NOTTINGHAM, EnglandA 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
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 effectsER content, PR content, the
Ki67 proliferation-associated antigen, and apoptotic indexwere
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.
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
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
He concluded that Faslodex is an effective antitumor agent that
efficiently reduces tumor ER content and significantly reduces tumor
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