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Upstaging Tamoxifen? New Classes of Drugs Emerging for Breast Cancer

Renee Twombly

The success of tamoxifen, once a failed contraceptive drug, has ushered in a boom of research into new therapies that may soon upstage tamoxifen itself, researchers say.

As a breast cancer treatment, the 31-year-old tamoxifen may be surpassed by new classes of drugs such as aromatase inhibitors and novel estrogen receptor down regulators.

Tamoxifen, approved for reducing the risk to breast cancer in high-risk women 4 years ago, is now competing with a younger cousin, raloxifene, purported to have fewer side effects than tamoxifen. Raloxifene is already battling with highly tailored third generation selective estrogen receptor modulators (SERMs).

Some researchers think of them as designer endocrines; others label them hormonal smart bombs that bind, block, or destroy production or use of estrogen. Whatever the method, the intent is the same: manipulation of estrogen in a woman’s body with one, two, or a series of hormone therapies, to prevent or treat breast cancer, while potentially strengthening aging bones and arteries.

"Tamoxifen is like the penicillin of World War II, which gave rise to a huge number of antibiotics," said V. Craig Jordan, Ph.D., D.Sc., the researcher who first studied tamoxifen as a breast cancer drug. "Tamoxifen is doing the same for hormone therapy," said Jordan, director of the breast cancer research program at Northwestern University Medical School, Chicago. "It has offered the clinical proof of principle that hormone therapy works, and the rest is a matter of refinement."



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Dr. V. Craig Jordan

 
The marriage between hormonal medicine and molecular biology of the breast is better characterized, and perhaps less controversial, in treatment of breast cancer than in prevention of the disease.

Tamoxifen is the best known antiestrogen therapy for treating breast cancer. It competes with estrogen to occupy receptors on breast cancer cells, and since the majority of breast tumors need estrogen to grow, tamoxifen can be a powerful anticancer drug. It has been shown to halt metastatic progression, and reduce recurrence by up to 50% in both pre- and postmenopausal women. But over time, tamoxifen can increase the risk of developing endometrial cancer and blood clots, and has no added benefit after 5 years and may even promote cancer growth.

So far, other SERMs have not shown added benefit in treatment. New animal research, published Feb. 20 in the Journal of the National Cancer Institute, showed that using raloxifene after 5 years of tamoxifen not only does not help further reduce recurrence of early breast cancer, it may stimulate the growth of endometrial cancers. The bottom line is that raloxifene and tamoxifen "are very similar agents," and should never be used consecutively, as some clinicians have prescribed in the absence of data, said Ruth O’Regan, M.D., of Northwestern University Medical School.

Now, a newer class of drugs, aromatase inhibitors, is gaining acceptance as a first-line treatment agent. Aromatase inhibitors hamper functioning of the enzyme aromatase, which converts androgen into estrogen, thus lowering total available estrogen in the body. That is important to a postmenopausal breast cancer patient because while her ovaries may not be making estrogen, her aromatase-rich breast tissue is.

Aromatase inhibitors have most commonly been used as second-line therapy in postmenopausal women who may have already used tamoxifen. But based on the FDA’s September 2000 approval of anastrozole (Arimidex), one kind of aromatase inhibitor, as a first-line treatment option for advanced or locally advanced postmenopausal hormonally receptive breast cancer, many physicians are recommending use of these drugs before tamoxifen in women with metastatic disease.

Aromatase inhibitors could also become popular as first-line therapy in the adjuvant setting. One reason is that early findings from an ongoing study, ATAC (Arimidex and Tamoxifen Alone or in Combination), showing that anastrozole as well as a combination of tamoxifen and anastrozole was found to be superior to tamoxifen alone. Anastrozole reduced the relative risk of disease recurrence by 17% when compared with tamoxifen, and the incidence of invasive and noninvasive contralateral breast cancer was decreased by 60%, according to an analysis presented in December at the San Antonio Breast Cancer Symposium.

