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    Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer.

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    Authors
    DeFriend, David J
    Howell, Anthony
    Nicholson, R I
    Anderson, Elizabeth
    Dowsett, M
    Mansel, Robert E
    Blamey, R W
    Bundred, Nigel J
    Robertson, J F
    Saunders, C
    Affiliation
    Department of Surgery, Withington Hospital, Manchester, UK.
    Issue Date
    1994-01-15
    
    Metadata
    Show full item record
    Abstract
    We have conducted a clinical trial of a novel pure antiestrogen, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5,(1 0)-triene-3,17 beta-diol (ICI 182780), to assess its tolerance, pharmacokinetics, and short term biological effects in women with primary breast cancer. Fifty-six patients were randomized to either a control group (n = 19), in which they received no preoperative treatment, or a treatment group (n = 37), in which they received daily i.m. injections of ICI 182780 at doses of 6 mg (n = 21) or 18 mg (n = 16) for 7 days prior to primary breast surgery. Serum drug concentrations, gonadotropin levels, and sex hormone-binding globulin levels were measured during the study period by radioimmunoassay. Expression of estrogen receptors (ER), progesterone receptors, the estrogen-induced protein pS2, and the cell proliferation-related antigen Ki67 was determined immunocytochemically in pre- and poststudy tumor samples. Treatment with ICI 182780 caused no serious drug-related adverse events and had no effect on serum gonadotropin or sex hormone-binding globulin levels. Minor adverse events occurred in 5 patients receiving the 6-mg dose and 3 patients receiving the 18-mg dose. The serum concentration of ICI 182780 was dose dependent but showed variation between individuals. There was evidence of an approximately 3-fold drug accumulation over the short treatment period but steady state levels were not reached by the end of the 7 days. In patients with ER-positive tumors, treatment with ICI 182780 was associated with significant reductions in the tumor expression of ER (median ER index, 0.72 before versus 0.02 after treatment; P < 0.001), progesterone receptor (median progesterone receptor index, 0.50 before versus 0.01 after treatment; P < 0.05), and Ki67 (median Ki67 labeling index, 3.2 before versus 1.1 after treatment; P < 0.05). Treatment with ICI 182780 also resulted in a significant reduction in pS2 expression (P < 0.05) but this appeared unrelated to tumor ER status. In conclusion, ICI 182780 was well tolerated after short term administration and produced demonstrable antiestrogenic effects in human breast tumors in vivo, without showing evidence of agonist activity. These properties identify ICI 182780 as a candidate agent with which to evaluate whether a pure estrogen antagonist offers any additional benefit in the treatment of human breast cancer over conventional nonsteroidal antiestrogens, typified by tamoxifen, which exhibit variable degrees of agonist activity.
    Citation
    Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. 1994, 54 (2):408-14 Cancer Res.
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/97086
    PubMed ID
    8275477
    Type
    Article
    Language
    en
    ISSN
    0008-5472
    Collections
    All Christie Publications

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