, Dixon JM.

    Breast Research Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK. w.r.miller@ed.ac.uk

    A series of in vitro and in vivo studies have been performed to establish the endocrine and clinical endpoints of the type I anti-aromatase agent exemestane in neoadjuvant therapy. In vitro studies demonstrated a dose-related inhibition of aromatase activity with exemestane, even when activity was measured in a system in which the aromatase enzyme was induced in fibroblasts preincubated with exemestane but assayed in the absence of the drug. In contrast, type II anti-aromatase agents (eg, aminoglutethimide, anastrozole, and letrozole) often caused a paradoxical increase in aromatase activity when measured under similar conditions. In vivo and in situ studies were performed in 12 postmenopausal women with untreated large or locally advanced estrogen receptor-rich tumors. The effect of exemestane 25 mg daily for 3 months on aromatization peripherally and in breast cancer and surrounding normal tissue was determined. Immediately before starting therapy, patients received an 18-hour infusion of radioactively labeled androgen and estrogen, followed by a wedge biopsy. This procedure was repeated after 3 months of treatment with exemestane, and the data were used to calculate peripheral and local aromatization. Changes in tumor volume were based on clinical examination, ultrasound, and mammography. Exemestane treatment was associated with a marked reduction in aromatization peripherally and in nonmalignant breast tissue in every patient and in breast tumor in all but one patient. Median reduction in tumor volume was 85.5% for clinical examination, 82.5% for ultrasound, and 84% for mammography. Eight of 10 patients who would have required mastectomy before treatment were able to undergo breast-conserving surgery after treatment. Clinical benefits were accompanied by a marked reduction in cellular proliferation and progesterone receptor expression. These data support the use of exemestane in neoadjuvant therapy of breast cancer in postmenopausal women.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11965226 [PubMed - indexed for MEDLINE]

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    36: Cancer Control 2002 Mar-Apr;9(2 Suppl):2-8 Related Articles, Links


    Anti-aromatase agents in the treatment and prevention of breast cancer.

    Goss P.

    Breast Cancer Prevention Program at the Princess Margaret Hospital, Toronto, Ontario, Canada. pegoss@interlog.com

    Anti-aromatase agents now have a central role in the management of breast cancer in postmenopausal women; they are superior to megestrol acetate as second-line therapy and to tamoxifen for initial therapy of metastatic disease. They also are highly active as neoadjuvant therapy. Two classes of anti-aromatase agents are available: steroidal (eg, exemestane) and nonsteroidal (eg, anastrozole, letrozole). Although both types of agents act on the aromatase enzyme, they do so by different mechanisms and have different effects on cellular aromatase activity. Nonsteroidal agents are associated with increased aromatase enzyme content and steroidal agents are associated with decreased content. The increase in aromatase content seen with the nonsteroidal agents may in part explain the development of resistance with these agents and the ability of the steroidal agent exemestane to induce a response when nonsteroidal agents fail. Because the anti-aromatase agents almost completely eliminate endogenous estrogen production, they not only affect breast cancer tissues, but also may alter the function of other estrogen-responsive tissues. However, preclinical data show that the steroidal agent exemestane may actually improve bone and lipid metabolism. In addition, no increase in clinical fracture rate has been noted in women treated with exemestane in metastatic trials; the fracture risk has not yet been studied following prolonged exposure in healthy women. Exemestane associated beneficial effects on these end organs may be due to the steroidal nature of both the parent compound and its principal metabolite, 17-hydroexemestane. Similar benefits have not been reported with nonsteroidal antiaromatase agents. Based on their excellent activity in the metastatic setting, anti-aromatase agents are now being evaluated in the adjuvant setting and in pilot studies for chemoprevention. These studies will provide long-term data in healthy women and will help to differentiate anti-aromatase agents, in terms of their efficacy in the treatment of breast cancer and their effects on end organs.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11965225 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    37: Harv Womens Health Watch 2002 Apr;9(8):7 Related Articles, Links


    New breast cancer drugs expand treatment options.

    Publication Types:
    News

    PMID: 11959538 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    38: Drugs 2002;62(6):957-66 Related Articles, Links


    Tamoxifen resistant and refractory breast cancer: the value of aromatase inhibitors.

    Goss PE, Strasser K.

    Breast Cancer Prevention Program, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada. pegoss@interlog.com

    Tamoxifen has dominated endocrine treatment of breast cancer for over two decades. It is useful in metastatic breast cancer, adjuvant therapy, preoperative treatment, ductal carcinoma-in-situ and chemoprevention. However, breast cancer may be refractory to tamoxifen or develop resistance to it with ongoing treatment. This resistance involves several mechanisms including receptor mutation causing 'estrogen hypersensitivity' and an increasing agonist effect of tamoxifen. Megestrol (megestrol acetate), in North America, and aminoglutethimide, in Europe, have been the traditional second line therapies after tamoxifen in advanced breast cancer. Aromatase (estrogen synthetase) inhibitors are a logical alternative to tamoxifen to antagonise the effects of estrogen on breast cancer. The third-generation non-steroidal aromatase inhibitors anastrozole, letrozole and vorozole, and the steroidal inhibitor exemestane, have been studied after tamoxifen versus either megestrol or aminoglutethimide. They showed enhanced efficacy and significantly superior toxicity profiles. Compliance with the inhibitors was also significantly better than with the traditional treatments. Aromatase inhibitors have most recently been shown to be superior to tamoxifen as initial therapy and are being extensively tested in the adjuvant setting after, or instead of, tamoxifen. Pilot studies of chemoprevention are also being undertaken. The aromatase inhibitors are an important new addition to the armamentarium of breast cancer therapy.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11929341 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    39: Clin Cancer Res 2001 Dec;7(12 Suppl):4402s-4410s; discussion 4411s-4412s Related Articles, Links


    Future use of selective estrogen receptor modulators and aromatase inhibitors.

    Howell A.

    CRC Department of Medical Oncology, University of Manchester, Christie Hospital, United Kingdom.

    Selective estrogen receptor modulators (SERMs) may act as estrogens or antiestrogens depending on the cell and tissue targets. The triphenylethylene SERMs are represented by tamoxifen and toremifene and a new agent with a novel carboxylic acid side chain (GW5638). Because of isomerization in the triphenylethylene molecule, "fixed ring" SERMs were introduced. The major one in development is the benzothiophene arzoxiphene (LY353381), which is now in Phase III clinical trial versus tamoxifen. A fourth group of SERMs is based on the estrogen molecule and comprises the so-called "pure" antiestrogen ICI 182,780 (fulvestrant, Faslodex) and a new oral analogue just entering trials, SR16234. The steroidal aromatase inhibitors [AIs (40H androstenedione 'and exemestane)] inactivate aromatase, whereas the triazole AIs (anastrozole and letrozole) inhibit the enzyme via the heme prosthetic group. Thus, there are two groups of AIs that show relative non-cross-resistance in advanced breast cancer and four groups of SERMs that also show a high degree of non-cross-resistance. With six different treatments and six or more clinical situations (prevention, neoadjuvant, adjuvant, and first- and second-line treatments for advanced disease) in which they may be used, the possible combinations of treatment are enormous. At present, we have few clinical pointers to optimal sequence of treatments. Now that most of the appropriate comparative trials have been performed, it may be the time to initiate novel approaches. These include alternating and sequential treatments, preferably with treatments changed before overt progression occurs.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11916232 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    40: Clin Cancer Res 2001 Dec;7(12 Suppl):4397s-4401s; discussion 4411s-4412s Related Articles, Links


    Preliminary data from ongoing adjuvant aromatase inhibitor trials.

    Goss PE.

    Princess Margaret Hospital, Toronto, Ontario, Canada. pegoss@interlog.com

    With recent results showing letrozole and anastrozole to be superior to tamoxifen as initial therapy for advanced disease, the aromatase inhibitors are poised to establish their place in the adjuvant therapy of postmenopausal receptor-positive breast cancer. A review of the rationale, design, and preliminary results of the ongoing adjuvant trials that include aromatase inhibitors will be presented, along with the ongoing or planned substudies. Two strategies employing aromatase inhibitors after tamoxifen are being evaluated. The MA.17 international intergroup trial is randomizing postmenopausal patients who are disease-free after 5 years of adjuvant tamoxifen to an additional 5 years of letrozole or placebo. In a similar design, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B33 trial is randomizing this patient population to 2 years of exemestane or placebo after the standard 5 years of adjuvant tamoxifen. The second approach under study is the use of both aromatase inhibitor and tamoxifen in sequence within the first 5 postoperative years. The International Cancer Collaboration Group (ICCG) trial is comparing 2 years of exemestane after 3 years of tamoxifen to a standard 5-year course of tamoxifen. Similarly, the ARNO trial is comparing 5 years of tamoxifen versus 2 years of tamoxifen followed by 3 years of anastrozole. In a four-arm study Breast International Group/Femara-Tamoxifen (BIG/FEMTA) conducted by the BIG, one arm contains letrozole given for 3 years after 2 years of tamoxifen. Several trials are investigating the role of anastrozole, letrozole, or exemestane as a 5-year adjuvant therapy to replace the standard 5 years of tamoxifen. Only the Arimidex and Tamoxifen, Alone or in Combination (ATAC) trial is testing a 5-year combination of tamoxifen plus an aromatase inhibitor in this setting. Companion studies of effects on end-organs other than the breast are ongoing in a number of these trials. Aromatase inhibitors are poised to alter the treatment paradigm of breast cancer and hopefully improve outcome for a substantial number of patients.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11916231 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    41: Clin Cancer Res 2001 Dec;7(12 Suppl):4360s-4368s; discussion 4411s-4412s Related Articles, Links


    Are differences in the available aromatase inhibitors and inactivators significant?

    Johnson PE, Buzdar A.

    Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

    Aromatase inhibitors are endocrine agents with a different mode of action than tamoxifen against breast tumors. In postmenopausal women, estrogen concentrations are maintained primarily via aromatase, a cytochrome P-450 enzyme that acts at the final step in the estrogen synthesis pathway. The first clinically available aromatase inhibitor, aminoglutethimide, was introduced for the second-line treatment of advanced breast cancer in the late 1970s. Despite proven efficacy in this setting, its widespread use was limited by its overall toxicity and its lack of selectivity for the aromatase enzyme. This led to the search for novel, more effective, and less toxic aromatase inhibitors. As a result, several aromatase inhibitors with a high degree of selectivity for aromatase and improved tolerability have become clinically available for the treatment of postmenopausal women with advanced breast cancer: (a) anastrozole; (b) letrozole; (c) fadrozole; (d) formestane; and (e) exemestane. Of these, formestane and exemestane are steroidal nonreversible aromatase inhibitors, also known as aromatase inactivators, whereas fadrozole, anastrozole, and letrozole are nonsteroidal reversible aromatase inhibitors. These agents differ in pharmacokinetics, selectivity, and potency, although all are more selective than aminoglutethimide. Some differences in adverse effect profile are also noticeable between and within these two classes of agents. The clinical significance of these differences is not yet evident but may well prove to be relevant in the long-term adjunctive setting.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11916226 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    42: Clin Cancer Res 2001 Dec;7(12 Suppl):4356s-4359s; discussion 4411s-4412s Related Articles, Links


    The role of tamoxifen and aromatase inhibitors/inactivators in postmenopausal patients.

    Pritchard KI.

    Toronto-Sunnybrook Regional Cancer Centre, University of Toronto, Ontario, Canada. kathy.pritchard@tsrcc.on.ca

    The traditional hormonal cascade of the 1970s and 1980s used tamoxifen followed by megestrol acetate and subsequently by aminoglutethimide. In the 1990s, however, three trials of third-generation aromatase inhibitors (AIs) compared with megestrol acetate and two trials of third-generation AIs compared with aminoglutethimide showed improved efficacy and decreased toxicity for the newer AIs. Thus, the hormonal cascade changed in the late 1990s, to one in which tamoxifen, followed by a third-generation Aromatase inhibitor (AI), followed by megestrol acetate, seemed more suitable. Now, however, several trials comparing anastrozole, letrozole, and exemestane to tamoxifen as first-line hormonal agents for metastatic breast cancer have shown that these drugs are at least equivalent and perhaps superior to tamoxifen in that setting in terms of response rate and time to progression. Results from 1021 patients randomized to receive anastrozole versus tamoxifen showed a slightly improved overall response rate (RR; 29% versus 26%), slightly improved clinical benefit (CB; 57% versus 52%), and a significantly improved time to progression (TTP; 8.5 months versus 7.0 months) in favor of anastrozole. In 907 women randomized to treatment with letrozole versus tamoxifen, significantly improved RR (30% versus 20%), CB (49% versus 38%), and TTP (9.4 months versus 6 months) have all been shown for those treated with letrozole. In addition, a randomized Phase II trial of 121 patients has shown nonsignificant benefits in favor of exemestane (RR 41% versus 14%; CB 56% versus 42%; TTP not available). To date, none of these trials has demonstrated any overall survival benefit. Additional follow-up in regard to survival in the trial of tamoxifen versus letrozole and an expanded Phase III trial of tamoxifen versus exemestane are ongoing.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11916225 [PubMed - indexed for MEDLINE]

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    43: Curr Med Res Opin 2001;17(3):217-22 Related Articles, Links


    Aromatase inhibitors.

    Cunnick GH, Mokbel K.

    St George's Breast Cancer Centre, St George's Hospital, London, UK.

    The new non-steroidal and steroidal aromatase inhibitors are at least as effective as megestrol acetate (MA) as second-line hormonal agents in postmenopausal women with breast cancer. However, they are superior to MA in terms of tolerability and adverse effects. Letrozole and exemestane have been shown to be superior to MA in terms of efficacy. Furthermore, exemestane and anastrozole demonstrated a survival advantage over MA. These drugs are therefore considered established second-line hormonal agents. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors as first-line therapy for ER-and/or PgR-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor positive tumours unsuitable for breast conserving surgery. Studies comparing these drugs head-to-head and with adjuvant tamoxifen are currently in progress. The potential role of these drugs in breast cancer prevention is worth investigating.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11900315 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    44: Clin Breast Cancer 2000 Oct;1(3):211-6 Related Articles, Links


    Exemestane: a novel aromatase inactivator for breast cancer.

    Jones SA, Jones SE.

    Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.

    Exemestane is a unique inactivator of the aromatase enzyme and differs from the two approved aromatase inhibitors. It is well absorbed at a daily oral dose of 25 mg and produces significant suppression of aromatase and plasma estrogen levels without androgenic side effects. Toxicity is mild with menopausal symptoms predominating. Exemestane is approved for the treatment of postmenopausal women with recurrent breast cancer. In reported clinical trials, exemestane was effective in patients failing tamoxifen, megestrol acetate, or even other aromatase inhibitors in phase II trials and was superior to megestrol acetate in a phase III randomized trial in which an early survival advantage for exemestane was observed. Studies evaluating first-line exemestane for adjuvant use and as a chemopreventive agent are underway.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11899645 [PubMed - indexed for MEDLINE]

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    45: Pharmacoeconomics 2002;20(2):101-8 Related Articles, Links


    Cost-effectiveness analysis of exemestane compared with megestrol in advanced breast cancer: a model for Europe and Australia.

    Lindgren P, Jonsson B, Redaelli A, Radice D.

    Stockholm Health Economics Consulting, Uppsala, Sweden. peter.l@healtheconomics.se

    OBJECTIVE: To investigate the cost effectiveness of exemestane compared to megestrol in post-menopausal women after tamoxifen failure. DESIGN AND SETTING: A modelling study from the third-party payer perspective in Australia, Belgium, France, Germany, Italy, The Netherlands, Spain and the United Kingdom. METHODS: A model was constructed, based on and driven by data on survival from a clinical study of these agents, including costs for exemestane and megestrol and costs for other treatments. Data from an observational study were used to calculate a country-specific daily cost for the other treatments. Life-years gained was used as the measure of effectiveness. Simulations were performed for 1080 days ('within trial analysis') and for a life-time perspective, in which survival after the end of the trial was assumed to be the same as the trend during follow up. Costs were presented in 1999 values. MAIN OUTCOME MEASURES AND RESULTS: When running the model for 1080 days, the cost effectiveness of exemestane compared to megestrol varied between about EUR5000 and EUR13000 per life-year gained. In Germany it was much lower (EUR1353) due to a higher cost of megestrol. The total expected cost effectiveness (model running until no survivors left) ranged from EUR3700 (Germany) to EUR9100 (The Netherlands). The estimated cost per life-year gained is well within limits generally considered cost effective. CONCLUSIONS: Exemestane is cost effective compared with megestrol for postmenopausal women with progressive advanced breast cancer after therapy with tamoxifen.

    PMID: 11888362 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    46: MMW Fortschr Med 2002 Jan 31;144(5):46-8 Related Articles, Links


    [Aromatase inhibitors of the 3rd generation. What can the "pill against breast cancer" really do?]

    [Article in German]

    Junker A, Wiedemann GJ, Possinger K.

    Sana Klinikum Remscheld GmbH, Apotheke, Remscheid.

