INVESTIGATION OF A NEW PURE ANTIESTROGEN (ICI-182780) IN WOMEN WITH PRIMARY BREAST-CANCER

We have conducted a clinical trial of a novel pure antiestrogen, lfiny l)nonyl]estra-1,3,5,(10)-triene-3,17beta-diol (ICI 182780), to assess its tolerance, pharmacokinetics, and short term biological effects in women with primary breast cancer. Fifty-six patients were randomized t o either a control group (n = 19), in which they received no preoperat ive treatment, or a treatment group (n = 37), in which they received d aily 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 concen trations, 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-indu ced protein pS2, and the cell proliferation-related antigen Ki67 was d etermined immunocytochemically in pre- and poststudy tumor samples. Tr eatment with ICI 182780 caused no serious drug-related adverse events and had no effect on serum gonadotropin or sex hormone-binding globuli n levels. Minor adverse events occurred in 5 patients receiving the 6- mg dose and 3 patients receiving the 18-mg dose. The serum concentrati on of ICI 182780 was dose dependent but showed variation between indiv iduals. There was evidence of an approximately 3-fold drug accumulatio n over the short treatment period but steady state levels were not rea ched by the end of the 7 days. In patients with ER-positive tumors, tr eatment with ICI 182780 was associated with significant reductions in the tumor expression of ER (median ER index, 0.72 before versus 0.02 a fter treatment; P < 0.001), progesterone receptor (median progesterone receptor index, 0.50 before versus 0.01 after treatment; P < 0.05), a nd Ki67 (median Ki67 labeling index, 3.2 before versus 1.1 after treat ment; P < 0.05). Treatment with ICI 182780 also resulted in a signific ant reduction in pS2 expression (P < 0.05) but this appeared unrelated to tumor ER status. In conclusion, ICI 182780 was well tolerated afte r short term administration and produced demonstrable antiestrogenic e ffects in human breast tumors in vivo, without showing evidence of ago nist activity. These properties identify ICI 182780 as a candidate age nt with which to evaluate whether a pure estrogen antagonist offers an y additional benefit in the treatment of human breast cancer over conv entional nonsteroidal antiestrogens, typified by tamoxifen, which exhi bit variable degrees of agonist activity.