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Evista for Chemoprevention of Breast Cancer: Better Late Than Never, FDA

Gilbert L. Ross, M.D.
Medical Progress Today
September 28, 2007

An aphorism never truer: when discussing breast cancer, an ounce of prevention is better for public health than the cures currently available, and much cheaper. So, after a long–and–winding eight–year period of data accumulation, we should applaud the FDA for finally approving Lilly's "designer estrogen," Evista (raloxifene), for use in postmenopausal high–risk women to lower their risk of invasive breast cancer. But we should question why the FDA took this long in the first place.

As of Friday the 14th, the drug, more scientifically termed a selective estrogen receptor modulator (SERM), also got FDA approval for cancer chemoprevention in postmenopausal women with osteoporosis (it has been available for osteoporosis prevention and treatment since 1999). Chemoprevention is the prescription of medication to lower the risk of a disease or condition from which the patient does not yet suffer but for which she is of higher susceptibility. In this case, women at high risk would take Evista as an agent of chemoprevention of breast cancer.

Until now, tamoxifen was the only FDA–approved drug to lower the risk of breast cancer, although neither it nor Evista is a panacea. While studies vary, in general these drugs reduce the risk by about one–half: in other words, if the rate of breast cancer is 8 per thousand, those taking a chemopreventive drug lower the risk to 4 per thousand. So hundreds of high–risk women would be treated to prevent only a few cancers. Also, like all drugs, these have their risks: both drugs can produce vein disease, including clots, and there is a higher risk of stroke.

So is Evista a real benefit or a potentially "dangerous drug?" The answer here depends on a careful assessment of the individual benefits and the risks. The increased risk of phlebitis (clots) or stroke is quite small, but any woman with a history of venous disease, or an increased risk of stroke, would be well advised to avoid these drugs—unless the doctor and patient find the benefits outweigh the risks.

The key is figuring out how much breast cancer risk a woman really has. An individual's criteria can be entered into a standardized decision key to make her risk clearer, though of course not certain. Factors influencing a woman's risk include: age, family history, menstrual onset, age at first pregnancy, alcohol intake, and obesity, among several others. After all the relevant factors are recorded, if her breast cancer risk is significantly elevated, she may be a candidate to take a chemoprevention drug. In the near future, it may be possible for personalized genetic evaluation to increase the accuracy of our risk prediction significantly.

There are other drugs for which there is evidence of a reduction in breast cancer risk, but large–scale studies have not yet been completed, so they have not been FDA–approved for that purpose. These are the aromatase inhibitors, and they work by interfering with the production of estrogen in breast tissue. They have been shown to work well to help reduce the spread of cancer already detected, and preliminary work regarding their use in chemoprevention has also yielded some encouraging results.

Let's hope that the aromatase inhibitor studies can be completed, and evaluated, much faster than the seven-plus years it took the FDA to bestow its seal of approval on raloxifene. Early studies published in 1998 and 1999 seemed to show that raloxifene markedly reduced breast cancer risk, but only now has FDA approval arrived.

Why the long delay? One major reason is the increased scrutiny given to new drug applications in the current risk–averse, "safety first" FDA. Until raloxifene was shown to be at least as safe and effective as the older tamoxifen—which was accomplished by the publication of the Study of Tamoxifen And Raloxifene (STAR) trial in June 2006—it was clear that approval would not be forthcoming. Nowadays, FDA's implicit rule seems to be that a new drug will not only have to be good, it will have to be better than the older drugs available.

Such a standard applies to no other industry—why should it apply to life–saving pharmaceuticals, given that a variety of drug options may increase the odds of helping diverse patients? Or, to put it another way, how many women were prevented from benefiting from this useful new drug during the years before FDA approval?

When a drug is not FDA–approved, even if doctors have heard of it, they are reluctant to prescribe it, in part out of fear of lawsuits. Many doctors are also fearful now of new drugs, given the recent heightened publicity about side effects from drugs like Vioxx and Avandia. Also, insurance companies often will not reimburse patients for drugs prescribed "off–label."

Given the still–tragic toll that breast cancer takes upon American women, we need all the effective therapies we can get to reduce the risk. Excess caution in drug approval takes lives—as does the FDA's exceedingly long learning curve on "off–label" uses of existing medicines. Former FDA Commissioner David Kessler has said that "we have to find creative ways of getting [new] cancer drugs to patients even if we end up being wrong a few times." Kessler is right, but is anyone at the FDA listening?

Gilbert Ross, M.D., is co-editor of the American Council on Science and Health booklet Weighing Benefits and Risks in Pharmaceutical Use
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