    Metastatic cancer of the breast in postmenopausal women can be treated with a number of "hormone-active" substances. The drugs of first choice are still anti-estrogens. Today, the three highly selective oral aromatase inhibitors anastrozole, letrozole and exemestane are additionally available for use in continuing progression under anti-estrogen treatment. Roughly one woman in three derives benefit from these new medications as reflected by objective remission or stabilization of the disease for more than 6 months. Neither chemical structure (steroidal/non-steroidal), nor the different nature of inhibition of the active centre of the aromatase, nor whether the inhibition of the enzyme is reversible or irreversible, has any influence on the parameters: response rate, response duration and clinical benefit.

    PMID: 11883037 [PubMed - indexed for MEDLINE]

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    47: Trends Endocrinol Metab 2002 Mar;13(2):61-5 Related Articles, Links


    Aromatase inhibitors in breast cancer.

    Brodie A.

    Department Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. abrodie@umaryland.edu

    Several compounds that selectively inhibit estrogen synthesis via aromatase have been developed. Steroidal substrate analogs, such as formestane and exemestane, inactivate aromatase by binding irreversibly to it. Non-steroidal inhibitors, such as the triazole compounds letrozole and anastrozole, are highly potent, reversible inhibitors with good specificity for aromatase. The intratumoral aromatase model for postmenopausal breast cancer has been used to investigate the efficacy of letrozole, anastrozole and exemestane in combination and sequentially. Combining letrozole or arimidex with tamoxifen or faslodex was not more effective than the aromatase inhibitors alone, but was more effective than tamoxifen alone. Letrozole was superior to and longer lasting than the other agents, suggesting that aromatase inhibitors control tumor growth effectively by inducing greater tumor response and extending treatment time. In addition, aromatase inhibitors can be effective in patients relapsing from tamoxifen. Because two types of aromatase inhibitors are available, steroidal enzyme inactivators and reversible non-steroidal inhibitors in sequential therapy could be useful if resistance to one type develops.

    PMID: 11854020 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    48: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):227-37 Related Articles, Links


    Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?

    Howell A, Howell SJ, Clarke R, Anderson E.

    CRC Department of Medical Oncology, Christie Hospital NHS Trust, M20 4BX, Manchester, UK. maria.parker@christie-tr.nwest.nhs.uk

    The agents used for endocrine therapy in patients with breast cancer have changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of choice, but could be replaced by the oestrogen receptor down-regulator ICI 182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III) soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase inhibitors of choice, they have been replaced by non-steroidal (anastrozole and letrozole) and steroidal (exemestane) inhibitors of high potency and low side effect profile. Previously, often used treatments such as progestogens (megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely used or confined to fourth or fifth line treatments. The LHRH agonist, goserelin, remains the treatment of choice for pre-menopausal patients with advanced breast cancer although recent randomised trials indicate a response, time to progression and survival advantage for the combination of goserelin and tamoxifen compared with goserelin alone.The newer treatments have led to questions concerning the optimum sequence of agents to use in advanced breast cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two trials of anastrozole compared with tamoxifen and one trial of letrozole compared with tamoxifen indicate that the new triazole aromatase inhibitors have a significant advantage over the anti-oestrogen with respect to time to progression and survival. Similarly, triazole aromatase inhibitors give faster and more complete responses compared with tamoxifen when used in post-menopausal women before surgery.Major research questions remain with respect to the aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone or in combination with tamoxifen compared with tamoxifen in the 'so-called' ATAC trial. Over 9000 patients have been randomised to this important study: the results will be available late-2001. A similar study comparing letrozole and tamoxifen started recently under the auspices of the Breast International Group. Importantly, this trial is also comparing the sequence of tamoxifen followed by letrozole (or vice versa). A similar trial of exemestane given after 2-3 years of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study comparing letrozole (or placebo) for 5 years after 5 years of adjuvant tamoxifen. These studies may show that aromatase inhibitors are superior to tamoxifen or that a sequence is preferable.ICI 182780 causes complete oestrogen receptor down-regulation leading to a the lack of agonist activity of the drug. Two trials of ICI 182780 compared with anastrozole for advanced disease will report later this year and a comparison with tamoxifen next year. Arzoxifene (SERM III) is being tested against tamoxifen. These studies are likely to result in new anti-oestrogens being introduced into the clinic.Most of our endocrine treatments deprived the tumour cell of oestradiol. In vitro experiments with MCF-7 cells indicate that tumour cells can adapt and then grow in response to low oestrogen concentrations in the tissue--culture medium. Importantly, the cells were shown to apoptose in response to high oestrogen concentrations. A recent clinical trial has demonstrated a high response rate to stilboestrol given after a median of four previous oestrogen depriving endocrine therapies. These data and the newer treatments available indicate a need to re-think our general approach to endocrine therapy and endocrine prevention.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11850229 [PubMed - indexed for MEDLINE]

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    49: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):133-41 Related Articles, Links


    Adjuvant trials of aromatase inhibitors: determining the future landscape of adjuvant endocrine therapy.

    Ragaz J.

    British Columbia Cancer Agency, 600, West 10th Avenue, British Columbia, V5Z 4E6, Vancouver, Canada. jragaz@bccancer.bc.ca

    This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant setting, and will summarize major strategies behind individual adjuvant trials using aromatase inhibitors. Studies with the third generation AIs including anastrozole, letrozole and exemestane, have shown better outcome and improved therapeutic ratio over second line hormonal approaches (i.e. progestins or aminoglutethimide) and, more recently, over tamoxifen also. These promising results have led recently to testing of AIs in the adjuvant setting for postmenopausal patients. Most trials now in progress are evaluating the role of new AIs versus tamoxifen (T) given x 5 years, which in most institutions is currently the standard hormonal adjuvant therapy for breast cancer. Three adjuvant approaches are being tested. First is the use of AI+T x 5 years in combination versus each agent alone, as reflected in the recently completed ATAC trial. Second is a sequential approach T first x 2-3 years followed by AIs x 2-3 years, or the other way round; and third, T x 5 years followed by AIs for additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many patients in the above trials will survive their first cancer. Hence, the non-oncological outcomes known to be affected by hormones are of rising importance. Therefore, the assessment of lipids as surrogates for cardiovascular morbidity, and of bone mineral status, as a marker for osteoporosis/bone fractures, is an important component of these trials. Also discussed in this review are proposals for future studies of AIs with focus on hormone resistance, such as early alteration of multiple hormonal agents or their intermittent use, the impact of the new generation of SERMs or 'pure' antiestrogens on activity of AIs, and the rising importance of AIs interacting with biologicals, cytokines or hormone modulators.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11850217 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    50: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):109-14 Related Articles, Links


    A summary of second-line randomized studies of aromatase inhibitors.

    Buzdar AU.

    Department of Breast Medical Oncology, M.D. Anderson Cancer Center, M.D. University of Texas, Box 424, 1515 Holcombe Blvd, Houston, TX 77030, USA. abuzdar@mdanderson.org

    The new generation of selective aromatase inhibitors (anastrozole, letrozole and exemestane) offer a significant efficacy and safety advantage over both older agents in this class (aminoglutethimide) and the progestins (megestrol acetate (MA)), as second-line treatment for postmenopausal women with advanced hormone-dependent breast cancer who have failed on tamoxifen therapy. Exemestane, a steroidal aromatase inhibitor, has been shown to have activity after failure with the non-steroidal aromatase inhibitors, anastrozole and letrozole, and could be used as third-line treatment. Although the newer aromatase inhibitors belong to the same class and appear, from indirect comparisons, to have similar efficacy compared with the older therapies, they have different pharmacokinetic and pharmacodynamic profiles, suggesting the potential for clinical differences. Compared with exemestane and letrozole, anastrozole shows greater selectivity for aromatase, as it lacks any evidence of an effect on adrenal steroidogenesis and has no androgenic effects. Therefore, it is clear that these agents should not be considered to be similar in all respects. In summary, the introduction of the aromatase inhibitors represents a significant step forward in the treatment of advanced breast cancer in postmenopausal women. Studies in the adjuvant setting will ultimately determine whether the differences in pharmacokinetics and phamacodynamics will be of clinical relevance.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11850214 [PubMed - indexed for MEDLINE]

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    51: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):93-102 Related Articles, Books, LinkOut


    Local endocrine effects of aromatase inhibitors within the breast.

    Miller WR, Dixon JM.

    Breast Unit, Department of Clinical Oncology, Western General Hospital, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK. w.r.miller@ed.ac.uk

    To determine the effects of aromatase inhibitors on oestrogen uptake, in situ aromatase activity and endogenous oestrogens in the breast, postmenopausal women with large primary ER-rich breast cancers have been treated neoadjuvantly for 3 months with either letrozole (2.5 or 10mg daily) or anastrozole (1 or 10mg daily) or exemestane (25mg daily). Patients were given an infusion of 3H-androstenedione and 14C-oestrone for 18h before and at the end of the study period. Blood, tumour and non-malignant breast were taken immediately after each infusion; oestrogens were extracted and purified. Tumour volume was measured before and during treatment at monthly intervals so that endocrinological changes could be related to clinical response. Treatment with each of the aromatase inhibitors was associated with a profound reduction in peripheral aromatase (as monitored by the level of plasma 3H-oestrone). There was no consistent effect on uptake of radioactively labelled oestrogen into breast tumours but a tendency for levels to increase after treatment in non-malignant breast. Conversely, therapy was associated with a marked inhibition of in situ oestrogen synthesis in both tumour and non-malignant breast (in occasional tissues, inhibitors appeared to be less effective but the effect was not related to clinical or pathological responses). Similar decreases were apparent in endogenous levels of oestrone and oestradiol. The absence of in situ aromatase activity tended to be associated with lack of clinical response to aromatase inhibition but the relationship was not absolute, limiting the utility of measurements of tumour aromatase as a predictive indices. Ex vivo studies of tissue aromatase indicated that such measurements consistently underestimate the inhibitory potential of reversible non-steroidal agents (and occasionally paradoxical in vitro increases in aromatase activity were seen with treatment). However, in situ assays demonstrate that new aromatase inhibitors such as anastrozole, exemestane and letrozole have profound effects on the local endocrinology within the postmenopausal breast, these being compatible with the clinico-pathological changes which occur with treatment.

    PMID: 11850212 [PubMed - indexed for MEDLINE]

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    52: J Steroid Biochem Mol Biol 2001 Dec;79(1-5):85-91 Related Articles, Books, LinkOut


    Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors.

    Boeddinghaus IM, Dowsett M.

    The Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road, SW3 6JJ, London, UK.

    The clinical development of aromatase inhibitors (AIs) has been closely guided by clinical pharmacological investigations. During the early phases of development studies were focused on dose-related pharmacological effectiveness and specificity. More recently attention has been given to the ********* changes which AIs elicit, with particular regard to their potential use in early breast cancer and the prophylactic setting. Pharmacological effectiveness has been studied with plasma oestrogen assays but primary oestrogens (E1 and E2) are not helpful in comparing the third generation inhibitors: anastrozole, letrozole, exemestane. All three of these compounds suppress whole body aromatisation by >96%. Most recently, we have established that significantly greater inhibition is achieved by letrozole than anastrozole at their clinically used dosages. This more complete inhibition is paralleled by significantly greater suppression of E1S.A broad panel of endocrine investigations has indicated that these compounds have essentially complete specificity at their clinical dosages. A minor androgenic effect of exemestane is revealed by a significant suppression of sex hormone binding globulin (SHBG). Lipid and bone biomarker data are being collected in many current studies. A pharmacokinetic interaction has been established between letrozole and tamoxifen, whereby reduced circulating levels of letrozole are found with combined application. Neither anastrozole nor letrozole have any effect on plasma concentrations of tamoxifen when given in combination with it.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11850211 [PubMed - indexed for MEDLINE]

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    53: Ann N Y Acad Sci 2001 Dec;949:134-42 Related Articles, Books, LinkOut


    The MORE trial: multiple outcomes for raloxifene evaluation--breast cancer as a secondary end point: implications for prevention.

    Dickler MN, Norton L.

    Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

    Breast cancer is a common disease in the United States and Europe and is therefore a major target for prevention strategies. Estrogen plays a central role in its pathogenesis, and treatment with estrogen deprivation has long been recognized to be an effective therapy. Tamoxifen is the first selective estrogen receptor modulator (SERM) to be widely used for the treatment of breast cancer and has been demonstrated to reduce the risk of breast cancer in high-risk women. Raloxifene is a second-generation SERM that has estrogenic effects on bone and lipid metabolism, and antiestrogenic effects on breast tissue. Unlike tamoxifen, raloxifene displays antiestrogenic effects on the endometrium and may serve as a safer alternative to tamoxifen in the prevention setting. The MORE trial is a multicenter randomized placebo-controlled trial designed to determine whether 3 years of raloxifene reduces the risk of fracture in postmenopausal women with osteoporosis. As a secondary end point of the trial, raloxifene was shown to reduce the risk of both in situ and invasive breast cancer by 65% (RR = 0.35; 95% CI = 0.21-0.58; P < 0.001). The benefits were most significant in women who developed estrogen receptor (ER)-positive cancers, with a relative risk of 0.10 (95% CI = 0.04-0.24). This reduced incidence of breast cancer may be due to an anticarcinogenic effect or to a slowing of growth of occult ER-positive cancer, with a shift to the right in the time-to-cancer curve. A second large-scale prevention trial in breast cancer comparing tamoxifen to raloxifene is presently enrolling cancer-free, but high-risk postmenopausal women (the STAR trial). Future directions include combined estrogen blockade of the breast by the addition of an aromatase inhibitor to a SERM. New trial designs, including those based on biochemical changes at the tissue level, will be required to allow future progress in this field with adequate rapidity.

    PMID: 11795345 [PubMed - indexed for MEDLINE]

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    54: Breast Cancer 2001;8(4):329-32 Related Articles, Books, LinkOut


    Aromatase and aromatase inhibitors.

    Toi M, Bando H, Saji S.

    Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113, Japan. maktoi77@wa2.so-net.ne.jp

    Aromatase inhibition provides both paracrine/intracrine and endocrine treatment. Recent accumulated data clarified that 3rd generation aromatase inhibitors potently suppress intratumoral estrogen synthesis particularly in postmenopausal patients. In the 2nd-line treatment for metastatic breast cancer patients, aromatase inhibitors achieved results antitumor activity at least equal to and sometimes better than that of tamoxifen. In the first-line treatment for metastatic breast cancer patients, a recent pivotal study clearly demonstrated that aromatase inhibitor was superior to tamoxifen. Based upon these results, various adjuvant trials which compare aromatase inhibitors with tamoxifen and attempt to determine optimal combination therapies and treatment periods with aromatase inhibitors are currently being conducted. In addition, preliminary studies conducted in neoadjuvant setting indicated that aromatase inhibitors showed an extremely high response rate, which predicts a future paradigm, that neoadjuvant therapy using aromatase inhibitors singly or in combination may become standard for hormone-responsive and post-menopausal breast cancer patients.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11791126 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    55: Breast Cancer 2001;8(4):305-9 Related Articles, Books, LinkOut


    Third-generation aromatase inhibitors in the treatment of advanced breast cancer.

    Nabholtz JM, Reese DM.

    Cancer Therapy Development Program and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Peter Ueberroth Building 3360B, 10945 Le Conte Avenue, Los Angeles, CA 90095-7077, USA. jean-marc.nabholtz@bcirg.com

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11791122 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    56: Surgery 2001 Dec;130(6):947-53 Related Articles, Books, LinkOut


    High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: a renewed role for adrenalectomy.

    Morris KT, Toth-Fejel S, Schmidt J, Fletcher WS, Pommier RF.

    Department of Surgery, Section of Surgical Oncology, Oregon Health Sciences University, Portland, OR 97201, USA.

    BACKGROUND: Stage IV hormone-sensitive breast cancer is often treated with aromatase inhibitors (anastrozole, letrozole, exemestane), which block the conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is intended to obviate the need for steroid replacement and antiquate adrenalectomy. METHODS: Patients who underwent oophorectomy and were being treated with new aromatase inhibitor therapy received serial measurements of serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during responsive and progressive phases of disease were compared. In vitro, human breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative) were treated with DHEA-S. Proliferation rates were measured by colorimetric assay. RESULTS: Disease in 12 of the 19 patients progressed. DHEA-S was less than 89 microg/dL in patients during the responsive phase and more than or equal to 89 microg/dL during disease progression, with 1 exception (P < .0005). Estrone and estradiol remained suppressed. After disease progression, the condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89 microg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells. CONCLUSIONS: DHEA-S levels more than or equal to 89 microg/dL predicted disease progression in states of low estrogen. Tissue culture results supported the role of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S.

    PMID: 11742322 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    57: Prescrire Int 2001 Aug;10(54):108-9 Related Articles, Books, LinkOut


    Exemestane: new preparation. No tangible advance in metastatic breast cancer after tamoxifen failure.