The role of aromatase inhibitors in breast cancer treatment should become clearer when survival figures from the ATAC trial become available, said University of Washington oncologist Julie Gralow, M.D., co-chair of the Southwestern Oncology Group, Breast Cancer Committee. "It’s exciting, because we are figuring out how best to use these different hormonal agents to avoid using chemotherapy," she said.

Yet a third class of drugs, estrogen receptor down regulators (ERDs), may likely be added into the future formula for treatment of adjuvant and metastatic disease, said C. Kent Osborne, M.D., of Baylor College of Medicine. These drugs bind to, and destroy, estrogen receptors on cancer cells, and the first candidate in this new class, fulvestrant, is being considered by the FDA for second-line therapy, Osborne said.

In two phase II trials, fulvestrant, administered by injection, was as effective as anastrozole in patients who had failed tamoxifen therapy. The disadvantages of both drugs are the same, in that they shut down estrogen use throughout the body, including the bones, he said. "An option might be to offer patients tamoxifen, then an aromatase inhibitor, then fulvestrant," Osborne said.

In the meantime, numerous clinical trials are under way in breast cancer patients that compare different aromatase inhibitors against each other and against tamoxifen, and pin ERDs against tamoxifen.

In 1998, tamoxifen was the first anticancer drug sanctioned for use in disease-free individuals. With great fanfare, the Breast Cancer Prevention Trial (BCPT) was halted early when data revealed that high-risk women who used tamoxifen had a 49% reduction in breast cancer incidence. But these results were tempered by the fact that these women had an increased risk of developing endometrial cancer and blood clots in their lungs and veins.

Now, because of its side effects, tamoxifen is being tested alongside raloxifene, a cousin SERM that is approved to prevent osteoporosis. Based on a preliminary observation there were fewer cases of breast cancer among women in a clinical trial who took raloxifene compared with a placebo control group, the National Cancer Institute launched one of the largest clinical trials in breast cancer history in 1999. With a goal of enrolling about 22,000 postmenopausal high-risk women, STAR (Study of Tamoxifen and Raloxifene) is pitting tamoxifen against raloxifene to see if raloxifene can prevent breast cancer as well as tamoxifen, but without added risks such as development of endometrial cancer.

But raloxifene itself may eventually give way to newer, highly specific SERMs, a number of which are now in the first phases of testing. One of them, known as SERM-3, is an advanced formulation of raloxifene and may be 10 times more potent as an antiestrogen than tamoxifen, said Joyce O’Shaughnessy, M.D., director of the chemoprevention research program, Baylor University Medical Center, Dallas. "SERM-3 looks very promising as a breast cancer preventive agent," she said. An upcoming trial of SERM-3 differs from the STAR trial in that participants may be pre- or postmenopausal and may remain on hormone replacement therapy.

Aromatase inhibitors are also being examined for breast cancer prevention, although researchers are concerned that long-term, systemic effects could lead to increased osteoporosis. IBIS II, a randomized, double-blind controlled trial comparing anastrozole and tamoxifen was scheduled to begin enrolling patients in Europe in December. Joint use of an aromatase inhibitor (exemestane) with a SERM (raloxifene) is also being investigated at Memorial Sloan-Kettering Cancer Center, New York, said Larry Norton, M.D., head of the division of solid tumor oncology. The idea is to lower the load of estrogen with an aromatase inhibitor and then use raloxifene, which he said "clearly reduces the incidence of breast cancer, and which works best in a low-level estrogen environment."



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Dr. Larry Norton

 
Norton, who is president of the American Society of Clinical Oncology, said the study is aimed not as a prevention study outright, but to look at biological end points—a goal many other studies should strive for, he argued. "The lesson here is that we have to concentrate on the biology and develop surrogate end points that let us look at what is happening at the tissue level," Norton said. "Or we can study every combination of different drugs in clinical trials for the next 100 years."



             
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