Faslodex, a Pure Antiestrogen, Shows Antitumor Activity

NOTTINGHAM, England—A new long-acting nonagonist antiestrogen, fulvestrant (Faslodex), significantly reduced estrogen and proges-terone receptor (ER/PR) content in breast tumors prior to surgery, compared with tamoxifen (Nolvadex) and placebo, according to a multicenter study presented at the San Antonio Breast Cancer Symposium.

No Agonist Activity

Fulvestrant, also known as ICI 182,780, “is a pure, steroidal antiestrogen. In vivo and in vitro studies have shown it to be devoid of agonist activity,” said lead investigator John F. R. Robertson, MD, of City Hospital, Nottingham, England. As such, he said, the compound is a member of a new class of antitumor agents, known as selective estrogen-receptor downregulators (SERDs). Tamoxifen, an example of a selective estrogen-receptor modulator (SERM), is a nonsteroidal antiestrogen that also has agonistic properties, he said.

The study included 200 previously untreated postmenopausal patients with T1-T3 breast cancers that were ER-positive or receptor status unknown.

Patients were randomized to one of five treatment groups. Three of the groups received fulvestrant (50, 125, or 250 mg) given as a single intramuscular injection. The fourth group received 20 mg/d of tamoxifen given for 14 to 21 days before surgery; and the final group got a placebo tamoxifen tablet given for 14 to 21 days before surgery.

Four markers of antitumor effects—ER content, PR content, the Ki67 proliferation-associated antigen, and apoptotic index—were assessed immunohistochemically in the pretreatment core biopsy and the post-treatment surgical biopsy. “Positivity in this study for each marker was regarded as any value greater than zero,” Dr. Robertson said.

ER-Positive Patients

Although the study enrolled patients who were ER status unknown, the analysis included only patients who were ER positive (155 patients).

The results showed that fulvestrant reduced the ER index from baseline assessment in a dose-dependent manner. Specifically, there was a 39% mean reduction in ER at 50 mg of fulvestrant; a 50% mean reduction at 125 mg; and a 59% mean reduction at 250 mg. These reductions were all significant, compared with placebo, and the reduction in ER at the highest fulvestrant dose was significantly greater, compared with tamoxifen (mean reduction, 36%).

The study also found a significant difference in PR expression with fulvestrant. There was a 12% mean reduction with 50 mg of fulvestrant; 52% reduction with 125 mg, and 67% reduction with 250 mg, while there was a 63% increase with tamoxifen and little change with placebo.

The two highest doses of fulvestrant significantly reduced PR, compared with placebo, and all three fulvestrant doses were significant, compared with tamoxifen. “We think these data show the agonistic properties of tamoxifen in increasing the PR expression,” Dr. Robertson said.

All three doses of fulvestrant significantly reduced Ki67, compared with placebo. However, the change in Ki67 expression was not significantly different with any dose of fulvestrant, compared with tamoxifen. There was no significant effect of fulvestrant at any dose on the apoptotic index, compared with tamoxifen or placebo.

First Direct Comparison

Dr. Robertson emphasized that “this is the first, direct comparison in a randomized study of tamoxifen to Faslodex, and what it shows is a superior reduction in ER and PR for Faslodex, compared to tamoxifen.”

He concluded that “Faslodex is an effective antitumor agent that efficiently reduces tumor ER content and significantly reduces tumor proliferative activity.”

Dr. Robertson noted that the “clinical relevance of these interesting biological data on Faslodex is currently being evaluated in phase III trials of postmenopausal women with advanced breast cancer.” These trials, he said, are using the 250-mg fulvestrant dose.