    (1) The reference second-line hormone treatment for breast cancer in postmenopausal women, after failure of anti-oestrogen therapy, is an aromatase inhibitor such as letrozole. (2) The clinical assessment file on exemestane, a new aromatase inhibitor licensed for this indication, contains no data from clinical trials versus letrozole or anastrozole, the other oral aromatase inhibitors. Data from non comparative trials fail to show whether cross-resistance between aromatase inhibitors exists. (3) In a double-blind trial involving 769 patients in whom tamoxifen had failed, the antitumour effect of exemestane appeared to be equivalent to that of the progestagen megestrol. (4) This trial showed that the adverse effect profile of exemestane was similar to that of other aromatase inhibitors, with mainly vasomotor flushes, nausea, fatigue and sweating. (5) In practice, the arrival of exemestane changes nothing in the hormone therapy of breast cancer in postmenopausal women, which should consist of tamoxifen (an anti-oestrogen) first; followed by the aromatase inhibitor letrozole if tamoxifen fails.

    PMID: 11718178 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    58: Cancer Chemother Pharmacol 2001 Oct;48(4):259-65 Related Articles, Books, LinkOut


    Role of anti-aromatase agents in postmenopausal advanced breast cancer.

    Murray R.

    Peter MacCallum Cancer Institute, St Andrew's Place, East Melbourne, Australia. robmurr@ozemail.com.au

    PURPOSE: Endocrine therapy is a well-recognized approach to the treatment of postmenopausal patients with advanced breast cancer, particularly those with estrogen receptor-positive tumors. The availability of anti-aromatase agents, both reversible (nonsteroidal) and irreversible (steroidal), provides clinicians with additional hormonal treatment options. METHODS: A MEDLINE search was conducted to identify studies that evaluated anti-aromatase therapy in the treatment of postmenopausal women with advanced breast cancer. In selecting studies, priority was given to randomized, controlled trials. RESULTS: Tamoxifen is the standard first-line therapy for advanced breast cancer. However, recent results have demonstrated the efficacy of newer anti-aromatase agents in this setting. Among patients who have progressed after tamoxifen therapy, anti-aromatase agents have emerged as first choice therapy based on their better tolerability and improved efficacy compared with megestrol acetate. Exemestane and anastrozole (irreversible and reversible anti-aromatase agents, respectively) have demonstrated survival benefits over megestrol acetate in second-line therapy. Anti-aromatase agents have also demonstrated efficacy in patients who have failed multiple hormonal therapies. Based on these data, an algorithm for the treatment of postmenopausal women with advanced breast cancer is proposed. CONCLUSIONS: The enhanced tolerability and superior efficacy of anti-aromatase inhibitors compared with megestrol acetate has resulted in these agents becoming the endocrine treatment of choice for women with advanced breast cancer who have progressed after tamoxifen treatment. The increased use of tamoxifen in the adjuvant setting and the demonstrated activity of aromatase inhibitors in first-line therapy will further increase the role of these agents.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11710624 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    59: BMJ 2001 Oct 20;323(7318):880-1 Related Articles, Books, LinkOut


    Aromatase inhibitors and inactivators in breast cancer.

    Lonning PE.

    Publication Types:
    Editorial

    PMID: 11668120 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    60: Clin Cancer Res 2001 Sep;7(9):2620-35 Related Articles, Books, LinkOut


    Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer.

    Buzdar A, Howell A.

    Department of Breast Medical Oncology, M. D., Anderson Cancer Center, University of Texas, Houston, 77030, USA.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11555572 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    61: Am J Ther 2001 Sep-Oct;8(5):333-44 Related Articles, Books, LinkOut


    Aromatase, aromatase inhibitors, and breast cancer.

    Brueggemeier RW.

    Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Hormones and Cancer Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. Brueggemeier.1@osu.edu

    Estrogens are involved in numerous physiologic processes and have crucial roles in particular disease states, such as mammary carcinomas. Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P-450 enzyme complex called aromatase. Aromatase is found in breast tissue, and the importance of intratumoral aromatase and local estrogen production is being unraveled. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in hormone-dependent breast cancer. Effective aromatase inhibitors have been developed as therapeutic agents for controlling estrogen-dependent breast cancer. Investigations into the development of aromatase inhibitors began in the 1970s and have expanded greatly in the past three decades. Competitive aromatase inhibitors are molecules that compete with the substrate androstenedione for noncovalent binding to the active site of the enzyme to decrease the amount of product formed. Steroidal inhibitors that have been developed to date build on the basic androstenedione nucleus and incorporate chemical substituents at varying positions on the steroid. The structure-activity relationships for steroidal inhibitors have become more refined in the past decade, and only some modifications can be made to the steroid and still keep its affinity for aromatase. Nonsteroidal aromatase inhibitors can be divided into three classes: aminoglutethimide-like molecules, imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase inhibitors are inhibitors that mimic the substrate, are converted by the enzyme to a reactive intermediate, and result in the inactivation of aromatase. Aromatase inhibitors, both steroidal and nonsteroidal, have shown clinical efficacy for the treatment of breast cancer. The initial nonselective nature of nonsteroidal inhibitors such as aminoglutethimide has been greatly reduced in the later generations of inhibitors, anastrozole and letrozole. Mechanism-based steroidal inhibitors such as 4-hydroxyandrostenedione and exemestane produce prolonged aromatase inhibition in patients. The potent and selective third-generation aromatase inhibitors anastrozole, letrozole, and exemestane are approved for clinical use as second-line endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11550075 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    62: Oncology (Huntingt) 2001 Aug;15(8):965-72; discussion 972, 977-9 Related Articles, Books, LinkOut


    Nonsteroidal and steroidal aromatase inhibitors in breast cancer.

    Hamilton A, Volm M.

    Kaplan Comprehensive Cancer Center, New York University, School of Medicine, New York 10016, USA. hamila01@med.nyu.edu

    Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies.

    Publication Types:
    Review
    Review Literature

    PMID: 11548977 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    63: Semin Oncol 2001 Jun;28(3):291-304 Related Articles, Books, LinkOut


    Endocrine therapy in the treatment of metastatic breast cancer.

    Buzdar AU.

    Department of Breast Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77037, USA.

    The goals of treating patients with metastatic breast cancer are to prolong survival, slow or halt disease progression, and enhance the patient's quality of life. In patients with estrogen receptor (ER)-positive cancers that are not progressing rapidly, endocrine therapy is generally the first treatment option. If a patient initially responds to an endocrine agent and then progresses, another endocrine agent may still provide benefit. Tamoxifen has been used as first-line therapy for metastatic breast cancer for many years. Until recently, no other endocrine agent has shown superiority to tamoxifen in this setting. The nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely accepted as second-line therapy after failure of tamoxifen; they have replaced megestrol acetate in this setting. Recently, anastrozole was shown to have at least equivalent efficacy and a superior side effect profile compared with tamoxifen for treating postmenopausal women in the first-line setting. Thus, this aromatase inhibitor has become a viable option for first-line therapy in postmenopausal women. Trials of letrozole in this setting are nearing completion. Exemestane has been shown to be an effective second-line agent and to have at least some efficacy as a third-line agent even after failure of a nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of new endocrine agents including the first member of a new class of endocrine agent, the estrogen-receptor downregulator class. Semin Oncol 28:291-304. Copyright 2001 by W.B. Saunders Company.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11402439 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    64: Oncology (Huntingt) 2001 May;15(5 Suppl 7):35-9 Related Articles, Books, LinkOut


    Adjuvant exemestane therapy after 5 years of tamoxifen: rationale for the NSABP B-33 trial.

    Mamounas EP.

    Case Western Reserve University, Cleveland, Ohio, USA. epmamounas@aol.com

    Tamoxifen (Nolvadex) has long been established as "standard" adjuvant therapy for receptor-positive, early-stage breast cancer. Results from clinical trials suggest that after approximately 5 years, tamoxifen may lose its effectiveness and may even become harmful if not stopped. At the time of tamoxifen discontinuation, "seemingly" disease-free patients may still have residual micrometastatic tumor cells. In a proportion of such patients, these cells may still be responsive to tamoxifen and thus could grow as a result of stopping the drug. The majority of clinical information, however, suggests that by 5 years of therapy, a greater proportion of patients will have micrometastatic tumor cells that have become resistant to tamoxifen and will be stimulated by continuation of the drug for a longer time. Because in both such cases the micrometastases are hormonally sensitive, a reasonable approach--in addition to stopping tamoxifen--is to decrease the level of estrogenic stimulation by introducing an aromatase inhibitor. The National Surgical Adjuvant Breast and Bowel Project is launching a clinical trial (NSABP B-33) to evaluate the sequential administration of 2 years of exemestane (Aromasin), a steroidal aromatase inactivator, after 5 years of tamoxifen in postmenopausal, receptor-positive patients who are disease-free at the time of tamoxifen discontinuation.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11396363 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    65: Oncology (Huntingt) 2001 May;15(5 Suppl 7):28-34 Related Articles, Books, LinkOut


    Aromatase inhibition and antiestrogen therapy in early breast cancer treatment and chemoprevention.

    Ingle JN.

    Mayo Clinic, Rochester, Minnesota, USA. ingle.james@mayo.edu

    The aromatase inhibitors represent an important class of hormonal agents for the management of breast cancer. The third-generation aromatase inhibitors have replaced megestrol acetate as second-line hormonal therapy in advanced breast cancer, and large clinical trials are maturing to establish their efficacy relative to tamoxifen (Nolvadex) in the first-line metastatic setting. The increased potency, increased specificity, and established efficacy of aromatase inhibitors in advanced breast cancer have provided the rationale for a large number of randomized trials in the adjuvant setting evaluating anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). These trials are addressing the value of these agents in sequence with, instead of, and in combination with tamoxifen. The relationship between estrogen exposure and breast cancer risk has long been accepted and traditionally related to estrogen-receptor-mediated events. The emergence of the estrogen genotoxicity hypothesis as a mechanism for breast cancer carcinogenesis provides additional rationale for considering aromatase inhibitors in the chemoprevention setting.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11396362 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    66: Vopr Onkol 2001;47(2):195-9 Related Articles, Books, LinkOut


    [Modern approaches to hormone therapy of breast cancer as a reflection of pathogenesis of the disease]

    [Article in Russian]

    Semiglazov VP.

    N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St. Petersburg.

    Experimental and epidemiological studies have pointed to a major role of estrogens in the pathogenesis of human breast cancer. The Oxford meta-analysis (1998) once again confirmed the efficacy of antiestrogens (tamoxifen) as adjuvant therapy. We need to know whether the new non-steroid antiestrogens (idoxifen, droloxifen and TAT-59) and selective estrogen receptor modulator (raloxifen), whith preclinical characteristics better than those of tamoxifen will be more efficient clinically. Large-scale trials to compare the new drugs with tamoxifen are under way. Faslodex, a pure antiestrogen, looks highly promising, too. Zoladex, a luteinising hormone-releasing hormone agonist, is looking as a better choice than ovariectomy or irradiation of the pelvis for ovarian ablation in premenopausal breast cancer. New aromatase inhibitors are more efficient than progestins and much safer than aminoglutethimide. It has been shown recently that these inhibitors keep metastatic breast cancer at bay longer, and with longer survival. The non-steroid inhibitors (anastrozole and letrozole) and the steroid oral drug exemestane are undergoing clinical trials as means of adjuvant treatment of breast cancer. The trial of arimidex and tamoxifen administered alone or in combination (ATAC) is unique since it is using a combination of tamoxifen and an aromatase inhibitor (anastrozole). New methods of endocrine therapy have resulted in less toxic and more convenient procedures. Also, longer therapeutic effects and survival are becoming more apparent.

    PMID: 11383456 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    67: Oncol Nurs Forum 2001 Apr;28(3):507-12; quiz 513-4 Related Articles, Books, LinkOut


    Erratum in:
    Oncol Nurs Forum 2001 Jun;28(5):794

    Metastatic breast cancer: understanding current management options.

    McGinn K, Moore J.

    Kaiser Permanente, South San Francisco, CA, USA. amcginn@microweb.com

    PURPOSE/OBJECTIVES: To review the standard treatment options for metastatic breast cancer, present recently approved chemotherapeutic and hormonal approaches, and describe novel biologic therapies, particularly the use of monoclonal antibodies. DATA SOURCES: Published articles, abstracts, and conference proceedings. DATA SYNTHESIS: Standard treatment options available to women with metastatic breast cancer include surgery, radiation therapy, hormonal therapy, chemotherapy, and palliative approaches. New chemotherapeutic approaches for the management of metastatic breast cancer include the recently approved agents paclitaxel, docetaxel, and capecitabine. New hormonal agents such as toremifene, letrozole, and exemestane also have been approved. Finally, an agent from a new class of agents--biologic response modifiers (BRMs)--now. Is available. Trastuzumab, a monoclonal antibody (one class of BRMs), is a new and promising approach available to a subpopulation of women with metastatic breast cancer. CONCLUSION: Although standard treatment options for the management of metastatic breast cancer may prolong survival for some, they have not resulted in a cure for the majority of women. Recent advances in the understanding of cancer cellular biology have led to newer approaches such as monoclonal antibodies and other BRMs that may offer hope of extended survival and improved quality of life for certain women. This field is growing quickly, and new targets for breast cancer therapy are being studied. IMPLICATIONS FOR NURSING PRACTICE: Nurses who become familiar with newer treatment options available for the management of metastatic breast cancer, including new chemotherapeutic and hormonal approaches and monoclonal antibody therapy, are better able to provide information and support for their patients. Clinicians must understand the criteria for patient selection for newer agents, particularly trastuzumab. In addition, recognizing adverse effects and knowing the management strategies for treatment-related toxicities help to ensure positive patient outcomes.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11338758 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    68: Reprod Toxicol 2001 Mar-Apr;15(2):195-213 Related Articles, Books, LinkOut


    Erratum in:
    Reprod Toxicol 2001 Sep-Oct;15(5):601-2

    Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits.

    Beltrame D, di Salle E, Giavini E, Gunnarsson K, Brughera M.

    Pharmacia & Upjohn, Worldwide Toxicology, 20014, Nerviano, Italy. diana.beltrame@eu.pnu.com

    Exemestane is an orally active, irreversible inactivator of aromatase, structurally related to the natural substrate androstenedione, in clinical use at 25 mg daily for the treatment of advanced breast cancer in postmenopausal women. The reproductive and developmental toxicity of exemestane was assessed in rats and rabbits with oral administration. Pivotal experiments included a fertility study (Segment I), in which female rats received exemestane doses of 4, 20, or 100 mg/kg/day from two weeks premating until GD 20 (cesarean-sectioned dams), or until GD 15 and then from D 1 to D 21 postpartum (dams allowed to deliver), and developmental toxicity studies (Segment II), in which rats and rabbits were treated from GD 6 through GD 17 (rats) or GD 18 (rabbits) at doses of 10, 50, 250, or 810 mg/kg/day and 30, 90, or 270 mg/kg/day, respectively. All rabbits and two-thirds of the rats were cesarean sectioned toward the end of pregnancy to determine litter parameters and examine structural abnormalities in the fetuses; the remaining one-third of the rats was allowed to litter and rear pups to weaning. No pivotal male fertility or peri- and postnatal studies were performed, taking into consideration the therapeutic use. Postnatal effects on the first generation offspring were assessed in both studies in rats, in the portion of dams allowed to deliver. Their F1 offspring were raised to adulthood, when they were evaluated for reproductive performance, and the F1 females were terminated on GD 20. The dosing schedule for the Segment I study in rats, which included a postnatal component, was established to exclude exposure before and during parturition (by withdrawing treatment from GD 16 until the end of parturition). This withdrawal of treatment was put in place because in a preliminary study with treatment including the peripartum period, doses from 5 to 200 mg/kg/day prolonged gestation and interfered with parturition.Overall, studies in rats showed that female fertility was not affected up to 100 mg/kg/day, but doses higher than 4 mg/kg/day, which is approximately the pharmacologically active dose (ED50 = 3.7 mg/kg), prolonged gestation and impaired parturition, leading to maternal deaths in labor and perinatal deaths of offspring. Rats killed on GD 20 showed nondose-related increases in resorptions at doses higher than 10 mg/kg/day, a reduction in fetal body weights at 20 and 100 mg/kg/day (fertility study) and 810 mg/kg/day (developmental toxicity study), and an increase in placental weights at all doses. Female fetuses exposed in utero until GD 20 at 100 mg/kg/day showed an increase in the anogenital distance, very likely related to an increase of the potent androgen DHT as a consequence of aromatase inhibition. Morphologic examinations in fetuses and born pups that were exposed in utero up to the end of the organogenesis period, as well as postnatal investigations on offspring up to adulthood, showed no treatment-related effects. In a developmental toxicity study in rabbits, treatment at 270 mg/kg/day affected maternal food intake and body weight gain, caused abortion or total resorption in about 30% of pregnant females, and reduced body weight and numbers of live fetuses, but did not affect fetal morphology. It was concluded that exemestane did not affect parturition in rats at 4 mg/kg/day or pregnancy in rabbits at 90 mg/kg/day (about 1.5 and 70 times the human dose, respectively, on a mg/m2 basis) and was not teratogenic in rats and rabbits.Exemestane is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women.

