Tamoxifen

Before Helene Wilson reached her 45th birthday she was warned in no uncertain terms about her chances of getting breast cancer. "You're a walking time bomb," her doctor told her.

Grim words, but hardly surprising. Helene's mother had died of breast cancer. So had her grandmother and two aunts. She discovered her first lump at age 29 and, though benign, it led to a parade of breast biopsies through the ensuing years. "I definitely had some red flags," she says.

Helene, from Blue Bell, Pennsylvania, is far from the only one with the same red flags: Ten million other American women are at high risk for breast cancer. And for many, it's like having a sword hanging over their beads. "It was nerve-racking going in for a biopsy every six months and always expecting them to find something," Helene recalls. "I got to the point I was willing to undergo a bilateral mastectomy just to have it over with."

Fortunately, she didn't have to go through such radical surgery. Instead, in the 1990s, Helene discovered tamoxifen. Also known by its brand name Novaldex, tamoxifen was already a popular treatment for those with breast cancer because of its ability to keep the cancer from spreading. Then researchers decided to see whether tamoxifen could prevent the disease in the first place. Helene signed on as a study subject and took a pill every day for five years. "About a year into the tamoxifen trial, I stopped having any problems whatsoever," she says.

The Breast Cancer Prevention Trial, as it was called, was a watershed event. The study of 13,000 women concluded that tamoxifen reduces the chances of getting breast cancer by 49 percent among those at high risk for the disease.

In 1998, after the study results were released by the National Cancer Institute, the U.S. Food and Drug Administration (FDA) approved tamoxifen as a breast cancer preventive for women older than 35 who meet the high-risk requirement. That makes tamoxifen the only cancer-prevention drug in existence with FDA approval.

Think about that for a minute. There's a pill on the market that can drastically cut the number of cases of a cancer that's diagnosed more than 180,000 times a year in the U.S. and that caused 40,000 deaths in 2003.

However, after six years on the market, tamoxifen hasn't exactly set the world on fire in its preventive role. Existing data doesn't distinguish between prescriptions for tamoxifen for prevention or treatment, so no one is sure just how many women are using tamoxifen to fend off breast cancer. "But it's a very small percentage," says Andrew N. Freedman, Ph.D., an epidemiologist for the National Cancer Institute (NCI).

Lack of awareness may be one reason for the small number of women taking the drug as a preventive. "There's a need to educate women and physicians about the possibilities of tamoxifen," says Dr. Worta McCaskill Stevens, an oncologist who conducts research on tamoxifen. "The existence of tamoxifen as a preventive is at least an opportunity for women to start the conversation with their doctor about breast cancer risk."

But the most important reason for tamoxifen's limited appeal as a preventive is that it has a dab of danger lurking within. Yes, tamoxifen reduces the risk of breast cancer. But in some cases it increases the risk of potential killers, including two kinds of cancer of the uterus, pulmonary embolism (an often-fatal blood clot in the lungs), and stroke. Because of these side effects, women can only stay on the drug for live years. After that, the drug stops working as well as a preventive yet the risks increase.

"Knowing about those risks, slight as they were, was a little scary," says Patricia Muir, a Pittsburgh schoolteacher who began taking tamoxifen at age 45. "But I decided to forge ahead because I really wanted to get that breast cancer risk under control."

HOW TAMOXIFEN WORKS

Tamoxifen retards activity of the hormone estrogen. Because breast cancer cells feed off estrogen, tamoxifen's antiestrogen effect slows breast cancer growth, making it a valuable therapy for cancer patients while other treatments are put to work. It also seems to be the reason why tamoxifen works to prevent breast cancer as well.

Unfortunately, on certain other cells, tamoxifen mimics estrogen, rather than inhibiting it. That can create some benefits, such as cholesterol reduction and slower bone density loss, but it also leads to that troublesome uptick in the rate of potentially serious problems.

What researchers are trying to figure out is when the potential benefit from tamoxifen clearly outweighs the risk of complications. Freedman's latest work looked at precisely that balance.

Analyzing an existing health information database, he concluded that of the 10.2 million U.S. women eligible to take preventive tamoxifen (that is, older than 35 and at high risk for breast cancer) about 2.4 million of them would get benefits significantly greater than the risk of negative side effects. For them, tamoxifen is a good bet.

The key, of course, is figuring out whether you're one of the 2.4 million. As it turns out, there's a pretty straightforward way to do that. It's called the Gail model (see box, page 280) and it gives you a number representing your risk of developing breast cancer within the next five years. Over 1.67 percent is considered high risk. Helene and Patricia had numbers at least triple that, prompting their decision to take the drug.

Should you make the same choice? Only you can answer that question. Even the NCI's Freedman, who has spent years pinpointing candidates most likely to benefit from tamoxifen, won't answer it. "All I can do is lay out numbers," he says. "The decision itself is very personal."

If you're under 40, chances are your Gail number won't be high enough to offset the risk of tamoxifen's side effects. High-risk women in their 50s are likely candidates if they've had a hysterectomy, which eliminates the uterine cancer worry. Women over 60 are generally at higher risk for the drug's side effects, negating its advantages.

Also, it's not always the numbers themselves that matter. It's what they mean to you. Many women cringe at the idea of taking something with potentially serious side effects for a disease they don't have. "Tamoxifen isn't sugar candy, but a very powerful drug," says Barbara Brenner, executive director of Breast Cancer Action, an advocacy group in San Francisco. "And we're talking about using it as an intervention in healthy people, people who aren't sick and may never get sick."

NCI researcher Dr. Leslie Ford, on the other hand, sees risk-reducing medications as a desirable pursuit. "That's what we do with cholesterol-lowering drugs like statins," she says. "High cholesterol isn't heart disease, but a known risk for it. So we give statins to people to reduce their risk."

Ford, though, agrees with the advocacy groups that tamoxifen's rare but potentially deadly side effects are a concern. That's why she, McCaskill-Stevens, and others at the NCI have embarked on another major trial that seeks to find a breast cancer preventive as potent as tamoxifen but without all the problems. The results of that study, involving the drug raloxifene, are due in 2006.

That's more good news for women like Helene Wilson. "Women need to be proactive," she says. "We need to see what we can do to prevent this disease instead of just waiting for it to happen. Anything you can do to take control of your own health is a good thing."

FIND OUT YOUR BREAST CANCER RISK

A statistical tool known as the Gail model is used to calculate your risk of developing breast cancer. You can estimate your own likelihood with the National Cancer Institute's Breast Cancer Risk Assessment Tool at http://cancer.gov/bcrisktool. You'll be asked a number of questions, including at which age you started menstruating, how old you were when your first child was born, and whether or not you've had a biopsy. The tool will estimate your breast cancer risk in the next five years as well as over your lifetime.

MORE ABOUT WOMEN'S HEALTH, www.bhg.com/health

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