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THE NATION

New Drugs Offer Hope in Breast Cancer Fight

Researchers say the treatment markedly reduces recurrence of the disease.

October 10, 2003|Thomas H. Maugh II | Times Staff Writer

A new class of drugs will change the way breast cancer is treated, significantly reducing the disease's recurrence in post-menopausal women who have completed the normal regimen of surgery and chemotherapy, an international team reported Thursday.

The new drugs, called aromatase inhibitors, could improve the survival chances of as many as half of the 213,000 American women who contract breast cancer each year.

One of the new drugs, called letrozole, proved so effective in a study of women who had already finished a five-year regimen of the drug tamoxifen that the study was halted prematurely and the results released on the Internet before their publication next month in the New England Journal of Medicine.

Among breast cancer survivors who have completed five years of prophylactic therapy with tamoxifen, the risk of recurrence is normally about 1% to 2% per year. Letrozole, sold under the brand name Femara by Novartis Inc., reduced recurrence by 43%.

"This is going to change the way we treat breast cancer," said Dr. James Doroshow of City of Hope in Duarte. "There are hundreds of thousands of women who could potentially benefit."

About two-thirds of all breast cancers are sensitive to circulating levels of estrogen, which stimulates the tumor's growth. Tamoxifen interferes with this process by blocking estrogen receptors throughout the body. Several clinical studies have shown that five years of treatment with tamoxifen after the conclusion of surgery and chemotherapy can sharply reduce recurrence of tumors.

But continued administration of tamoxifen after five years produces no additional benefit and may, in fact, harm women, the studies have shown.

A recurrence of the disease while women are taking tamoxifen or afterward requires a new course of chemotherapy, surgery or radiation.

The aromatase inhibitors were designed to block the body's production of estrogen, thereby preventing the hormone from stimulating tumor growth. In the new study, for example, circulating levels of estrogen were reduced by 95%.

The aromatase inhibitors cannot be used in pre-menopausal women, however, because they do not block estrogen production in the ovaries, which is the predominant source in young women.

Femara and the closely related drugs anastrazole (sold as Arimidex by AstraZeneca) and exemestane (sold as Aromasin by Pharmacia) are already used to treat metastatic breast cancer and locally aggressive breast cancer. Because they worked by a different mechanism than tamoxifen, clinicians hoped they could be effective when tamoxifen's benefits wore off.

To test this idea, a team headed by Dr. Paul Goss of Princess Margaret Hospital in Toronto enrolled 5,187 Canadian, American and European post-menopausal women who had been taking tamoxifen for four to six years. After they completed their tamoxifen regimen, half the women received daily doses of letrozole and half received a placebo.

The study was intended to monitor the women for five years, but when the preliminary results were evaluated by a safety committee after 2.4 years, the drug's effects were so impressive that the study could not ethically be continued. Women receiving the placebo were informed of the results and encouraged to take letrozole.

The team found that 75 of the women taking letrozole had their cancers recur, compared with 132 of those taking a placebo. Overall, 13% of those taking a placebo had a recurrence, compared with 7% of those taking letrozole. Seventeen women taking the placebo died of breast cancer, compared with nine of those taking letrozole, but there were not enough deaths for the difference to be clinically significant, Goss told a news conference Thursday.

The benefit of the drug "was substantially greater than expected," Dr. Norman Wolmark of Allegheny General Hospital in Pittsburgh noted in an editorial accompanying the study.

The findings were so dramatic, Goss said, that "I would argue 'take letrozole' to any woman who has previously been exposed to tamoxifen."

The side effects of letrozole -- as with those of tamoxifen -- are essentially the symptoms of menopause: a higher risk of osteoporosis, hot flashes, sweating, edema, sore muscles and fatigue. About 4.5% of those taking letrozole stopped taking the drug because of side effects, compared with 3.6% of those taking a placebo.

Although stopping the study early was "absolutely necessary ethically," Doroshow said, it left many questions unanswered. Clinicians have no idea, for example, how long letrozole treatment will remain effective and whether there are unforeseen long-term risks.

Doroshow noted that some physicians are already beginning to prescribe letrozole instead of tamoxifen for women who have just completed chemotherapy, because its side effects are milder. That also opened further questions, such as whether letrozole should be followed by tamoxifen, which sequence of the two drugs would be most effective and could they be used together?

"It will be another 10 years before we know the answers to those questions," Doroshow said.

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