    PMID: 11297878 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    69: J Clin Oncol 2001 Apr 1;19(7):2107-8 Related Articles, Books, LinkOut


    Comment on:
    J Clin Oncol. 1999 Nov;17(11):3418-25.
    J Clin Oncol. 2000 Apr;18(7):1399-411.

    Steroidal side effects of exemestane.

    Nabholtz JM.

    Publication Types:
    Comment
    Letter

    PMID: 11283149 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    70: Bull Cancer 2000 Dec;87 Spec No:31-39 Related Articles, Books, LinkOut


    [Aromatase inhibitors: a review of clinical trials]

    [Article in French]

    Kerbrat P, Lefeuvre C.

    Departement d'oncologie medicale, Centre Eugene-Marquis, rue de la Bataille-Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France.

    To increase the therapeutic index of second line hormonal treatment of breast cancer, new aromatase inhibitors have been synthetized; they belong to two groups: type I (formestane and exemestane) are steroidal irreversible and specific inhibitors, type II (anastrozole, letrozole and vorozole) are non steroidal reversible inhibitors, interfering with the aromatase heme. Several phase II and III trials demonstrated that these drugs are, at least, as active as aminoglutethimid or progestins in second line treatment, and are less toxic. Recently, an identical activity have been observed for anastrozole and tamoxifen in first line. In metastatic and adjuvant settings, large trials are ongoing to clarify the exact value of these drugs.

    Publication Types:
    Review
    Review Literature

    PMID: 11250606 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    71: Bull Cancer 2000 Dec;87 Spec No:23-29 Related Articles, Books, LinkOut


    [Aromatase inhibitors: pharmacological aspects]

    [Article in French]

    de Cremoux P.

    Laboratoire de physiopathologie et de pharmacologie, Institut Curie, 26, rue d'Ulm, 75248 Paris Cedex 05, France.

    Selective new aromatase inhibitors are a new class of agents that are of considerable interest in the treatment of hormone-dependent breast cancer in postmenopausal women. Aromatase is an enzymic complex that catalyses the conversion of the adrenal androgens androstenedione and testosterone to estrone. In postmenopausal women, the process of peripheral aromatisation accounts for the majority of circulating estrogens. The selective inhibition of estrogen production by aromatase inhibitors is an efficient strategy for breast cancer treatment. These compounds are classified as irreversible inhibitors of aromatase (type I), and comprise steroidal compounds. Reversible inhibitors of aromatase, which comprises non-steroidal compounds are type II aromatase inhibitors. Second and third generation aromatase inhibitors are considerably more potent and more specific in their ability to inhibit aromatase, as compared with first generation compounds (aminoglutethimide).

    Publication Types:
    Review
    Review Literature

    PMID: 11250605 [PubMed - indexed for MEDLINE]

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    72: Bull Cancer 2000 Dec;87 Spec No:7-22 Related Articles, Books, LinkOut


    [Preclinical evaluation of aromatase inhibitors antitumor activity]

    [Article in French]

    Auvray P, Bichat F, Genne P.

    Oncodesign Biotechnology, Parc technologique de la Toison-d'Or, 28, rue de Broglie, 21000 Dijon, France.

    Aromatase is an enzymatic complex responsible for the conversion of androgens into estrogens; these hormones are important in development, reproduction, but also in the growth of estrogen-dependent cancer. This enzyme is present in 60-70% of the breast cancer. The aromatase inhibitors are important drugs in the breast cancer treatment of postmenopausal women. In order to study their in vivo activity, animal models have been developed, e.g. rat with tumour induced by 7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice with aromatase transfected MCF-7 xenograft. In this review, we were interested in preclinical results obtained with both classes: steroidal and nonsteroidal inhibitors. The former group, as substrate analogs formestane or exemestane, are irreversible, selective and long-lasting inhibitors of aromatase. The nonsteroidal molecules, such as letrozole or anastrozole, are reversible inhibitors with high affinity. Finally, knowledge of the enzyme active site, with molecular modeling and site-directed mutagenesis, could be useful to develop new inhibitor families, more specific and potent in vivo.

    Publication Types:
    Review
    Review Literature

    PMID: 11250604 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    73: Cancer 2001 Feb 1;91(3):484-9 Related Articles, Books, LinkOut


    Cost-effectiveness analysis of exemestane compared with megestrol in patients with advanced breast carcinoma.

    Hillner BE, Radice D.

    Department of Internal Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA 23298-0170, USA. hillner@hsc.vcu.edu

    BACKGROUND: The objective of this study was to determine the potential economic implications resulting from using exemestane (EXE), a new steroidal, irreversible aromatase inactivator, compared with megestrol acetate (MA) in patients with advanced breast carcinoma. METHODS: The model used the clinical results from the manufacturer-sponsored, international, randomized, controlled, double-blind trial of patients with postmenopausal, tamoxifen-refractory advanced breast carcinoma. Seven hundred sixty-nine women were randomized to EXE 25 mg per day or MA 40 mg four times daily EXE was well tolerated, significantly delayed tumor progression (relative risk [RR], 0.82; 95% confidence interval [95% CI], 0.70-0.97), and prolonged survival (RR, 0.77; 95% CI, 0.59-0.99). Lifetime effectiveness projections were made using the trial efficacy results to the U.S. market using a 1000-day ( approximately 3-year) time frame. Because the median survival of patients who received EXE was not reached, it was projected from the Cox model. There were no differences in the rate of hospitalization. The average wholesale prices for EXE and MA were used. RESULTS: Patients who received EXE were projected to have a mean survival benefit of 53.5 days (estimated 95% CI, 2-100 days) and to incur at an additional cost of $1559 per patient (estimated 95% CI, 880-2075 dollars). The incremental cost effectiveness (CE) ratio using EXE was 10,600 dollars per life year gained (estimated 95% CI, 6200-209,000 dollars). If MA had no costs, then the CE ratio increased to 12,200 dollars per life year. Using a 5-year projection, the CE ratio for EXE was 5900 dollars per life year. The projected survival at 1000 days was 53.9% in the EXE cohort compared with 44.8% in the MA cohort. CONCLUSIONS: EXE, compared with MA, is projected to increase survival at a modest added cost. If treatment with EXE delays or defers initiating more costly therapies, then it may even be cost saving. Copyright 2001 American Cancer Society.

    Publication Types:
    Clinical Trial
    Randomized Controlled Trial

    PMID: 11169930 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    74: J Clin Oncol 2001 Feb 1;19(3):881-94 Related Articles, Cited in PMC, Books, LinkOut


    Comment in:
    J Clin Oncol. 2001 May 15;19(10):2767.

    Aromatase inhibitors in the treatment and prevention of breast cancer.

    Goss PE, Strasser K.

    Division of Hematology/Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada. pegoss@interlog.com

    PURPOSE: The purpose of this article is to provide an overview of the current clinical status and possible future applications of aromatase inhibitors in breast cancer. METHODS: A review of the literature on the third-generation aromatase inhibitors was conducted. Some data that have been presented but not published are included. In addition, the designs of ongoing trials with aromatase inhibitors are outlined and the implications of possible results discussed. RESULTS: All of the third-generation oral aromatase inhibitors--letrozole, anastrozole, and vorozole (nonsteroidal, type II) and exemestane (steroidal, type I)--have now been tested in phase III trials as second-line treatment of postmenopausal hormone-dependent breast cancer. They have shown clear superiority compared with the conventional therapies and are therefore considered established second-line hormonal agents. Currently, they are being tested as first-line therapy in the metastatic, adjuvant, and neoadjuvant settings. Preliminary results suggest that the inhibitors might displace tamoxifen as first-line treatment, but further studies are needed to determine this. CONCLUSION: The role of aromatase inhibitors in premenopausal breast cancer and in combination with chemotherapy and other anticancer treatments are areas of future exploration. The ongoing adjuvant trials will provide important data on the long-term safety of aromatase inhibitors, which will help to determine their suitability for use as chemopreventives in healthy women at risk of developing breast cancer.

    Publication Types:
    Review
    Review Literature

    PMID: 11157042 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    75: Anticancer Drugs 2000 Oct;11(9):701-6 Related Articles, Books, LinkOut


    Survival in patients with metastatic breast cancer: analysis of randomized studies comparing oral aromatase inhibitors versus megestrol.

    Messori A, Cattel F, Trippoli S, Vaiani M.

    Laboratorio SIFO di Farmacoeconomia, Centro Informazione Farmaci, Azienda Ospedaliera Careggi, Florence, Italy. md3439@mclink.it

    In patients with metastatic breast cancer, second-line therapy with aromatase inhibitors can improve survival in comparison with megestrol. We conducted a meta-analysis to assess the effectiveness of aromatase inhibitors versus megestrol. After a Medline search, three trials (evaluating letrozole, anastrozole or exemestane versus megestrol) were included in the survival meta-analysis. Our methodology retrieved patient-level information on survival. In comparison with megestrol, aromatase inhibitors prolonged survival at levels of statistical significance (relative death risk for oral aromatase inhibitors=0.79, 95% confidence interval 0.69-0.91; p=0.0011). A lifetime analysis of the pooled survival curves of aromatase inhibitors versus megestrol found a mean survival gain of 4.1 months per patient. Aromatase inhibitors confer a significant survival benefit to patients with metastatic breast cancer as compared with megestrol. A preliminary calculation of the cost per life year gained shows that the pharmacoeconomic profile of these drugs is favorable.

    Publication Types:
    Meta-Analysis

    PMID: 11129731 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    76: Anticancer Drugs 2000 Sep;11(8):609-16 Related Articles, Books, LinkOut


    Exemestane in advanced breast cancer.

    Buzdar A.

    University of Texas MD Anderson Cancer Center, Houston 77030, USA. abuzdar@mdanderson.org

    Exemestane is an orally active steroidal aromatase inhibitor that has demonstrated efficacy in the treatment of postmenopausal patients with advanced breast cancer. This compound exhibits a good tolerability and safety profile, which may result from its highly selective mechanism of action. Exemestane binds irreversibly to the aromatase enzyme causing inactivation of the enzyme. This irreversible loss of enzyme may contribute to the sustained inhibition of estrogen synthesis noted following exemestane administration. Exemestane is a potent inhibitor of aromatization reducing estrogen synthesis in vivo by greater than 97%. The recommended dose of exemestane is 25 mg once daily. Although dosages up to 600 mg/day have been tested, the maximum tolerated dose of exemestane has not been reached in clinical study. The most frequently reported drug-related adverse events are hot flushes, nausea and fatigue, which are consistent with the estrogen-suppressive effects of the drug. Discontinuation due to adverse events is rare. Exemestane is a safe and well-tolerated alternative for the treatment of postmenopausal patients with advanced breast cancer.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11081451 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    77: Expert Opin Investig Drugs 2000 Aug;9(8):1897-905 Related Articles, Books, LinkOut


    Pharmacology and clinical experience with exemestane.

    Lonning PE.

    Department of Medicine, Section of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway. plon@haukeland.no

    Since the introduction of the first generation aromatase inhibitor, aminoglutethimide, for breast cancer treatment 30 years ago, we now have at hand novel, potent and well-tolerated steroidal and non-steroidal compounds, allowing near complete inhibition of oestrogen synthesis. The third-generation aromatase inhibitor, or more accurately termed inactivator, exemestane, is a potent suppressor of oestrogen synthesis and is shown to be an effective antitumour agent in postmenopausal breast cancer patients. Exemestane has been shown to be effective in patients failing multiple endocrine regimens. A large randomised study has revealed that exemestane improves time-to-disease progression as well as overall survival compared with megestrol acetate as second-line therapy in patients failing tamoxifen. In current studies, exemestane is compared with tamoxifen as first-line therapy for metastatic disease. Sequential therapy with tamoxifen followed by exemestane is also being compared with tamoxifen monotherapy in the adjuvant setting. In addition, the drug may have potential for breast cancer prevention.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11060785 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    78: Eur J Cancer 2000 Sep;36 Suppl 4:S86-7 Related Articles, Books, LinkOut


    Exemestane improves survival compared with megoestrol acetate in postmenopausal patients with advanced breast cancer who have failed on tamoxifen. results Of a double-blind randomised phase III trial.

    Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Cervek J, Fowst C, Polli A, Di Salle E, Massimini G, Piscitelli G.

    Universitatsklinik, Goethe-Universitat, 60596, Frankfurt, Germany. m.kaufmann@em.uni-frankfurt.de

    Exemestane is an aromatase inactivator. 769 Postmenopausal women with advanced breast cancer who had failed on tamoxifen were randomised to exemestane or megoestrol acetate in this double-blind trial. Objective response rate was similar between treatments. Median time to progression, time to treatment failure and overall survival was significantly longer with exemestane. Drug-related withdrawals and drug-related deaths were more common with megoestrol acetate.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase III
    Multicenter Study
    Randomized Controlled Trial

    PMID: 11056333 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    79: Eur J Cancer 2000 Sep;36 Suppl 4:S81-2 Related Articles, Books, LinkOut


    Clinico-pharmacological aspects of different hormone treatments.

    Lonning PE.

    Department of Oncology, Haukeland University Hospital, N-5021, Bergen, Norway. plon@haukeland.no

    During the last decade, several new drugs and classes of drugs have become available for breast cancer treatment. Thus, in addition to tamoxifen we have got several new selective oestrogen receptor modulators (SERMs) with a partially different pharmacological profile. The first generation aromatase inhibitor, aminoglutethimide, has been replaced by more potent and less toxic inhibitors belonging to the triazole class (anastrozole and letrozole) and, more recently, the steroidal aromatase inactivator exemestane [1-3]. These drugs have all revealed a better toxicity profile and, in general, an improved antitumour activity, compared with conventional therapy. Faslodex, the first representative of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in patients resistant to tamoxifen [4].

    PMID: 11056330 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    80: Hosp Med 2000 Sep;61(9):650-5 Related Articles, Books, LinkOut


    Irreversible aromatase inactivation: treatment for breast cancer.

    Johnston SR.

    Royal Marsden Hospital, London.

    Third-generation aromatase inhibitors extend treatment options for postmenopausal breast cancer patients refractory to initial antioestrogen therapy. This article reviews advances and recent developments in hormonal therapy, focusing in particular on exemestane, a new class of aromatase inactivator.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11048608 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    81: Oncology (Huntingt) 2000 Sep;14(9):1291, 1294 Related Articles, Books, LinkOut


    Longer time to tumor progression with exemestane vs tamoxifen in advanced breast cancer.

    Publication Types:
    News

    PMID: 11033826 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    82: Int J Oncol 2000 Nov;17(5):1037-41 Related Articles, Books, LinkOut


    New aromatase inhibitors in the treatment of advanced breast cancer.

    Crucitta E, Lorusso V, Attolico M, Sambiasi D, Mazzei A, De Lena M.

    Operative Unit of Medical Oncology, Oncology Institute of Bari, Bari, Italy.

    New aromatase inhibitors are an exciting treatment option for postmenopausal women with hormone sensitive breast cancer. They have been shown to reduce tumors in a significant number of patients, and exhibit definite antitumor activity at a relatively low daily dose, and are highly potent, highly selective, and well-tolerated. Results from recent clinical phase III studies have confirmed their efficacy and the key role they have in the therapy for advanced breast cancer in postmenopausal women. The agents available for clinical use are: letrozole, anastrozole, and exemestane. These drugs have demonstrated high activity in women failing tamoxifen in locally advanced or metastatic disease. This communication reviews the clinical use of aromatase inhibitors, particularly in second and first line hormonal treatment of advanced breast cancer.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11029510 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    83: Nippon Rinsho 2000 Apr;58 Suppl:322-7 Related Articles, Books, LinkOut


    [Aromatase inhibitors for treatment of advanced breast cancers]

    [Article in Japanese]

    Sonoo H.

    Department of Breast & Thyroid Surgery, Kawasaki Medical School.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 11026013 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    84: Rev Med Suisse Romande 2000 Jun;120(6):495-500 Related Articles, Books, LinkOut


    [Aromatase inhibitors in the treatment of breast cancer]

    [Article in French]

    Perey L.

    Centre pluridisciplinaire d'oncologie, Lausanne.

    PMID: 11014093 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    85: Eur J Cancer 2000 May;36(8):976-82 Related Articles, Books, LinkOut


    High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment.

    Kvinnsland S, Anker G, Dirix LY, Bonneterre J, Prove AM, Wilking N, Lobelle JP, Mariani O, di Salle E, Polli A, Massimini G.

    Radiumhospital, Oslo, Norway.

