A Heartbeat Away from Preventing Cancer?

Statins lower cholesterol. Now, evidence is mounting that they may forestall tumors, too

Cancer researchers dream of coming up with a drug as safe and effective in fighting tumors as statins are against heart disease. These cholesterol-lowering drugs, the world's best-selling medicines, are among the pharmaceutical industry's brightest success stories. As statins gained popularity in the 1990s, rates of atherosclerosis, heart attacks, and death from heart disease all declined. During the same period, deaths from cancer crept up -- and new cancer drugs were few and far between. The drugs that have won approval do little more than hold the disease at bay for a few months or years.

There is, however, a growing body of evidence indicating that statins may be able to do for cancer what they've done for heart disease. Several recent studies have found that statins such as Merck (MRK ) & Co.'s Zocor and Pfizer (PFE ) Inc.'s Lipitor may be able to prevent cancers of the skin, breast, and pancreas from developing in the first place.

The link is not well understood, nor are all oncology specialists convinced that there even is a link. Most of the data come from epidemiological studies that found a statistical relationship between statin use and the decline of cancer incidence. With such studies, there is always the chance that something else could be causing the decline. Nevertheless, the huge annual meeting of the American Society of Clinical Oncology (ASCO), to be held in Chicago on May 31-June 3, plans to highlight the latest studies linking statins to cancer prevention. Such pride of place could bring statins to the forefront in the growing body of research on chemoprevention.

It's understandable that cancer specialists would long for a pill that could actually prevent tumor growth. About 50% of cancer victims die of their disease -- a survival rate that has improved little in the past 30 years. Early detection can improve the odds of survival, but once cancer has spread through the body, the disease almost always wins the fight against any treatment, whether it's surgery, radiation, or a medicine. Drugs that prevent tumors from developing in the first place could have a much greater impact on health care and the field of oncology than any treatment. "My personal opinion is that prevention should be as important as finding a cure," says Dr. Frank G. Haluska, director of melanoma research at Massachusetts General Hospital in Boston.

For drug companies, though, seeking a cure is a lot easier. "There are a lot of unknown risks attached to giving a drug for years to a healthy population," says Carolyn R. Aldigé, president of the Cancer Research & Prevention Foundation in Alexandria, Va. Proving that such a drug works would take far longer than proving a cure, since many cancers take a decade to develop from a premalignant state. Clinical trials of drugs that might prevent cancer must run five years or more and enroll tens of thousands of patients. That's a cost burden few pharmaceutical companies are willing to undertake, says Aldigé -- particularly as the drugs under study may end up losing patent protection before the end of any prevention trial.

For the health-care establishment, the effort seems more than worth it. Consider AstraZeneca (AZN ) PLC's 20-year-old breast-cancer treatment, tamoxifen, which is sold as Nolvadex. After an enormous prevention trial spanning five years and involving 13,000 patients, the National Cancer Institute (NCI) determined in 1998 that the drug reduced the incidence of the disease in high-risk women by 50%. In October, 1998, tamoxifen became the first drug approved by the Food & Drug Administration specifically for the prevention of cancer -- a move that AstraZeneca says boosted the drug's sales by about 10%.

The tamoxifen story, however, also highlights the disadvantages of chemoprevention. Although the drug can lower the risk of breast cancer, it slightly increases the risk of endometrial cancer, a rare but deadly disease. In an attempt to find a safer alternative, the NCI is conducting a seven-year, 22,000-patient prevention trial to gauge tamoxifen's effectiveness and safety in comparison with Evista, a similar drug from Eli Lilly (LLY ) & Co. approved five years ago for the treatment of osteoporosis. Results from this trial won't be available before 2006.

Like Evista, most chemoprevention drugs under study were originally developed for other diseases. By using existing drugs, researchers can draw on a large body of data about safety already in hand -- an important consideration when administering a drug every day for years to healthy people. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most popular candidates for chemoprevention, and they are being tested in patients at high risk of developing cancers of the breast, colon, and other organs. Merck's Proscar, a drug developed for the treatment of enlarged prostates, is being tested against prostate cancer, while inhaled steroids used to treat asthma, and retinoids (artificial vitamin A) commonly deployed against severe acne, are both being tested against lung cancer. The Cox-2 drugs -- Pfizer's Celebrex and Merck's Vioxx -- were originally developed for arthritis but are now popular candidates for chemoprevention. Celebrex has already been approved by the FDA to prevent colon polyps, a common precursor to colon cancer.

Drugs developed specifically for chemoprevention are almost nonexistent, but many oncologists believe the new class of targeted cancer therapies may be the next best thing. These drugs, much more easily tolerated than chemotherapy, aim to contain the tumor with minimal side effects. Houston's M.D. Anderson Cancer Center is enrolling patients in a prevention trial of AstraZeneca's Iressa, a targeted therapy approved by the FDA in early May for the treatment of lung cancer. Iressa will be given to former smokers with precancerous lesions in their lungs, in an effort to stop these growths from turning deadly. "The opportunity to use a targeted agent in chemoprevention is enormous," says Dr. Waun Ki Hong, head of the division of cancer medicine at Anderson.

The biotech companies that have developed most of the targeted therapies rarely have the resources to run large prevention trials, however. Consequently it is the NCI, rather than private industry, that is taking the lead in the search for chemopreventives. The institute is investigating more than 400 compounds, of which 40 are now in clinical trials. "The cancer field is 25 years behind heart disease when it comes to prevention," says James L. Mulshine, head of the NCI's intervention section. "We want to have the equivalent of a statin for cancer."

Whether statins themselves might be that equivalent is an open question. The drugs block an enzyme called HMG-CoA, used by the liver to form cholesterol. Some lab research indicates that statins may also block epidermal growth factors and blood vessel growth factors -- two biological processes that are key to the development of cancer.

Most studies linking cancer prevention and statins have been epidemiological: A study of 7,791 women in a trial researching osteoporosis fractures found that after five years the incidence of breast cancer was significantly lower among statin users than nonusers -- 2.1 per 1,000 vs. 4.1 per 1,000.

Biological evidence on behalf of statins came from a Japanese animal trial reported last year. A research team led by Dr. Toshiyuki Kusama of Osaka Medical Center administered the statin Lescol, made by Novartis (NVS ), to mice. Researchers then injected the animals with pancreatic cancer cells. Only 10 of the 12 mice treated with Lescol developed cancer, compared with all of the untreated mice. A second set of experiments found that Lescol was effective in stopping the disease when given after the cancer cells had been introduced.

It will probably be years before this test's applicability to humans can be assessed. In the meantime, Cancer Research's Aldigé speculates that as the epidemiological evidence mounts, more and more people with a family history of cancer or some other high-risk factor will convince their doctors to prescribe potential chemopreventives -- with or without FDA approval. Given the deadliness of cancer, they may conclude it is a risk worth taking.

By Catherine Arnst in New York

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