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Preventive Oncology Recognizes 25 Years of Discoveries

Tom Reynolds

In 1975, cancer researcher and chronicler Michael Shimkin, M.D., of the University of California, San Diego, declared it "the right time to propose a new specialty, Preventive Oncology," which he hoped would take a leadership role in the nascent field of preventive medicine.

Shimkin (Preventive Medicine, June 1975) made the distinction between primary and secondary prevention; pointed to the natural history and effect of treatment on premalignant lesions and the effectiveness of interventions, such as screening mammography, as high-priority, under-researched areas in cancer prevention; and predicted that people of the future will visit "preventories" to undergo screening tests, receive health education, and even engage in community activism on health-related issues such as "air pollution, water supplies, and industrial incursions."

Another writer in that era, John Lee, M.D., of the University of Washington, Seattle, lauded progress against occupational carcinogens, many of which had already been banned or controlled (Postgraduate Medicine, January 1972).

On general risk factors, these writers cover ground that is still heavily trod: tobacco, diet, radiation, and other usual suspects. But from a 21st century vantage point, many key players are conspicuously absent. Not a single gene is named, nor are chemopreventive agents or biomarkers discussed. There is no mention of apoptosis or angiogenesis, antioxidants or isoflavones, SERMs or NSAIDs.

Judging simply from the proliferation of new terms and acronyms introduced into the field, it is clear that 25 years later there is a new era in cancer prevention. So far, the impact on mortality rates is modest, but real—a decline of about 0.4% per year beginning in the mid 1990s, said John C. Bailar III, M.D., Ph.D., of the University of Chicago, which also reflects the impact of treatment—and it is on pace with the decline in mortality from all other causes, he said.



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Dr. John C. Bailar III

 
In public health terms, "we’ve moved from epidemiological associations and some concrete cause and effect knowledge to the point where, in many cases, we can knowledgeably intervene," said Peter Greenwald, M.D., Dr.P.H., director of the National Cancer Institute’s Division of Cancer Prevention.



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Dr. Peter Greenwald

 
What are the most significant developments in the past quarter century?

Experts cited a wide variety of scientific discoveries and societal changes, some already helping reduce cancer death rates and others promising to do so in the new century:

Tobacco control: The first Surgeon General’s report on smoking and health appeared in 1964, and persuaded some people to kick the cigarette habit. But not until the 1980s were research-based, systematic efforts to facilitate smoking cessation widely implemented. "When I got to NCI in 1981, there were a tremendous number of studies about the etiology of lung cancer—and nothing about the etiology of smoking or what you could do about it, how you could impact smoking rates on a population basis," Greenwald said. "Now, the tide of public opinion has turned, and smoking rates have gone down." Reduced smoking prevalence among men in the United States resulted in a downturn in lung cancer mortality rates in men beginning about a decade ago. (Women, who demographically took up smoking later than men, also lag behind in quitting, and their lung cancer death rates continue to rise.)

Screening and early detection: Writers in the 1970s acknowledged the value of the Pap test in reducing cervical cancer mortality. "It’s been very hard all along to get women who are at highest risk for cervical cancer to get themselves screened, but we’ve had some recent progress in that area," said Bailar. The evidence for mammography’s benefit was less well established, but since the Health Insurance Plan of New York’s landmark study on breast cancer screening in 1971, a number of large trials have established that screening women in their 50s and 60s reduces breast cancer death. Its effectiveness in other age groups is still debated. Screening men for prostate cancer with the prostate-specific antigen test led to a jump in incidence, but its value in preventing death from the disease remains unproven. An international European trial should provide some answers, while NCI’s Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial is evaluating screening methods for those four tumor types.

Diet: The observation that diet is related to cancer risk is decades old but poorly understood. Today, as Bailar wryly observed, "A lot of people know exactly which aspects of diet are involved in cancer but unfortunately they don’t agree," In fact, he said, "the evidence is not that strong for any one component, whether it’s fat, fiber, cruciferous vegetable, carotenes, or whatever. We just don’t know." Greenwald noted that we do have some knowledge to guide dietary choices. Excess caloric intake and obesity increase the risk of some cancers, while fruits and vegetables appear to have a preventive effect. Efforts are under way to identify which micronutrients in food have the greatest anticancer effects. Definitive answers are still awaited, but early studies suggest promise for soy isoflavones, polyphenols from tea, selenium, calcium, and several vitamins.