    This phase II, multicentre, open-label, clinical trial evaluated antitumoral efficacy, tolerability and endocrine effects following 25 mg of treatment with oral exemestane given daily to postmenopausal women with metastatic breast cancer. Eligibility criteria included oestrogen and/or progesterone positivity or a prior response to hormonal therapy if receptor status was unknown; prior failure to tamoxifen therapy; and progressive disease. Patients were divided into three strata: patients who did not respond to tamoxifen or progressed after disease stabilisation (SD) for less than 6 months (stratum 1); patients who, after an initial response or SD lasting at least 6 months, experienced disease progression whilst on tamoxifen (stratum 2); patients with recurrent metastatic disease during or within 12 months of discontinuing adjuvant tamoxifen (stratum 3). Of the 137 patients who received exemestane, 4 experienced a complete response (CR) and 28 a partial response (PR), for an overall response rate of 23%. Another 33 patients had SD for > or = 24 weeks, resulting in an overall success rate of 47%. The median time to objective response was 16.1 weeks (95% confidence interval (CI) 9.9-24.1). The median response duration was 69.4 weeks, the median duration of overall success 59.1 weeks, the median time to progression (TTP) 25.1 weeks and the median time to treatment failure (TTF) 24 weeks. Response to previous hormonal therapy had little effect on the results, except that there was a trend toward a higher overall success rate in patients who did not respond to previous hormonal therapy. After 8 weeks of therapy, serum levels of oestradiol (E2), oestrone (E1) and oestrone sulphate (E1S) were suppressed to 15.2%, 9.7% and 10.7% of baseline, respectively. The most common adverse events of drug-related or indeterminate cause were hot flushes (14%), dizziness (9%), nausea (8%) and increased sweating (5%). Exemestane had a favourable effect on performance status and tumour-related signs and symptoms, both of which improved or stabilised in approximately 67% and 68% of patients respectively. Exemestane is a unique therapy that is highly active and well tolerated as a new treatment for women with metastatic breast cancer.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase II
    Multicenter Study

    PMID: 10885600 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    86: Drugs 2000 Jun;59(6):1279-96 Related Articles, Books, LinkOut


    Exemestane: a review of its use in postmenopausal women with advanced breast cancer.

    Clemett D, Lamb HM.

    Adis International Limited, Mairangi Bay, Auckland, New Zealand. demail@adis.co.nz

    Exemestane is an orally active irreversible steroidal aromatase inactivator that effectively suppresses in vivo aromatase activity and circulating estrogen levels in postmenopausal women with advanced breast cancer. In clinical trials, tumour responses were elicited by exemestane regardless of disease site, importantly, in patients with visceral disease. In patients with disease refractory to tamoxifen, once daily exemestane 25 mg produced objective response rates of 15 to 28% that were sustained for a median duration of 69 to 76 weeks. In a large comparative study, exemestane and megestrol showed similar clinical efficacy according to objective response and overall success rates. However, the duration of overall success and times to disease progression and treatment failure were significantly prolonged with exemestane compared with megestrol. Additionally, a significant survival advantage for exemestane over megestrol was reported. Exemestane retains efficacy in patients refractory to multiple hormonal therapies. In patients whose disease had progressed after tamoxifen and megestrol, objective response rates of 11 and 13% were reported, and responses were similar regardless of whether megestrol resistance was de novo or acquired. Objective responses also occurred in studies that explored sequential use of exemestane after failure of aminoglutethimide (26% with exemestane 200 mg/day) or other nonsteroidal aromatase inhibitors (6.6% with exemestane 25 mg/day). Additionally, tumour responses (objective response 6.1%, overall success rate 24.7%) were reported in patients who had not responded to their last hormonal treatment. As first-line treatment, once daily exemestane 25 mg elicited objective and overall success rates of 42 and 58%, compared with 16 and 31% for once daily tamoxifen 20 mg. Exemestane was generally well tolerated in clinical trials at once daily dosages up to 600 mg. At the 25 mg recommended once daily dosage, the most commonly occurring adverse events were nausea, hot flushes, fatigue, increased sweating and dizziness. Weight gain occurred in significantly more patients receiving megestrol than among those treated with exemestane. Androgenic events have been reported in a small number of patients receiving once daily exemestane 200 mg, but were rarely reported at the recommended dosage. Conclusions: Exemestane is effective in postmenopausal patients with tamoxifen-refractory advanced breast cancer, prolonging time to disease progression and treatment failure and improving survival compared with megestrol treatment. Moreover, exemestane has an acceptable tolerability profile and a convenient once daily oral dosage regimen. Available data indicate that exemestane maintains its efficacy in patients with visceral metastases and does not show cross-resistance with nonsteroidal aromatase inhibitors. Preliminary data indicate that exemestane is also effective as first-line therapy for advanced breast cancer.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10882163 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    87: J Clin Oncol 2000 Jun;18(11):2234-44 Related Articles, Books, LinkOut


    Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial.

    Lonning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mickiewicz E, Celio L, Pitt P, Mita M, Aaronson NK, Fowst C, Arkhipov A, di Salle E, Polli A, Massimini G.

    Department of Oncology, Haukeland University Hospital, Bergen, Norway. plon@haukeland.no

    PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase II
    Multicenter Study

    PMID: 10829043 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    88: Med Lett Drugs Ther 2000 Apr 17;42(1076):35-6 Related Articles, Books, LinkOut


    Exemestane for advanced breast cancer.

    PMID: 10803175 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    89: J Pharm Biomed Anal 2000 Apr;22(3):451-60 Related Articles, Books, LinkOut


    LC-MS-MS determination of exemestane in human plasma with heated nebulizer interface following solid-phase extraction in the 96 well plate format.

    Cenacchi V, Baratte S, Cicioni P, Frigerio E, Long J, James C.

    Pharmacia and Upjohn, Drug Metabolism Research, Milan, Italy.

    A sensitive, specific and rapid analytical method for the quantitation of exemestane (EXE) in human plasma has been developed. EXE, 6-methylen-androsta-1,4-diene-3,17-dione, is an orally active irreversible steroidal aromatase inhibitor used for the therapy of metastatic postmenopausal breast cancer, with estrogen-dependent pathological conditions. The method involves extraction of EXE from human plasma by solid phase extraction using C2 endcapped sorbent in the 96 well plate format (50 mg/2 ml). After conditioning of the sorbent with 1 ml of acetonitrile (x2) the plates were rinsed with 1 ml of water (x2). The prepared samples (0.5 ml plasma, spiked with [13C3] EXE as internal standard (IS) and diluted with 0.5 ml water) were loaded and drawn through the plate with a minimum of vacuum. The plates were then washed with 1 ml acetonitrile:water (10:90) followed by a drying step for 30 min at full vacuum. Elution was by 0.15 ml of 0.1% trifluoracetic acid in acetonitrile (x2) under a minimum of vacuum. Aliquots of 80 microl were finally injected into the LC-MS-MS system. A Zorbax SB C8 column (4.6 x 150 mm, 5 microm) was used to perform the chromatographic separation; the mobile phase was 100% acetonitrile. MS detection used the heated nebulizer interface, with multiple reaction monitoring (MRM) (297-->121 m/z for EXE and 300-->123 m/z for IS) operated in positive ion mode. A weighed linear regression analysis (weighing factor 1/x2) was used to calculate EXE concentration in standard and unknown samples. The method was fully validated in the concentration range 0.05-25 ng ml(-1).

    PMID: 10766362 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    90: Crit Rev Oncol Hematol 2000 Feb;33(2):137-42 Related Articles, Books, LinkOut


    Steroidal aromatase inhibitors in elderly patients.

    Bajetta E, Zilembo N, Bichisao E, Pozzi P, Toffolatti L.

    Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

    The choice of treatment for elderly breast cancer patients needs particular care because the presence of physiological functional impairments can modify the drug bioavailability in an unpredictable manner. Hormonal treatment remains one of the choices and, although tamoxifen has proved to be effective in any setting, the use of selective aromatase inhibitors is arousing. Depending on their chemical structure, aromatase inhibitors are either steroidal (such as exemestane and formestane) or non-steroidal (such as letrozole, vorozole and anastrozole). Formestane has been studied in elderly patients with breast cancer and has been found to induce an overall response rate of 51% (95% CI, 35-67%). The drug suppresses estradiol (E2) levels, and changes in other hormones (FSH, LH and SHBG) are observed, but with poor clinical significance, thus confirming its selectivity and potency. Formestane has also been demonstrated to be as effective as tamoxifen. Exemestane and non-steroidal aromatase inhibitors appear to be very promising drugs.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10737375 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    91: J Clin Oncol 2000 Apr;18(7):1399-411 Related Articles, Books, LinkOut


    Comment in:
    J Clin Oncol. 2000 Dec 15;18(24):4109.
    J Clin Oncol. 2001 Apr 1;19(7):2107-8.

    Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group.

    Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL, Massimini G.

    Universitatsklinik, Frankfurt, Germany.

    PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase III
    Multicenter Study
    Randomized Controlled Trial

    PMID: 10735887 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    92: Endocr Relat Cancer 1999 Mar;6(1):75-92 Related Articles, Books, LinkOut


    Use of aromatase inhibitors in breast carcinoma.

    Santen RJ, Harvey HA.

    Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.

    Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.

    Publication Types:
    Review
    Review, Academic

    PMID: 10732791 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    93: Endocr Relat Cancer 1999 Jun;6(2):259-63 Related Articles, Books, LinkOut


    Aromatase inhibitors and their use in the sequential setting.

    Coombes RC, Harper-Wynne C, Dowsett M.

    Cancer Research Campaign, Department of Cancer Medicine, Imperial College School of Medicine, Charing Cross Hospital, London, UK.

    Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that the main mechanism of action of aminogluthemide was via inhibition of the enzyme aromatase thereby reducing peripheral levels of oestradiol in postmenopausal patients. The second-generation drug, 4-hydroxyandrostenedione (formestane), was introduced in 1990 and although its use was limited by its need to be given parenterally it was found to be a well-tolerated form of endocrine therapy. Third-generation inhibitors include vorozole, letrozole, anastrozole and exemestane, the former three being non-steroidal inhibitors, the latter being a steroidal inhibitor. All are capable of inhibiting aromatase action by >95% compared with 80% in the case of 4-hydroxyandrostenedione. The sequential use of different generations of aromatase inhibitors in the same patients is discussed. Studies suggest that an optimal sequence of these compounds may well result in longer remission in patients with hormone receptor positive tumours.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10731118 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    94: Endocr Relat Cancer 1999 Jun;6(2):231-4 Related Articles, Books, LinkOut


    Use of aromatase inhibitors in the adjuvant treatment of breast cancer.

    Baum M.

    Institute of Surgical Studies, University College London, UK.

    The value of endocrine treatment of early breast cancer has been illustrated by the antioestrogen, tamoxifen, which has now been available for nearly 30 years. However, if the recognised side effects and pharmacological properties of tamoxifen are taken into consideration, it is possible that other endocrine treatments that are now available can provide equal or superior efficacy, along with improved tolerability. One such group of agents is the aromatase inhibitors specifically the new-generation triazole aromatase inhibitors, such as anastrozole and letrozole, which have both shown tolerability and efficacy advantages over standard treatments in postmenopausal women with advanced breast cancer. There are convincing reasons why the new generation of aromatase inhibitors have advantages over tamoxifen. For instance, from their agonist properties, the effects on the endometrium and tumour stimulation seen with tamoxifen would not be expected, nor would the visual disturbances that have been associated with the triphenylethylene compounds, including tamoxifen. A number of aromatase inhibitors, for instance, anastrozole, letrozole and exemestane, are currently being investigated for treatment of early breast cancer. The results of the trials of aromatase inhibitors and tamoxifen will, in the next few years, define whether or not the new-generation aromatase inhibitors have a role to play in the treatment of postmenopausal women with early breast cancer.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10731114 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    95: Endocr Relat Cancer 1999 Jun;6(2):219-25 Related Articles, Books, LinkOut


    Role of aromatase inhibitors in advanced breast cancer.

    Buzdar AU.

    Department of Medical Oncology, The University of Texas, MD Anderson University Cancer Center, Houston 77030, USA.

    A number of potent and selective non-steroidal aromatase inhibitors are now available for treatment of advanced breast cancer in postmenopausal women, of which anastrozole and letrozole, in particular, represent a significant advantage over the earlier agents in terms of both efficacy and tolerability. These agents are rapidly becoming established as the second-line therapy of choice in postmenopausal women with advanced disease, progressing on tamoxifen, and data on their efficacy as first-line treatment compared with tamoxifen will be available in the near future. Exemestane, a new, steroidal aromatase inhibitor which potentially lacks cross-resistance with non-steroidal agents is still in clinical development. The full potential of the new-generation aromatase inhibitors in the treatment of breast cancer is currently being investigated in a large program of clinical trials evaluating their use as adjuvant treatment following surgery in postmenopausal patients with early disease.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10731112 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    96: Endocr Relat Cancer 1999 Jun;6(2):187-95 Related Articles, Cited in PMC, Books, LinkOut


    Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

    Miller WR.

    Breast Research Unit, Western General Hospital, Edinburgh, UK.

    Both mammary adipose tissue and breast cancers have the ability to aromatize androgens into oestrogens. Such potential may maintain the growth of hormone-dependent tumours. It has therefore been important to determine the effects of new aromatase inhibitors such as formestane, exemestane, anastrozole and letrozole on oestrogen biosynthesis and concentrations of endogenous hormones within the breast. Studies based on in vitro incubations of breast cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50 nM (although the relative efficacy varies between tissues and test systems). Despite this potential, in vitro incubations of breast tissues from patients treated with type II inhibitors such as aminoglutethimide and letrozole can display paradoxically high aromatase activity; this appears to be caused by the reversible nature of the inhibition, coupled with induction/stabilization of the aromatase enzyme. To assess in situ effects within the breast, postmenopausal women with large primary breast cancers have been treated neoadjuvantly with aromatase inhibitors using a protocol that included (i) breast biopsy before treatment, (ii) definitive surgery after 3 months of treatment and (iii) infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before biopsy and surgery. With this study design, it has been shown that drugs such as letrozole profoundly inhibit in situ aromatase activity and reduce endogenous oestrogens within the breast.

    PMID: 10731108 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    97: Endocr Relat Cancer 1999 Jun;6(2):181-5 Related Articles, Books, LinkOut


    Drug and hormone interactions of aromatase inhibitors.

    Dowsett M.

    Academic Department of Biochemistry, The Royal Marsden NHS Trust, London, UK.

    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 letrozole is used alone.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10731107 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    98: Bull Cancer 1999 Oct;86(10):821-7 Related Articles, Books, LinkOut


    [Aromatase inhibitors]

    [Article in French]

    Feutrie ML, Bonneterre J.

    Hopital civil d'Armentieres, 112, rue Sadi-Carnot, 59285 Armentieres.

    Aromatase inhibitors used in breast cancer, are drugs that inhibit the transformation of androstenedione and testosterone, respectively in estradiol and estrone. Two classes have been described: steroidal inhibitors which act competitively and irreversibly and non steroidal inhibitors which block the P 450 cytochrome. The first one is aminoglutethimide which has an adrenal effect on 11, 18 and 21 hydroxylase. Rogletimide, less powerful and less specific is a aminoglutethimide analogue. The response rates obtained with formestane is not different. The clinical development has been stopped due to a lack of specificity. Letrozole, vorozole, exemestane and anastrozole are more powerful and more specific. Letrozole and vorozole are at least as efficient and better tolerated than aminoglutethimide. Anastrozole, letrozole and vorozole are at least as efficient as megestrol acetate and better tolerated in advanced breast cancer patients receiving a second line hormone therapy.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10572233 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    99: Drugs 1999 Oct;58(4):675-80; discussion 681-2 Related Articles, Books, LinkOut


    Exemestane.

    Scott LJ, Wiseman LR.

    Adis International Limited, Auckland, New Zealand. demail@adis.co.nz

    Exemestane is a steroidal agent which causes inactivation of the aromatase enzyme by binding irreversibly to the substrate binding site. Oral exemestane 25 mg/day inactivates peripheral aromatase activity (approximately 98% inactivation) and reduces basal plasma estrone, estradiol and estrone sulphate levels by 85 to 95% in postmenopausal women with advanced breast cancer. Phase II trials indicate that oral exemestane 25 mg/day is an effective second- or third-line agent in the treatment of postmenopausal women with advanced breast cancer (achieving an objective response in up to 28 and 26% of patients, respectively). Results from a phase III trial indicate that exemestane achieves a similar objective response rate to megestrol as a second-line therapy; however, exemestane achieved a significantly longer duration of overall success, time to disease progression and survival time. Exemestane is at least as well tolerated as megestrol, but is associated with significantly fewer bodyweight changes, mainly bodyweight gain (> or = 10%). Other common adverse events are hot flushes, nausea and fatigue.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10551437 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    100: J Clin Oncol 1999 Nov;17(11):3418-25 Related Articles, Books, LinkOut


    Comment in:
    J Clin Oncol. 2001 Apr 1;19(7):2107-8.

    Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group.

    Jones S, Vogel C, Arkhipov A, Fehrenbacher L, Eisenberg P, Cooper B, Honig S, Polli A, Whaley F, di Salle E, Tiffany J, Consonni A, Miller L.

    U.S. Oncology Research at Baylor-Sammons Cancer Center, Dallas, TX, USA.

