By Duke Medicine News and Communications

SAN ANTONIO, TX – A new cancer drug called letrozole (trade name Femara®) worked better at shrinking breast cancer tumors than did the front-line breast cancer drug tamoxifen among a group of postmenopausal women with estrogen-positive tumors, according to a study coordinated by a Duke University Medical Center physician.

Sixty percent of women taking letrozole showed tumor shrinkage after four months on the drug, whereas 41 percent of women taking tamoxifen showed tumor shrinkage. Patients taking letrozole also underwent fewer mastectomies (complete breast removal) than women who were taking tamoxifen.

Moreover, letrozole actually slowed the rate of cell division -- and hence, tumor growth – better than tamoxifen did, according to cellular studies conducted on the actual tumors.

Results of the study are being presented Monday, Dec. 10, at the 24th Annual San Antonio Breast Cancer Symposium. The study was funded by Novartis Pharmaceuticals Corp., which manufactures letrozole.

"We are very excited by letrozole's potential because it appears to block the growth-promoting effects of estrogen within cancer cells better than tamoxifen does," said Dr. Mathew Ellis, a Duke oncologist and lead author of the study. "Estrogen is involved in up to 80 percent of all breast cancers, so blocking its effects is vital to successful treatment.

"Although our results are preliminary, letrozole appears to block estrogen more effectively than does tamoxifen, suggesting that letrozole may work for women whose tumors are relatively resistant to tamoxifen," said Ellis, who also is clinical director of the Breast Cancer Program at the Duke Comprehensive Cancer Center.

Letrozole could even replace the more toxic chemotherapy drugs in some patients, or it could be taken together with other non-cytotoxic drugs like Herceptin for maximum effect, the researchers theorize. Its distinct mechanism of action makes letrozole quite different from current therapies like tamoxifen and other, more toxic chemotherapies, Ellis said.

Ellis cautioned that, while his results are highly significant, they must be replicated in larger and more standard types of studies. The current study design was unique because it examined the drugs' ability to shrink tumors before women had surgery to remove their tumors rather than after surgery, as is commonly done to eradicate any undetected cancer cells. Also, the sample size of 324 women is not large enough upon which to base a change in routine clinical practice, he said.

Letrozole works by depriving the tumor of estrogen. Specifically, letrozole inhibits an enzyme called aromatase, which converts the male hormone androgen into the female hormone estrogen. Women taking letrozole, therefore, make almost no estrogen at all. Without estrogen, tumor cells that rely on the hormone for growth cannot divide and do not continue to grow.

Tamoxifen has a very different mechanism of action. It binds to small sites in the cancer cell called estrogen "receptors" and blocks estrogen from docking there. The receptors, plugged up with tamoxifen instead of estrogen, initiate a different sequence of events than they would in the presence of estrogen.

However, tamoxifen's presence on the receptor still triggers some estrogen-regulated genes to exert their influence within the cell, albeit in ways not fully understood. This effect may blunt the effectiveness of tamoxifen against some breast cancers.

Ellis says letrozole's ability to completely block estrogen from the cell is, in part, responsible for its apparent benefits over tamoxifen in some women.

In addition, he said, tamoxifen allows two other proteins – called ErbB-1 and ErbB-2 -- to amplify the growth-promoting effects of estrogen inside the cell. Letrozole, on the other hand, nullifies the action of these proteins because they rely on the estrogen receptor being stimulated to exert their action.

Knowing how the ErbB-1 and ErbB-2 proteins interact with the estrogen receptor to promote cancer is vital for several reasons, Ellis said. If researchers can identify which women express these proteins in their cancer cells, they can use them as biological "markers" to predict which women will respond to a given cancer treatment.

For example, women whose tumors made or "expressed" either of these proteins (ErbB-1 or ErbB-2) appeared to be largely resistant to the effects of tamoxifen, the study showed. Letrozole, however, was very effective in these types of tumors, shrinking them in 88 percent of women.

Several upcoming studies will compare letrozole's effects to tamoxifen in larger numbers of breast cancer patients, said Ellis. These larger studies should provide abundant data to confirm or refute letrozole's effects.

Ellis is a consultant for Novartis Pharmaceuticals Corp. and a member of their speakers' bureau.

Joining Ellis in the study were researchers from Universitaets Frauen-und Poliklinik, Hamburg, Germany; Instituto Valenciano de Oncologia, Valencia, Spain; Institut Bergonie, Bordeaux, France; and West General Hospital, Edinburgh, United Kingdom.