Chemoprevention: The term was coined in the late 1970s by Michael Sporn, M.D., then at NCI, for the concept that biologically active molecules might be administered not only as tumor-destroying chemotherapy, but to prevent tumors from forming or growing in the first place. An important early success of this approach was the 1991 finding from a group led by Waun Ki Hong, M.D., of the University of Texas M.D. Anderson Cancer Center, that by taking a pill containing the vitamin A-related compound 13-cis-retinoic acid, patients could prevent recurrence of head and neck cancer. The biggest triumph for chemoprevention to date was the nationwide Breast Cancer Prevention Trial, which in 1998 showed that risk of breast cancer could be reduced by nearly half in high-risk women who took the drug tamoxifen. The BCPT served both as proof-of-concept and as a prototype for other chemopreventive agents that work as selective estrogen receptor modifiers. The Study of Tamoxifen and Raloxifene trial is now testing tamoxifen against raloxifene, a second-generation SERM, and these hormonal agents are potential preventives for other cancers, including prostate.

Molecular epidemiology: Cancer researchers are working to identify and validate molecular markers of cancer that could make possible evaluation of promising agents without the long wait for cancer end points. Before the early 1980s, "cancer epidemiology studies were largely statistical associations between exposure and disease incidence, with very little mechanistic insight or use of laboratory methods—a black box," said I. Bernard Weinstein, M.D., of Columbia University in New York, who helped create the field of molecular epidemiology. Weinstein and others urged researchers to include cancer-associated biomarkers in their analyses, bringing a new level of precision to these studies.



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Dr. I. Bernard Weinstein

 
Infectious agents: Viruses and bacteria have been implicated as causes of several cancers—human papillomavirus in the uterine cervix, Helicobacter pylori in the stomach, and hepatitis viruses in the liver. "There has been a revolution in our understanding of the role of infectious agents in cancer causation," Weinstein said, "and this has major implications for prevention that we never would have dreamt of 25 years ago." Antibiotics and vaccines are already being tested against the latter two, and work is ongoing to create a vaccine against HPV.

Sunlight: Despite John Lee’s contention in 1972 that "permanent retirement into the shade is a poor way of controlling malignant changes in pigment cells," many fair-skinned people susceptible to melanoma have in fact begun to retreat from the sun, using sunscreens and avoiding the extreme summer tanning that was once almost universally practiced.

Multistep carcinogenesis: A series of discoveries by Bert Vogelstein, M.D., and colleagues at Johns Hopkins University, Baltimore, elucidated the stepwise process by which multiple genes go awry to cause colon polyps and then cancer. Their identification of the molecular "bad actors" that operate at each stage of the process offers multiple points for potential intervention. Similar pathways are being described in lung and other cancers. Also in recent years, scientists have learned that not only mutations, but epigenetic events such as changes in DNA methylation can operate in carcinogenesis.

Apoptosis: In the past, cancer’s uncontrolled growth spree was understood solely in term of increased cell proliferation rates. In the past 2 decades scientists have come to realize that glitches in the normal process of cellular suicide are just as important. Some anticancer drugs are now believed to work by restoring apoptosis, and the cell death program presents potential molecular prevention targets.

Angiogenesis: The insights of Judah Folkman, M.D., of Harvard Medical School and Children’s Hospital, Boston, on the important role played by new blood vessel growth in tumors, led to the development of antiangiogenic drugs now in clinical trials to treat cancer. Because angiogenesis begins early in cancer, such agents may also turn out to be useful in prevention.

Bailar and Weinstein will be among the participants in a March 12 symposium on "Twenty-five years of preventive oncology" at the 25th annual meeting of the American Society of Preventive Oncology (http://www.aspo.org) in New York City.



             
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