    PURPOSE: To assess the antitumor activity, safety, and hormone-suppressive effects of the irreversible aromatase inactivator, exemestane (Aromasin, Pharmacia & Upjohn, Kalamazoo, MI), administered as third-line hormone therapy to postmenopausal women with metastatic breast cancer that is refractory to tamoxifen and megestrol acetate. PATIENTS AND METHODS: Exemestane was administered at a dose of 25 mg/d orally until patients experienced disease progression. The efficacy and safety of exemestane were clinically and radiographically evaluated. The impact of exemestane treatment on tumor-related signs and symptoms was assessed. The effect of exemestane on serum levels of estrogens and other steroidal hormones was determined. RESULTS: Ninety-one patients were treated. There were four complete responses (CR) and eight partial responses (PR), for an objective response rate of 13% in the entire treated population. The overall success rate (CR, PR, or stable disease [SD] >/= 24 weeks) was 30%. The median duration of response and overall success was 9 months and 8 months, respectively. Most patients with CR/PR (83%; 10 of 12 patients) and SD >/= 24 weeks (80%; 12 of 15 patients) had improved or stable tumor-related signs and symptoms. Mean levels of circulating estrone (E(1)), estradiol (E(2)), and estrone sulfate decreased to 11%, 22%, and 13% of baseline levels, respectively (at week 8 or 16 of treatment). One half of the patients had undetectable E(1) and E(2) levels during treatment, including at the time of disease progression. Mild nausea (20% of patients) and hot flashes (20%) were the most common drug-related adverse events and were generally grade 1. CONCLUSION: Exemestane is an active and well-tolerated third-line hormonal therapy that represents a new treatment option for postmenopausal patients with advanced breast cancer that has become refractory to standard first- and second-line hormonal therapies.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase II
    Multicenter Study

    PMID: 10550136 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    101: Drug Saf 1999 Oct;21(4):297-309 Related Articles, Books, LinkOut


    Risks and benefits of aromatase inhibitors in postmenopausal breast cancer.

    Michaud LB, Buzdar AU.

    Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

    Aromatase inhibitors were first reported in the early 1970s and have been used to treat breast cancer since that time. Until recently, essentially the only agent available in this class was aminoglutethimide, a nonspecific inhibitor with multiple adverse effects and drug interactions. Selective and potent aromatase inhibitors are now available (formestane, exemestane, fadrozole, anastrozole and letrozole), and we review the risks and benefits of these agents in order to assist clinicians in making treatment decisions. Formestane is an injectable steroidal aromatase inhibitor with significant activity against metastatic breast cancer. It has been shown to have similar efficacy and superior tolerability compared with megestrol, and is similar to tamoxifen in the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It has been shown to be effective third-line therapy after tamoxifen and megestrol in postmenopausal patients with metastatic breast cancer. All the nonsteroidal (imidazole/triazole) aromatase inhibitors are orally available. Fadrozole has similar activity to megestrol and tamoxifen in the setting of metastasis, but has been shown in phase II trials to inhibit cortisol and aldosterone production. Anastrozole and letrozole have similar toxicity profiles. Compared with megestrol, anastrozole improves overall survival and has superior tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms of overall survival and time to progression, and is also better tolerated. Although there is a strong rationale for using these agents in the treatment of breast cancer, the information presently available is insufficient to recommend any one agent over another. Direct comparative studies are lacking, and comparing agents across studies is limited by many biases and may not be valid. Formestane is only available as an injection and exemestane is not commercially available in many countries, making these agents more difficult to recommend over the other 3 agents. Fadrozole is less potent and less selective in inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and tamoxifen appear to be similar; however, comparative data show no advantage of fadrozole over letrozole. Anastrozole and letrozole are generally considered to be similar agents. The clinical future of the selective aromatase inhibitors is promising, and these agents may change the way postmenopausal breast cancer is treated at all stages of the disease.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10514021 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    102: Neth J Med 1999 Aug;55(2):50-8 Related Articles, Books, LinkOut


    New aromatase inhibitors for the treatment of advanced breast cancer in postmenopausal women.

    de Jong PC, Blijham GH.

    Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands.

    Inhibition of the enzyme aromatase, the rate limiting step in estrogen production, is an effective endocrine treatment of advanced postmenopausal breast cancer. Recently, several new aromatase inhibitors have been developed to improve efficacy and reduce toxicity compared to the prototype aromatase inhibitor aminoglutethimide. Aromatase inhibitors can be divided into two types. The first are the non-steroidal inhibitors that have a mechanism of action similar to aminoglutethimide. The second are the steroidal inhibitors that function as a false substrate for aromatase. Of the non-steroidal aromatase inhibitors, two drugs, anastrozole and letrozole, have recently been registered for the second line endocrine treatment of advanced postmenopausal breast cancer after failure on tamoxifen. The phase III studies of these drugs indicate at least equal efficacy compared to current second line treatment with aminoglutethimide or megestrol acetate. Their toxicity profile, however, is much more favourable. This makes them the drugs of choice for the second line endocrine treatment of advanced breast cancer in postmenopausal patients, who failed during adjuvant or first line treatment with tamoxifen. Of the steroidal aromatase inhibitors, the orally active drug exemestane is still in phase III clinical study; the registration is expected in 1999.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 10474272 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    103: Drugs 1999 Aug;58(2):233-55 Related Articles, Books, LinkOut


    Comprehensive pharmacology and clinical efficacy of aromatase inhibitors.

    Njar VC, Brodie AM.

    Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, USA.

    The goal of hormone therapy is to deprive breast tumours of estrogens, since estrogens have been implicated in the development or progression of tumours. This can be accomplished by the use of antiestrogens that block estrogen action or by inhibiting aromatase, the enzyme that catalyses the final and rate-limiting step in estrogen biosynthesis. A number of steroidal and nonsteroidal compounds have been developed as aromatase inhibitors. This review highlights the valuable role that a few of these aromatase inhibitors have played, and continue to play, in the treatment of breast cancer. Following background information regarding the biochemistry of aromatase, the rationale for its inhibition, and an outline of the test systems for evaluating and characterising aromatase inhibitors, the discussion focuses on the new generation of aromatase inhibitors that are in clinical trials or clinically available. Specifically, it discusses the pharmacology and clinical efficacy of formestane, exemestane, rogletimide, fadrozole, vorozole, anastrozole and letrozole. The role of these agents as the optimal second-line agents (after tamoxifen) for the treatment of advanced breast cancer has been established; their prospects in other clinical settings and as potential breast cancer chemopreventives are warranted but are yet to be fully determined.

    Publication Types:
    Review
    Review, Academic

    PMID: 10473018 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    104: Clin Chem 1999 Feb;45(2):252-6 Related Articles, Books, LinkOut


    Influence of aromatase inhibitors on plasma total homocysteine in postmenopausal breast cancer patients.

    Anker GB, Refsum H, Ueland PM, Johannessen DC, Lien EA, Lonning PE.

    Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.

    In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, aminoglutethimide (n = 30), formestane (n = 12), and exemestane (n = 10), and the progestin megestrol acetate (n = 21) on plasma total homocysteine (tHcy) in patients suffering from advanced breast cancer. Treatment with 1 g/day aminoglutethimide for 2 and 3-5 months increased plasma tHcy by a mean value of 24.5% [95% confidence interval, 10.5-40.4%] at 2 months and 35.8% (95% confidence interval, 18.2-55.9%) at 3-5 months, corresponding to increases in the mean plasma tHcy of 1.90 and 3.67 micromol/L, respectively. In contrast, none of the other treatment options influenced plasma tHcy concentrations. The finding that aminoglutethimide, but none of the other aromatase inhibitors or megestrol acetate, influenced plasma tHcy suggests that this effect is achieved by mechanisms not related to suppression of plasma estrogens or to the glucocorticoids administered in concert.

    PMID: 9931048 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    105: Recent Results Cancer Res 1998;152:277-84 Related Articles, Books, LinkOut


    Aromatase inhibitors and their use in the adjuvant setting.

    Coombes RC.

    Department of Cancer Medicine, Imperial College School of Medicine, Charing Cross Hospital, London, UK.

    Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that the main mechanism of action of aminoglutethemide was via inhibition of the enzyme aromatase, thereby reducing peripheral levels of estradiol in post-menopausal patients. The second-generation drug 4-hydroxyandrostenedione was introduced in 1990, and although its use was limited by its need to be given parenterally, it was found to be a well-tolerated form of endocrine therapy. The third-generation inhibitors include vorozole, letrozole, anastrozole and exemestane, the former three being non-steroidal inhibitors, the latter being a steroidal inhibitor. All these compounds are capable of reducing estrogen levels to within 5%-10% of baseline levels compared with 20%-30% base line levels in the case of 4-hydroxyandrostenedione. Studies are currently in progress to determine the value of these third-generation aromatase inhibitors in the adjuvant setting. These studies include head-to-head comparison of aromatase inhibitor with tamoxifen, sequential aromatase inhibitor after tamoxifen and first-line aromatase inhibitor followed by adjuvant tamoxifen. Current issues revolve around the toxicity of these compounds in terms of effects on the cardiovascular system and bone.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 9928565 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    106: Anticancer Drugs 1998 Sep;9(8):675-83 Related Articles, Books, LinkOut


    Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study.

    Paridaens R, Thomas J, Wildiers J, Vermeiren P, Lobelle JP, di Salle E, Ornati G, Zurlo MG, Polli A, Lanzalone S, de Belder K.

    UZ Gasthuisberg, Dienst Gezwelziekten, Leuven, Belgium.

    Exemestane is an irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5-600 mg. The median duration of exemestane treatment was 13 weeks (range: 3-166 weeks). The maximal tolerated dose was not reached because of lack of treatment-related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1-46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48-99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase I

    PMID: 9823425 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    107: Clin Cancer Res 1997 Jul;3(7):1101-8 Related Articles, Books, LinkOut


    Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study.

    Johannessen DC, Engan T, Di Salle E, Zurlo MG, Paolini J, Ornati G, Piscitelli G, Kvinnsland S, Lonning PE.

    Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.

    Clinical and endocrinological effects of exemestane (6-methylenandrosta-1,4-diene-3,17-dione; PNU 155971) were evaluated in an open Phase I study. Thirteen postmenopausal women suffering from advanced breast cancer received exemestane in escalating doses over a 12-week period. Starting on 5 mg once daily (o.d.), exemestane was subsequently escalated at 2-week intervals to 10, 25, 50, 100, and 200 mg o.d. Each patient subsequently continued treatment on the highest tolerated dose until time of progression. One patient terminated treatment after 6 days due to diarrhea that was probably not related to drug therapy, although a relationship could not be excluded. Apart from this, no serious side effects were seen during the dose escalation period. Exemestane (10 mg o.d.) caused maximal suppression of plasma estradiol (E2) and estrone (E1) to a mean of 14.6 and 5.8% of pretreatment levels, respectively, whereas 25 mg of exemestane o.d. suppressed estrone sulfate (E1S) to 8.9% of pretreatment levels. No fall in adrenal steroid levels was recorded. Exemestane (5 mg o.d.) suppressed urinary E2 and E1 to a mean of 11.9 and 12.2% of pretreatment levels, respectively. Administering exemestane at doses of 50-200 mg o.d. caused no further suppression of urinary E1, whereas urinary E2 fell to 6-7% of pretreatment levels. Median time to progression was 63 weeks. We conclude that exemestane is a well-tolerated aromatase inhibitor that effectively suppresses plasma and urinary estrogens in postmenopausal patients with breast cancer.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase I
    Multicenter Study

    PMID: 9815789 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    108: Breast Cancer Res Treat 1998;49 Suppl 1:S45-52; discussion S73-7 Related Articles, Books, LinkOut


    Pharmacological profiles of exemestane and formestane, steroidal aromatase inhibitors used for treatment of postmenopausal breast cancer.

    Lonning PE.

    Haukeland University Hospital, Bergen, Norway.

    Steroidal aromatase inhibitors like formestane and exemestane are useful drugs for endocrine treatment of postmenopausal breast cancer. In addition, these drugs should be considered valuable probes to explore the biology of breast cancer with particular emphasis on possible relations between the degree of estrogen suppression and clinical efficacy and the possible role of intratumor estrogen synthesis. The fact that steroidal and non-steroidal aromatase inhibitors bind to different parts of the aromatase enzyme suggests these drugs may act in concert aggravating plasma estrogen suppression. Thus, use of a steroidal and a non-steroidal aromatase inhibitors in concert may be one way to improve breast cancer treatment and may also provide important information to a better understanding of the dose-response relationship between estrogen suppression and clinical effects. Further, the finding that patients progressing on non-steroidal aromatase inhibitors may respond to formestane as well as exemestane suggests these drugs may have differential effects, probably on the aromatization in the tumor tissue. Further studies are warranted to explore the influence of steroidal and non-steroidal aromatase inhibitors on intratumor aromatase activity and intratumor estrogen concentrations and to correlate these findings to intratumor drug concentrations. The findings that steroidal aromatase inhibitors may have clinical effects in patients progressing on treatment with the non-steroidal aromatase inhibitor aminoglutethimide is challenging, and suggest further studies to evaluate possible benefits of using different novel aromatase inhibitors in concert or sequence.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 9797017 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    109: Clin Cancer Res 1998 Sep;4(9):2089-93 Related Articles, Books, LinkOut


    In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients.

    Geisler J, King N, Anker G, Ornati G, Di Salle E, Lonning PE, Dowsett M.

    Department of Oncology, Haukeland University Hospital, Bergen, Norway.

    The effect of exemestane (6-methylenandrosta-1,4-diene-3,17-dione) 25 mg p.o. once daily on in vivo aromatization was studied in 10 postmenopausal women with advanced breast cancer. Aromatization was determined before treatment and after 6-8 weeks on therapy by administering a bolus injection of [3H]androstenedione (500 microCi) and [14C]estrone (5 microCi) followed by measurement of the isotope ratio of urinary estrogens after high-performance liquid chromatography purification. In addition, plasma endogenous estrogens were measured with highly sensitive radioimmunoassays after separation with high-performance liquid chromatography. Treatment with exemestane suppressed whole body aromatization from a mean pretreatment value of 2.059% to 0.042% (mean suppression of 97.9%). Plasma levels of estrone, estradiol, and estrone sulfate were found to be suppressed by 94.5%, 92.2%, and 93.2%, respectively. This is the first study revealing near total aromatase inhibition in vivo with the use of a steroidal aromatase inhibitor. The observation that exemestane is a highly potent aromatase inhibitor, together with the fact that the drug is administered p.o. and causes limited side effects, suggests that exemestane is a promising new drug for the treatment of hormone sensitive breast cancer.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase II
    Multicenter Study

    PMID: 9748124 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    110: Cancer Chemother Pharmacol 1998;42(1):46-52 Related Articles, Books, LinkOut


    Influence of treatment with aminoglutethimide on plasma and red-blood-cell glutathione status in breast cancer patients.

    Berntsen H, Lonning PE, Ekse D, Netteland B, Johannessen DC, Berge R, Svardal A.

    Department of Oncology, Haukeland University Hospital, Bergen, Norway.

    PURPOSE: Elevated cellular glutathione has been associated with resistance to cancer chemotherapy. Treatment with the aromatase inhibitor aminoglutethimide increases the concentration of gamma-glutamyl transpeptidase (gamma-GT) in breast cancer patients. This enzyme catalyzes the first step in the degradation of extracellular glutathione, and the products formed may act as precursors for intracellular glutathione synthesis. METHODS: Plasma and red-blood-cell glutathione levels were determined in 26 patients suffering from advanced breast cancer before and during treatment with aminoglutethimide (n = 16) or the steroidal aromatase inhibitors exemestane or formestane (n = 10) and in 5 cancer patients receiving dexamethasone. RESULTS: Pretreatment values for gamma-GT in the total patient group (n = 31) correlated negatively with the level of reduced (P < 0.0001), oxidized (P < 0.025), and total glutathione (P < 0.005) in plasma. Plasma gamma-GT levels increased by a mean value of 249% during treatment with aminoglutethimide. The concentration of reduced and oxidized glutathione in plasma decreased to 42.7% (P < 0.0005) and 80.6% (P < 0.005) of their pretreatment levels, respectively. This fall in reduced plasma glutathione correlated negatively with the increase in gamma-GT (P < 0.001). The ratio of oxidized to reduced glutathione increased by 88.9% (P < 0.005), and this increase correlated positively with the increase in gamma-GT (P < 0.005). Treatment with the steroidal aromatase inhibitors (exemestane and formestane) or dexamethasone did not influence the plasma thiol status. CONCLUSIONS: We conclude that aminoglutethimide influences plasma glutathione disposition by mechanisms not related to estrogen suppression or due to glucocorticoids given in concert.

    PMID: 9619757 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    111: Eur J Cancer 1997 Oct;33(11):1767-73 Related Articles, Books, LinkOut


    Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on aminoglutethimide: a phase II multicentre multinational study. Exemestane Study Group.

    Thurlimann B, Paridaens R, Serin D, Bonneterre J, Roche H, Murray R, di Salle E, Lanzalone S, Zurlo MG, Piscitelli G.

    Department of Internal Medicine C, Kantonsspital, Gallen, Switzerland.

