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.