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The drug tamoxifen reached another milestone in June 2000 with its approval by the U.S. Food and Drug Administration (FDA) for ductal carcinoma in situ, or DCIS. Women who have had DCIS -- a small, non-invasive group of abnormal cells -- are at high risk of developing invasive breast cancer. Tamoxifen reduces that risk substantially, according to the study that led to FDA approval.

In this 1,804-patient trial, women first received lumpectomy and radiation therapy, a standard treatment for DCIS, and then were randomly divided into two groups to receive either tamoxifen or a placebo. After five years, the tamoxifen group had 43 percent percent fewer cases of invasive breast cancer.

The study is the latest, but by no means last, in a series of findings from clinical trials exploring the uses of tamoxifen. First studied as a treatment for advanced breast cancer, the drug later moved into studies to treat early breast cancer, and then into primary prevention trials.

But even with FDA approval in these three settings, the tamoxifen story is not yet over. Researchers continue to ask questions about the drug. For instance, when used for prevention of breast cancer, will it reduce overall death rates from that disease?

The landmark Breast Cancer Prevention Trial in the United States showed that tamoxifen reduced incidence (number of new cases) of breast cancer in postmenopausal women at increased risk who had been taking the drug for about four years. The study was not designed to show whether the tamoxifen would reduce breast cancer death rates, however.

Some information on mortality may come from the International Breast Cancer Intervention Study, which is comparing tamoxifen to a placebo in 7,000 women at increased risk of the disease. The primary aim of this trial is to compare the incidence of breast cancer in the two groups, but it will also assess mortality, other cancers, cardiovascular disease, and fractures according to Jack Cuzick, Ph.D., of the Imperial Cancer Research Fund, London.

Cuzick spoke at a workshop at the National Institutes of Health, Bethesda, Md., in April, 2000, when enrollment had passed the 6,000 mark. He projected all 7,000 participants needed would be enrolled by the end of the year.

New Combinations

For some investigators, tamoxifen's success in both prevention and treatment studies has set the stage for its use in combination with other agents that may also span these two uses. "It helps to think of breast cancer as a continuum," said JoAnne Zujewski, M.D.,who leads several breast cancer clinical trials at the National Cancer Institute in Bethesda. "I'm interested in compounds that may be useful from prevention to in situ disease to invasive cancer."

Such compounds include a class of drugs known as retinoids -- 4HPR or Fenretidine is one of most-studied - and another group known as farnesyl transferase inhibitors. In a pilot prevention study , Zujewski and colleagues have shown that Fenretidine combined with tamoxifen is safe and, they concluded, warrants further study as a preventive agent.

Treatment studies have also combined tamoxifen and Fenretidine. In metastatic disease, these include a Phase I/II study by Melody Cobleigh, M.D., and colleagues at the University of Chicago and a Phase II study by Zujewski and colleagues at NCI. In early breast cancer, studies of the combination are under way in Chicago and in Italy, at the National Institute for Cancer Research, where A. Decenzi, M.D. has been working with the two drugs.

Another retinoid, 9-cis-retinoic acid, has also been studied in combination with tamoxifen to treat metatastic breast cancer. Zujewski said that results from a Phase I trial showed the combination is safe and that Phase II trials of tamoxifen in combination with 9-cis or similar retinoids are under consideration.

Comparisons

In other studies, tamoxifen now serves as the benchmark against which newer therapies are measured. Perhaps the most widely watched of the current tamoxifen trials is the one comparing it to raloxifene for the primary prevention of breast cancer in women at increased risk. The Study of Tamoxifen and Raloxifene (STAR), launched in July 1999, has enrolled about 6,000 of the 22,000 women needed for the study.

Raloxifene is also an estrogen-like drug -- both it and tamoxifen are called selective estrogen receptor modulators or SERMS - and was originally developed to prevent osteoporosis.Other novel SERMs are in development, including one known as LY353381, which is now being tested against tamoxifen in a small Phase I trial.

Treatment studies have compared tamoxifen to Arimidex, an aromatase inhibitor, and a randomized trial of the two drugs has been under way for several years. This trial has completed enrolling patients and preliminary results could be available next year, according to a spokesperson for AstraZeneca Pharmaceuticals, maker of both drugs and sponsor of the trial.

Another DCIS Trial

Also under way is more tamoxifen research in DCIS. Approved by the FDA for use with radiotherapy, the drug will now be tested without radiotherapy in a large trial conducted by the Radiation Therapy Oncology Group and the Cancer and Leukemia Group B, both NCI-sponsored Cooperative Clinical Trials Groups. Patients in this trial will be randomized, after lumpectomy, to receive either tamoxifen with radiation therapy - the combination that was just approved by the FDA -- or tamoxifen alone.

This trial is one of the first to be open to members of all NCI-sponsored Groups through the new Cancer Trial Support Unit (CTSU ). One aim of the CTSU is to speed and facilitate the completion of trials, so enrollment in this trial may proceed rapidly.

Other Cancers

Tamoxifen has also been tested in several other kinds of cancer. In melanoma, studies have had conflicting results, but one recent small, Phase II study, whose results were published in the July 2000 issue of the British Journal of Cancer, suggested that the combination of tamoxifen and cisplatin was beneficial. The finding "warrants confirmation in a prospective randomized trial," according to investigators, E.F. McClay and colleagues of the University of California, San Diego.

Earlier trials looked at tamoxifen as a treatment for a wide range of other cancers, including prostate, kidney, ovarian, and endometrial tumors. With the exception of ovarian cancer, there has been little response to tamoxifen in these trials.

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