    In a European multicentre phase II study, 80 postmenopausal patients (pts) with advanced breast cancer progressing on aminoglutethimide (AG) at daily doses of > or = 500 mg were enrolled. Seventy-eight received exemestane (200 mg daily orally), including 33 pts resistant to prior AG, 39 pts who had progressed after an initial response to AG, and 6 pts whose response to AG was either unavailable or not evaluable. Three pts were pretreated with AG only, 69 with tamoxifen and AG, and 6 with tamoxifen, AG and other hormone therapies; 55% had also previously received chemotherapy. The predominant site of disease was visceral in 34 cases, bone in 27 and soft tissue in 17. Based on Peer Review assessment, the overall objective response rate (CRs plus PRs) was 26% (12% in pts resistant to AG and 33% in AG-responsive pts). Disease stabilisation > or = 24 weeks was achieved in an additional 13% of patients (15% of those resistant to AG and 13% of those AG-responsive), resulting in an overall success rate of 39% (28-50, 95% confidence interval). The median duration of objective response, overall success and median TTP were 59, 48 and 21 weeks, respectively. Toxicities were usually mild to moderate in severity, with hot flushes (21%), nausea (19%), dizziness (12%), weakness (12%), increased sweating (12%), androgenic symptoms (10%) and peripheral oedema (9%) as the most common side-effects. Only 2 pts (3%) discontinued treatment due to adverse events. These results are very promising considering that exemestane was administered as third- or fourth-line hormonal treatment in most cases and confirm previous observations about the lack of cross-resistance when steroidal aromatase inhibitors are sequenced with the non-steroidal aromatase inhibitor AG.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase II
    Multicenter Study

    PMID: 9470830 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    112: Cancer Epidemiol Biomarkers Prev 1998 Jan;7(1):65-78 Related Articles, Books, LinkOut


    Aromatase inhibitors as potential cancer chemopreventives.

    Kelloff GJ, Lubet RA, Lieberman R, Eisenhauer K, Steele VE, Crowell JA, Hawk ET, Boone CW, Sigman CC.

    Chemoprevention Branch, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland 20852, USA.

    Epidemiological and experimental evidence strongly supports a role for estrogens in the development and growth of breast tumors. A role for estrogen in prostate neoplasia has also been postulated. Therefore, one chemopreventive strategy for breast and prostate cancers is to decrease estrogen production. This can be accomplished by inhibiting aromatase, the enzyme that catalyzes the final, rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is of clinical interest for cancer therapy, and selective, potent aromatase inhibitors have been developed. Several of these agents have demonstrated chemopreventive efficacy in animal models. The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to serve as potential chemopreventive agents are the subjects of this review. After background information regarding aromatase is presented, the data for each inhibitor are summarized separately. The discussion focuses on those inhibitors that are clinically available or in clinical trials, including: aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane, exemestane, and atamestane. On the basis of results from preclinical studies, aromatase inhibitors may be promising agents for clinical trials in populations at high risk for developing estrogen-dependent cancers. Total suppression of aromatase may have adverse effects, as is evident in postmenopausal women (increased osteoporosis, cardiovascular disease, and urogenital atrophy). However, on the basis of preclinical studies of chemopreventive efficacy and chemotherapeutic applications of aromatase inhibitors showing dose-response efficacy, it may be possible to obtain chemopreventive effects without total suppression of aromatase and circulating estrogen levels. Suppressing local estrogen production may be an alternative strategy, as suggested by the discovery of a unique transcriptional promoter of aromatase gene expression, I.4, in breast adipose tissue. The development of drugs that target this promoter region may be possible.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 9456245 [PubMed - indexed for MEDLINE]

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    113: J Steroid Biochem Mol Biol 1997 Apr;61(3-6):151-5 Related Articles, Books, LinkOut


    Exemestane experience in breast cancer treatment.

    Lonning PE, Paridaens R, Thurlimann B, Piscitelli G, di Salle E.

    Department of Oncology, Haukeland University Hospital, Bergen, Norway.

    Exemestane is a very potent, orally active, selective and long-lasting steroidal irreversible inhibitor of aromatase. It is 150 times more potent than aminoglutethimide (AG) in inhibiting human placental aromatase (Ki of 4.3 and 671 nM, respectively). The compound is presently under phase III evaluation in Europe and the U.S.A. for the treatment of postmenopausal advanced breast cancer (ABC). Clinical pharmacology studies have been carried out with single doses ranging from 0.5 to 800 mg and repeated doses of up to 600 mg a day, in 132 postmenopausal healthy volunteers and in 185 postmenopausal women with ABC. Results obtained using a very specific and sensitive analytical method (high performance liquid chromatography-radioimmunoassay; HPLC-RIA) indicated that exemestane is extremely effective in inhibiting plasma estrogens levels. Estrogen inhibition is clearly evident at 5 mg a day and maximal suppression for E2, E1 and E1S (>85%, >90% and >90%, respectively) is obtained at 10-25 mg a day. Data from non-controlled phase II studies involving more than 400 patients indicated a clear anti-tumour activity in postmenopausal ABC patients failing multiple hormonal treatments. In 62 patients progressing on AG (> or = 500 mg a day) exemestane treatment resulted in an objective response rate of approximately 24%; disease stabilization > or = 24 weeks was observed in an additional 24% of cases. With regard to safety, although daily doses up to 600 mg were administered, the maximal tolerated dose was not achieved; reported symptoms were mainly related to the pharmacological action of the compound and were usually mild to moderate in severity, resulting in the discontinuation of therapy in less than 3% of cases. In conclusion, the available results suggest that exemestane treatment is associated with minimal toxicity, and may be of significant benefit for ABC women who have exhausted conventional therapy.

    Publication Types:
    Review
    Review, Tutorial

    PMID: 9365185 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    114: Eur J Cancer 1997 Apr;33(4):587-91 Related Articles, Books, LinkOut


    The minimal effective exemestane dose for endocrine activity in advanced breast cancer.

    Bajetta E, Zilembo N, Noberasco C, Martinetti A, Mariani L, Ferrari L, Buzzoni R, Greco M, Bartoli C, Spagnoli I, Danesini GM, Artale S, Paolini J.

    Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

    Phase I studies have demonstrated that exemestane, an irreversible oral aromatase inhibitor, is able to suppress circulating oestrogen levels. In our previous experience, doses ranging from 2.5 to 25 mg induced a similar suppression of oestrogens. The aim of this study was to identify the minimum effective exemestane dose on the basis of endocrine activity. 20 evaluable postmenopausal advanced breast cancer patients were randomly given exemestane 0.5, 1, 2.5 or 5 mg, in double-blind conditions. Oestrone (E1), oestradiol (E2), oestrone sulphate (E1S), gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate serum levels were evaluated from the first day of treatment to the 7th, 14th, 28th and 56th day. Serum E1, E2 and E1S levels were suppressed by all doses starting from day 7; the degree of inhibition versus baseline was 25 up to 72% for E1, 30 up to 62% for E2 and 16 up to 52% for E1S, with higher doses achieving greater suppression; these changes were maintained over time. A significant increase in FSH and LH levels was observed for all doses. Treatment tolerability was satisfactory. The endocrine effects of exemestane appear to be dose related and 0.5 and 1 mg are ineffective for adequately suppressing circulating oestrogens.

    Publication Types:
    Clinical Trial
    Randomized Controlled Trial

    PMID: 9274439 [PubMed - indexed for MEDLINE]

    --------------------------------------------------------------------------------


    115: Br J Cancer 1995 Oct;72(4):1007-12 Related Articles, Books, LinkOut


    Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor.

    Zilembo N, Noberasco C, Bajetta E, Martinetti A, Mariani L, Orefice S, Buzzoni R, Di Bartolomeo M, Di Leo A, Laffranchi A, et al.

    Division of Medical Oncology B, Istituto Nazional per lo Studio e la Cura dei Tumori, Milan, Italy.

    The androstenedione derivative, exemestane (FCE 24304), is a new orally active irreversible aromatase inhibitor. Fifty-six post-menopausal advanced breast cancer patients entered this study to evaluate the activity of four low exemestane doses in reducing oestrogen levels. The drug's tolerability and clinical efficacy were also assessed. Exemestane was orally administered to four consecutive groups at daily doses of 25, 12.5, 5 and 2.5 mg, and the changes in oestrogen, gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate levels were evaluated. Drug selectivity was studied by measuring 17-hydroxycorticosteroid urinary levels. After 7 days of treatment, mean oestrone and oestradiol levels had decreased by respectively 64% and 65% (a decrease which was maintained over time); in the 2.5 mg group, oestrone sulphate levels also decreased by 74%. Gonadotrophin levels were significantly higher, whereas no changes in the other serum hormone levels or any interference with adrenal synthesis were detected. Treatment tolerability was satisfactory: nausea and dyspepsia were reported in 16% of patients. The overall objective response rate was 18%. In conclusion, exemestane is effective in reducing oestrogen levels at all of the tested doses and shows interesting clinical activity.

    PMID: 7547212 [PubMed - indexed for MEDLINE]

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    116: Breast Cancer Res Treat 1995;36(3):287-97 Related Articles, Books, LinkOut


    Plasma changes in breast cancer patients during endocrine therapy--lipid measurements and nuclear magnetic resonance (NMR) spectroscopy.

    Engan T, Krane J, Johannessen DC, Lonning PE, Kvinnsland S.

    Department of Oncology and Radiotherapy, University Hospital of Trondheim, Norway.

    Side-effects following long-term endocrine therapy might have clinical implications. The aim of this study was to study potential methods to detect effects on plasma induced by hormonal therapies. The composite methylene (chemical shift between 1.2-1.4 ppm) and methyl (0.8-0.9 ppm) aliphatic peaks of the 1H magnetic resonance spectrum (500 MHz) were analysed in consecutive plasma samples of 23 cancer patients drawn before and during treatment with hormonally acting drugs. The aliphatic peaks were analyzed for line width at half-height and then averaged. In addition, 13C magnetic resonance spectroscopy (125 MHz) analyses were done in selected patients. The blood samples were analyzed for triglyceride, cholesterol, apolipoprotein A1 (apo A1), and apolipoprotein B (apo B) levels. The methylene line width increased significantly after 9 weeks of tamoxifen (41.4 vs. 37.6 Hz). A trend of differences was observed in the saturated part of the 13C magnetic resonance spectrum. A significant decrease in total cholesterol (mean decrease, 13%), increases in apo A1 (9%) and in the ratio of apo A1 to apo B (28%), but unchanged total triglycerides were found, indicating a decrease in LDL and increase in HDL lipoproteins in these patients following tamoxifen therapy. During dose escalation with the aromatase inhibitor exemestane, the methylene line width seemed to decrease (31.9 vs 38.8 Hz, at 12 weeks and baseline, respectively). Significant decreases in total (13%) and HDL (32%) cholesterol, apo A1 (25%), and total triglyceride (16%) levels were found during the same interval. The apo A1/apo B ratio decreased by 25%. For patients on dexamethasone, the proton aliphatic line widths increased one day after the initiation of therapy. The changes in line shape observed during dexamethasone therapy indicated lower levels of triglyceride-rich relative to triglyceride-poor lipoproteins, consistent with results from the lipid analyses. In conclusion, nuclear magnetic resonance spectroscopy might have potential to detect effects on plasma induced by endocrine therapy. The lipid analyses in these patients were in support of the changes in lipid profile as evaluated by nuclear magnetic resonance spectroscopy.

    PMID: 8573711 [PubMed - indexed for MEDLINE]

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    117: J Steroid Biochem Mol Biol 1994 Jun;49(4-6):289-94 Related Articles, Books, LinkOut


    Novel aromatase and 5 alpha-reductase inhibitors.

    Di Salle E, Briatico G, Giudici D, Ornati G, Zaccheo T, Buzzetti F, Nesi M, Panzeri A.

    Pharmacia, R&D Oncology, Nerviano, Milano, Italy.

    Inhibitors of aromatase and 5 alpha-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17 beta-amidic side chains, three compounds, namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5 alpha-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, respectively. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compounds were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.

    PMID: 8043491 [PubMed - indexed for MEDLINE]

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    118: Steroids 1993 Nov;58(11):527-32 Related Articles, Books, LinkOut


    Synthesis and aromatase inhibition by potential metabolites of exemestane (6-methylenandrosta-1,4-diene-3,17-dione).

    Buzzetti F, Di Salle E, Longo A, Briatico G.

    Research and Development, Farmitalia Carlo Erba Srl, Milano, Italy.

    Exemestane (6-methylenandrosta-1,4-diene-3,17-dione; FCE 24304) is an orally active irreversible aromatase inhibitor which is in phase II clinical evaluation for the potential therapy of postmenopausal breast cancer. A series of exemestane analogs, with modifications at the 6-methylene group and with additional reduction at the 17-keto group, were synthesized as potential metabolites and tested in vitro for their effect on human placental aromatase. All these new analogs were found to be less potent in inhibiting aromatase than exemestane. The most effective compound was the 17 beta-hydroxy-derivative (compound 2), which is 2.6-fold less potent than exemestane [50% inhibitory concentration (IC50) 69 and 27 nM, respectively]. The various C-6 modified derivatives of the 17-oxo series were found to inhibit the aromatase enzyme in the following descending order: 6-methylene (exemestane) > 6-spirooxirane (6) > 6 beta-hydroxymethyl (11) > 6-hydroxymethyl (7) > 6 beta-carboxy (13), showing IC50 values of 27, 206, 295, 2,300, and 7,200 nM, respectively. The 17 beta-hydroxy analogs of some of the above mentioned compounds were also synthesized (3,4,12) and found to be 3-8-fold less potent than the corresponding 17-keto analogs.

    PMID: 8273115 [PubMed - indexed for MEDLINE]

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    119: J Chromatogr 1993 Oct 29;620(2):225-31 Related Articles, Books, LinkOut


    Determination of exemestane, a new aromatase inhibitor, in plasma by high-performance liquid chromatography with ultraviolet detection.

    Breda M, Pianezzola E, Benedetti MS.

    Pharmacokinetics and Metabolism Department, R&D, Farmitalia Carlo Erba, Nerviano, Milan, Italy.

    A sensitive and selective high-performance liquid chromatographic method for the determination of 6-methylen-androsta-1,4-diene-3,17-dione (exemestane) and its 17-dihydro metabolite in human plasma has been developed. The analytes and internal standard (Norgestrel) were extracted from plasma samples with a methylene chloride-iso-octane mixture; the organic phase was dried and the residue was reconstituted with an acetonitrile-water mixture, then analyzed by reversed-phase liquid chromatography. Quantification was achieved by ultraviolet detection of the eluate. The linearity, precision and accuracy of the method were evaluated. No interference from the constituents of human blank plasma was observed. The lower limit of quantification was 10 ng/ml plasma. The suitability of the method for in vivo samples was checked by analysis of plasma samples drawn from healthy male volunteers who had received a 200-mg single oral dose of the test compound.

    PMID: 8300790 [PubMed - indexed for MEDLINE]

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    120: J Steroid Biochem Mol Biol 1993 Mar;44(4-6):677-80 Related Articles, Books, LinkOut


    Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats.

    Zaccheo T, Giudici D, Di Salle E.

    Laboratory of Endocrinology, R and D, Farmitalia Carlo Erba, Milano, Italy.

    The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.c., induced 26% complete (CR) and 18% partial (PR) tumor regressions, compared to 0% CR and 6% PR observed in controls. Tamoxifen, given at 1 mg/kg/day p.o., induced 16% CR and 13% PR. The combined treatment caused 41% CR and 16% PR, thus resulting in a higher antitumor effect than either single treatment. The appearance of new tumors was reduced by each single treatment and almost totally prevented by the combined treatment. Serum prolactin (PRL) levels, assayed 4 h after the last dose, were unchanged in the group treated with the combination, whereas tamoxifen alone caused a slight increase of serum PRL. These results indicate that estrogen deprivation through aromatase inhibition and estrogen receptor antagonism causes a better inhibition of DMBA-induced mammary tumors than either treatment modality alone.

    PMID: 8476783 [PubMed - indexed for MEDLINE]

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    121: Cancer Res 1992 Nov 1;52(21):5933-9 Related Articles, Books, LinkOut


    Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women.

    Evans TR, Di Salle E, Ornati G, Lassus M, Benedetti MS, Pianezzola E, Coombes RC.

    Department of Medical Oncology, St. George's Hospital Medical School, London, England.

    Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. A single-dose administration of exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione), a new irreversible aromatase inhibitor, was investigated in 29 healthy postmenopausal female volunteers. The compound, given at p.o. doses of 0.5, 5, 12.5, 25, 50, 200, 400, and 800 mg (n = 3-4), was found to be a well tolerated, potent, long-lasting, and specific inhibitor of estrogen biosynthesis. The minimal dose which produced the maximum suppression of plasma estrogens was 25 mg, reducing plasma estrone, estradiol, and estrone sulfate to 35, 28, and 39% of basal values, respectively. This maximum suppression, observed at 3 days, persisted for at least 5 days after administration of a single dose. However, there was no interference on cortisol, aldosterone, 17-hydroxyprogesterone, or dehydroepiandrostenedione sulfate plasma levels. Peak plasma exemestane concentrations of 27, 221, 343, and 414 ng/ml were reached within 2 h after administration of 50, 200, 400, and 800 mg, respectively. Plasma concentrations declined rapidly and fell under the detection limit (10 ng/ml) at 4 (50 mg) or 24 h (200 and 400 mg). No clinically significant adverse events which could be attributed to the drug were reported. Apart from transient eosinophilia in 3 patients, all biochemical and hematological laboratory parameters were within 1.25-fold of the normal ranges.

