Fulvestrant Reduces Cell Turnover Index More Than Tamoxifen

SAN FRANCISCO—A new measure to evaluate the effect of preoperative antiestrogen agents on tumor growth in early estrogen-receptor (ER)-positive breast cancer suggests that fulvestrant (Faslodex, ICI 182,780, investigational) is superior to tamoxifen (Nolvadex). Fulvestrant is an estrogen-receptor downregulator and is considered a pure antiestrogen.

The new measure, cell turnover index (CTI), takes into account both cell proliferation and apoptosis, according to investigator Nigel J. Bundred, MD, consultant surgeon, South Manchester University Hospital, Manchester, UK.

Tumor growth is a balance between cell proliferation and cell death, Dr. Bundred said at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 1660). While both cell proliferation and apoptosis rates are used separately as endpoints in drug trials, they are biologically linked in tumors. "Clearly, drugs that lower proliferation but increase apoptosis are desirable," he said.

While the study purpose initially was to confirm preliminary findings that fulvestrant has different biologic effects in breast tumors than tamoxifen, researchers also wanted to determine if CTI is a better method for analyzing drug effect on tumors. CTI is measured by a log transformation after dividing the proliferation index (measured by Ki67 immunostaining) by the apoptosis index (measured by TUNEL staining).

Dr. Bundred and his colleagues used data from a randomized, placebo-controlled trial comparing three doses of a preoperative single intramuscular injection of fulvestrant (50 mg, n=39; 125 mg, n=38; 250 mg, n=44) with preoperative tamoxifen (20 mg daily for 14 to 21 days, n=36) in women with early operable ER-positive breast cancer.

Dr. Bundred’s earlier reports had shown that both tamoxifen and fulvestrant (125 mg and 250 mg) significantly reduced proliferation, compared with placebo, but did not significantly alter apoptosis (despite a 16% rise in median apoptotic index for Faslodex 250 mg, compared with baseline).

In the current study, Dr. Bundred reported that both tamoxifen and fulvestrant reduced proliferation in the tumors, compared with placebo. There was a significant rise in apoptosis with fulvestrant against tamoxifen, but not against placebo.

The drop in CTI from baseline was 49% with fulvestrant 250 mg, 21% with tamoxifen, and 4% with placebo, Dr. Bundred said. The CTI difference between fulvestrant and tamoxifen was significant (P = .026), he noted.

The effects of fulvestrant at both 125 and 250 mg were significant, compared with placebo, whereas tamoxifen had no significant effect on CTI, compared with placebo.

"Clearly, Faslodex is working much faster than tamoxifen—and this indicates that if you are comparing two good drugs like these, you need a much more sensitive marker of change, one that takes into account both apoptosis and cell proliferation," he said.

Dr. Bundred also said that CTI may have potential as a measure for drug response in patients receiving antiestrogens preoperatively. A CTI study, he said, may be a way of showing effect in a 2-week trial without having to look for tumor shrinkage. "The alternative requires 3 months of treatment and a delay of surgery," Dr. Bundred said.

Potentially, he said, "you could identify the best preoperative drug for a given woman with a CTI and then maintain her on adjuvant therapy with that drug after surgery." He added that further investigation is required to determine whether CTI is a more sensitive measure for assessing the effect of drugs on tumor growth than its individual components.