    Publication Types:
    Clinical Trial
    Clinical Trial, Phase I
    Controlled Clinical Trial

    PMID: 1394219 [PubMed - indexed for MEDLINE]

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    122: J Steroid Biochem Mol Biol 1992 Sep;43(1-3):137-43 Related Articles, Books, LinkOut


    Exemestane (FCE 24304), a new steroidal aromatase inhibitor.

    di Salle E, Ornati G, Giudici D, Lassus M, Evans TR, Coombes RC.

    Oncology Line, Research and Development, Nerviano (Mi), Italy.

    Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological properties have been compared to 4-hydroxyandrostenedione (4-OHA). In preincubation studies with human placental aromatase, exemestane, like 4-OHA, showed enzyme inactivating properties with a similar affinity (Ki 26 vs 29 nM) and a lower rate of inactivation (t1/2 13.9 vs 2.1 min). Conversely, when tested in pregnant mares' serum gonadotropin-treated rats, exemestane was more potent in reducing microsomal ovarian aromatase activity than 4-OHA, after both subcutaneous (ED50 1.8 vs 3.1 mg/kg) and oral dosing (ED50 3.7 vs greater than 100 mg/kg). No interference of exemestane on desmolase or 5 alpha-reductase activity was found. The compound did not show any relevant binding affinity to steroidal receptors, but slight binding to the androgen receptor (approximately 0.2% of dihydrotestosterone), like 4-OHA. In the first phase I trial, healthy postmenopausal volunteers were given single oral doses of exemestane, ranging from 0.5 to 800 mg, and plasma [estrone (E1), estradiol (E2) and estrone sulphate (E1S)] and urinary estrogens (E1 and E2) were measured up to 5-8 days. The minimal effective dose in decreasing estrogens was 5 mg. At 25 mg the maximal suppression was observed at day 3: plasma estrogens fell to 35 (E1), 39 (E2) and 28% (E1S), and urinary estrogens fell to 20 (E1) and 25% (E2) of basal values, these effects still persisting on day 5. No effects on plasma levels of cortisol, aldosterone, 17-hydroxyprogesterone, DHEAS, LH and FSH, and no significant adverse events were observed up to the highest tested dose of 800 mg exemestane.

    Publication Types:
    Clinical Trial
    Review
    Review, Tutorial

    PMID: 1525055 [PubMed - indexed for MEDLINE]

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    123: J Chromatogr 1992 Feb 28;593(1-2):25-8 Related Articles, Books, LinkOut


    High-performance liquid chromatographic analysis of FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) and FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione), two new aromatase inhibitors.

    Del Nero S, Di Somma M, Vigevani A.

    Department of Analytical Chemistry, R & D Farmitalia Carlo Erba Srl, Milan, Italy.

    The cytochrome P-450-dependent aromatase enzyme plays an important role in hormone-dependent diseases. Many products that inhibit this type of enzyme were obtained: FCE 24304 (I) and FCE 24928 (II) proved to possess remarkable activity and are presently under development. Compounds I and II and their synthetic intermediates are analyzed by means of a high-performance liquid chromatographic method, affording rapid and efficient separation, good resolution and identification of all the examined compounds. The linearity, specificity, sensitivity, precision and accuracy for the method are also provided.

    PMID: 1639908 [PubMed - indexed for MEDLINE]

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    124: Eur J Cancer 1991;27(9):1145-50 Related Articles, Books, LinkOut


    Comparison of the effects of the irreversible aromatase inhibitor exemestane with atamestane and MDL 18962 in rats with DMBA-induced mammary tumours.

    Zaccheo T, Giudici D, Ornati G, Panzeri A, di Salle E.

    Oncology Line, Research and Development, Farmitalia Carlo Erba, Erbamont Group, Milan, Italy.

    The antitumour activity of the steroidal aromatase inhibitors exemestane (FCE 24304), MDL 18962 and atamestane (SH 489) was evaluated on 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumours in rats. The compounds were given subcutaneously at daily doses of 10 and 50 mg/kg for 4 weeks. Exemestane was also given orally, at daily doses of 100 and 200 mg/kg. Subcutaneous exemestane induced 30% (10 mg/kg) and 73% (50 mg/kg) regressions of established tumours and strongly reduced the appearance of new tumours. Conversely, atamestane, MDL 18962 and oral exemestane did not affect growth of established tumours nor influenced the appearance of new neoplasms. Aromatase activity of ovarian microsomes (OAA) was reduced by 85%-93% after subcutaneous exemestane and by 25%-59% after MDL 18962, and was unaffected after atamestane. Oral exemestane caused a reduction in OAA of 72%-74%. Serum luteinising hormone (LH) levels were reduced at both the subcutaneous doses of exemestane and at the higher dose of MDL 18962. Atamestane caused an increase in LH levels, while no effect was observed with oral exemestane. The LH-lowering effect of subcutaneous exemestane, the less marked effect of MDL 18962, and the ineffectiveness of oral exemestane were also observed after 10 days of treatment in ovariectomised rats. The antigonadotrophic effect of subcutaneous exemestane, which is probably due to its slight androgenic effect, could contribute to its antitumour activity in the DMBA tumour model in intact rats, through a counteraction of the negative feedback of oestrogens on gonadotropin secretion.

    PMID: 1835626 [PubMed - indexed for MEDLINE]

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    125: J Steroid Biochem Mol Biol 1990 Nov 20;37(3):369-74 Related Articles, Books, LinkOut


    4-Aminoandrostenedione derivatives: a novel class of irreversible aromatase inhibitors. Comparison with FCE 24304 and 4-hydroxyandrostenedione.

    Di Salle E, Giudici D, Ornati G, Briatico G, D'Alessio R, Villa V, Lombardi P.

    Oncology Line R&D, Farmitalia Carlo Erba, Nerviano, Italy.

    FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione) was selected among a series of 4-aminoandrostenedione derivatives as a novel irreversible aromatase inhibitor. Its in vitro and in vivo properties have been studied and compared to FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) and 4-OHA (4-hydroxyandrostenedione). FCE 24928 caused time-dependent inhibition of human placental aromatase with a t1/2 of 4 min and Ki of 59 nM. Enzyme inactivation by FCE 24928 was faster than by FCE 24304 (t1/2 13.9 min). In PMSG-treated rats, microsomal ovarian aromatase activity was reduced 24 h after FCE 24928 dosing by both the s.c. (ED50 1.2 mg/kg) and the oral (ED50 14.1 mg/kg) routes. The compound was more potent than FCE 24304 and 4-OHA (ED50 1.8 and 3.1 mg/kg s.c.). FCE 24928 did not show any interference with 5 alpha-reductase and desmolase activity nor any significant binding affinity for androgen and estrogen receptors. Slight binding affinity for androgen receptor was observed with FCE 24304 and 4-OHA (0.21 and 0.25% of DHT). In immature, castrated rats, FCE 24928 did not show any intrinsic androgenic activity, up to 100 mg/kg/day s.c., in contrast to a slight androgenic activity observed with FCE 24304 at 10 mg/kg s.c.

    PMID: 2257240 [PubMed - indexed for MEDLINE]

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    126: Ann N Y Acad Sci 1990;595:357-67 Related Articles, Books, LinkOut


    Novel irreversible aromatase inhibitors.

    di Salle E, Giudici D, Briatico G, Ornati G.

    Oncology Department, Farmitalia Carlo Erba-Erbamont Group, Milan, Italy.

    PMID: 2375613 [PubMed - indexed for MEDLINE]

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    127: J Steroid Biochem 1989;34(1-6):431-4 Related Articles, Books, LinkOut


    Aromatase inhibition and experimental antitumor activity of FCE 24304, MDL 18962 and SH 489.

    di Salle E, Briatico G, Giudici D, Ornati G, Zaccheo T.

    Farmitalia C. Erba, R.&D./Oncology, Milano, Italy.

    Human placental aromatase inhibitory properties of FCE 24304, MDL 18962, SH 489 and 4-hydroxyandrostenedione (4-OHA) were compared. The compounds caused time-dependent enzyme inactivation with t1/2 values of 13.9, 13.1, 45.3 and 2.1 min and Ki values of 26.0, 0.7, 2.0 and 29.0 nM respectively. The antitumor activity of FCE 24304, MDL 18962 and SH 489 was studied on the DMBA-induced mammary tumor in rats, at daily s.c. doses of 10 and 50 mg/kg. FCE 24304 induced 30 and 73% regressions of established tumors, associated with 86 and 93% decrease in total ovarian aromatase activity. SH 489 and MDL 18962 did not affect tumor growth. FCE 24304, like 4-OHA, was shown to inhibit LH hypersection in castrated rats. A gonadotropin suppressive effect could contribute to the antitumor activity of aromatase inhibitors in intact DMBA-induced tumor bearing rats.

    PMID: 2516584 [PubMed - indexed for MEDLINE]

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    128: Cancer Chemother Pharmacol 1989;25(2):95-8 Related Articles, Books, LinkOut


    Effect of the irreversible aromatase inhibitor FCE 24304 on DMBA-induced mammary tumors in ovariectomized rats treated with testosterone.

    Zaccheo T, Di Salle E.

    R & D/Oncology, Farmitalia Carlo Erba, Erbamont Group, Milano, Italy.

    The antitumor activity of the irreversible aromatase inhibitor FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) was studied in ovariectomized, testosterone propionate (TP)-treated rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors that were used as a postmenopausal tumor model. When given s.c. at 20 mg/kg per day, 3 days a week for 4 weeks, TP was effective in maintaining tumor growth in ovariectomized rats (51% tumor regression in control animals vs 94% in ovariectomized rats). FCE 24304 given s.c. twice daily at 100 mg/kg per day, 6 days a week for 4 weeks, induced 96% regression, thus inhibiting the growth-promoting effect of TP. When the effect of various doses of FCE 24304 was evaluated, in comparison with a 52% tumor regression rate in control (ovariectomized, TP-treated) rats, tumor regressions amounted to 88% and 96% at s.c. FCE 24304 doses of 10 and 50 mg/kg per day, respectively, and to 76%, 88%, and 81% at oral doses of 10, 50, and 100 mg/kg per day, respectively. When FCE 24304 was given alone to ovariectomized rats, it did not affect ovariectomy-induced tumor regression (87% vs 94%). In conclusion, FCE 24304 was effective by both the s.c. and oral routes against DMBA-induced mammary tumors in ovariectomized TP-treated rats, a postmenopausal mammary tumor model.

    PMID: 2513137 [PubMed - indexed for MEDLINE]

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    129: Cancer Chemother Pharmacol 1989;23(1):47-50 Related Articles, Books, LinkOut


    A new irreversible aromatase inhibitor, 6-methylenandrosta-1,4-diene-3,17-dione (FCE 24304): antitumor activity and endocrine effects in rats with DMBA-induced mammary tumors.

    Zaccheo T, Giudici D, Lombardi P, di Salle E.

    R. & D./Oncology, Farmitalia Carlo Erba Research Center, Milano, Italy.

    The antitumor activity of the new irreversible aromatase inhibitor 6-methylenandrosta-1,4-diene-3,17-dione (FCE 24304) was studied in rats with 7,12-dimethylbenzanthracene (DMBA)-induced tumors; several endocrine parameters were evaluated in these animals. The compound was given s.c. and p.o. twice daily, 6 days/week, for 4 weeks. The control group showed 13% tumor regression (0% complete remission, CR; 13% partial remission, PR). FCE 24304 given s.c. induced 44% (22 + 22) regressions at the dose of 3 mg/kg per day, 70% (40 + 30) at 10 mg/kg per day, 73% (27 + 46) at 30 mg/kg per day, and 70% (50 + 20) at 100 mg/kg per day. FCE 24304 given orally induced 25% (17 + 8) tumor regressions at 30 mg/kg per day and 50% (17 + 33) at 100 mg/kg per day. Rats were killed 4 h after the last dose and the aromatase activity of ovarian microsomes (OAA) was evaluated. OAA was reduced by 56% after s.c. treatment with 3 mg/kg per day FCE 24304; complete OAA suppression (greater than or equal to 96%) was obtained starting at 10 mg/kg per day s.c. Oral treatment slightly reduced OAA only at a dose of 100 mg/kg per day (36%). Body weight increased in all the groups s.c. treated with FCE 24304 but not in those treated orally. The weights of the pituitary, adrenals, and uterus were reduced in rats treated s.c. with 10 and 30 mg/kg per day; at 100 mg/kg per day, a decrease in ovarian weight was observed while uterus weight was similar to that of controls. Oral FCE 24304 increased ovarian weight at a dose of 30 mg/kg per day but not at 100 mg/kg per day. Serum prolactin (PRL) and luteinizing hormone (LH) levels did not change. In conclusion, FCE 24304 given s.c. proved highly effective against DMBA-induced tumors in rats but had less activity when given orally. Its intrinsic androgenic activity, higher after s.c. than after oral treatment, could contribute to the antitumor effect in the intact (premenopausal) rat model.

    PMID: 2491793 [PubMed - indexed for MEDLINE]

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    130: J Steroid Biochem 1988;30(1-6):391-4 Related Articles, Books, LinkOut


    6-Methylenandrosta-1,4-diene-3,17-dione (FCE 24304): a new irreversible aromatase inhibitor.

    Giudici D, Ornati G, Briatico G, Buzzetti F, Lombardi P, di Salle E.

    Farmitalia C. Erba, R.&D./Oncology, Nerviano (MI), Italy.

    FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione), a new irreversible aromatase inhibitor, has been identified and characterized in vitro and in vivo. The compound caused time-dependent inactivation of human placental aromatase with a t1/2 of 13.9 min and ki of 26 nM. When tested in PMSG-treated rats, ovarian aromatase activity was reduced 24 h after dosing by both the s.c. (ED50 1.8 mg/kg) and the oral (ED50 3.7 mg/kg) routes. No interference with 5 alpha-reductase activity nor any significant binding affinity for estrogen receptor was found. Slight binding affinity for the androgen receptor (RBA 0.2% of DHT) was observed.

    PMID: 3386266 [PubMed - indexed for MEDLINE]

  4. #4
    Senior Member mvmaxx's Avatar
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    And for a summary, based on what I know and have read, Aromasin basically does not effect the lipid profile as Arimidex and Letrozole do. It also suppresses estrogen to a higher degree than either compound.

    Average dose would probably be 25mg EOD to E3D.

  5. #5
    Senior Member mvmaxx's Avatar
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    Here's a post written by DrJMW (a real doctor and contributor to this site) in regards to the negative effects on the lipid profile caused by Letrozole.

    Originally posted by DrJMW
    I have posted this article before. Arimidex also negatively affects the lipid profile. Aromasin is by far the safest and most effective antiestrogen.




    Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.
    Eur J Cancer 2001 Aug;37(12):1510-3 (ISSN: 0959-8049)
    Elisaf MS; Bairaktari ET; Nicolaides C; Kakaidi B; Tzallas CS; Katsaraki A; Pavlidis NA
    Department of Internal Medicine, Medical School, University of Ioannina, GR 451 10 Ioannina, Greece. melisaf@cc.uoi.gr.
    Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.

  6. #6
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    Originally posted by mvmaxx
    And for a summary, based on what I know and have read, Aromasin basically does not effect the lipid profile as Arimidex and Letrozole do.

    These studies would disagree with Arimidex negatively effecting lipid profiles.......................




    Clin Cancer Res. 2003 Jan;9(1 Pt 2):468S-72S. Related Articles, Links


    Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors.

    Buzdar AU.

    Department of Breast Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. abuzdar@mdanderson.org

    The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments in postmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure.

    -----------------------------

    Cancer. 2002 Nov 1;95(9):2006-16. Related Articles, Links


    An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane.

    Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM.

    Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. abuzdar@mdanderson.org

    BACKGROUND: The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS: In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS: At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS: All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated. Copyright 2002 American Cancer Society.


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    Novice beaf's Avatar
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    PERFECT, thanks a lot!

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    Senior Member mvmaxx's Avatar
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    Originally posted by StoneColdNTO
    These studies would disagree with Arimidex negatively effecting lipid profiles.......................
    It's amusing that you can search and find medical documents that totally contradict each other. I guess it goes to show that the only fool proof way of knowing is to get blood tests before, during and post cycle to see how it effects you.


    I can't stand getting blood taken so that's not a very good option for me.

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    I this ALL you can come up with? I`m still unconveinced.

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    Originally posted by mvmaxx
    It's amusing that you can search and find medical documents that totally contradict each other. I guess it goes to show that the only fool proof way of knowing is to get blood tests before, during and post cycle to see how it effects you.

    No kidding......

    In physics they say "For every action, there is an opposite reaction"

    I guess the same holds true for studies.............LOL !!
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