MICHAEL THUN, MD, MS
Identification of the causes of cancer is the essential first step in the prevention of suffering and death from tumors that are potentially avoidable. This knowledge alone is generally insufficient to identify effective interventions, however. Translational research bridges the gap between knowledge and practice by strengthening the evidence for causation, communicating the magnitude of risk and disease burden that might potentially be avoided, countering misperceptions that discourage healthy behaviors, and evaluating the effectiveness of specific interventions.
Dr. Michael Thun, the emeritus vice president of epidemiology and surveillance research at the American Cancer Society, has devoted most of his career to translational research on cancer prevention. Thun recently received the 19th Annual AACR-ACS Award for Research Excellence in Cancer Epidemiology and Prevention for his contributions over 30 years. The award cited his seminal research on aspirin and cancer prevention, etiologic and surveillance research on lung cancer in relation to the changing design of cigarettes, and the development of a high-impact epidemiologic research program at the American Cancer Society (ACS). What may ultimately be most important is the leadership that he and his esteemed colleague, the late Dr. Eugenia (Jeanne) Calle, provided in developing epidemiologic research at ACS into a world class center for research on the causes and prevention of cancer. Among their many influential publications are nine published within the last decade, each of which was cited more than 1000 times. These address the relation of aspirin to cancer prevention, overweight and obesity to cancer mortality, alcohol consumption to all-cause mortality, and particulate air pollution to death from cardiopulmonary disease.
The common thread that connects these diverse topics is Thun's interest in applying epidemiologic tools to resolve critical scientific questions that impede cancer prevention. He became interested in epidemiology during his residency in internal medicine. He had previously earned a BA from Harvard in 1970 and a medical degree from the University of Pennsylvania in 1975. He realized that many of the diseases suffered by his patients were preventable, but that training in medicine alone would not equip him to address this critical issue.
To gain practical experience, Thun began working with the state epidemiologist of New Jersey in 1978, investigating toxic exposures. After two years of studying firemen and heavily polluted communities in New Jersey, however, Thun concluded that the health effects from environmental pollutants could not be assessed reliably in small studies of the general population. In 1980, Thun joined the Centers for Disease Control and Prevention, Epidemic Intelligence Service, hoping that studies of well-defined, highly exposed occupational populations would provide clearer answers. Assigned to the National Institute for Occupational Safety and Health, he focused his research on whether long-term exposures to heavy metals, such as cadmium and uranium, caused demonstrable health problems at levels then permitted by federal limits. His studies of kidney toxicity and lung cancer among workers highly exposed to cadmium documented increased risk of both endpoints associated with exposure levels below the permissible limit. This research, together with studies from Sweden, motivated the Occupational Safety and Health Administration (OSHA) to reduce the legal exposure limit to cadmium in the workplace from 200 μg/m3 to 10 μg/m3, averaged over an eight-hour workday.
In 1988, the ACS moved its national headquarters from New York to Atlanta; shortly after, Thun was recruited as Director of Analytic Epidemiology. Already an expert on the health risks of occupational and environmental exposures, Thun wished to broaden his research. The massive ACS cohort studies provided the opportunity to do so. These included Cancer Prevention Study I (CPS-I), founded in 1959 with one million men and women in 25 states, and CPS-II, launched in 1982, with 1.2 million Americans nationwide. Thun and coworkers further enhanced these resources by reenrolling a subgroup of 175,000 CPS-II participants into the CPS-II Nutrition cohort to be followed for cancer incidence as well as mortality, and by collecting and archiving blood samples from 40,000 participants and buccal (cheek cell) DNA from an additional 70,000.
Thun's research on aspirin use and reduced risk of fatal colon cancer was prompted by a 1991 publication in the Journal of the National Cancer Institute by Lynn Rosenberg and colleagues, showing an inverse association of regular aspirin use with incidence of colorectal cancer. The article cited references to laboratory experiments in which nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin inhibited the development of chemically-induced colorectal cancer in rodents. Although intriguing, these initial results were greeted skeptically because of the study's retrospective (case-control) design. Thun and colleagues replicated the findings in the massive, prospective CPS-II cohort and published their results in the New England Journal of Medicine. Their report coincided with the discovery of a second isoform of the cyclooxygenase (COX) enzyme, the target inhibited by NSAIDS, and later with the development of selective COX-2 inhibitors. This confluence of events drew tremendous attention to the issue of NSAIDs and cancer prevention, and revived interest in the role of inflammation in cancer.
Abundant evidence has since accumulated that aspirin and other NSAIDs inhibit the development of adenomatous polyps, colorectal cancer, and possibly other cancers. Despite this, neither aspirin nor other NSAIDs are currently recommended for cancer prevention in the general population. All NSAIDs cause some increase in the risk of gastrointestinal bleeding. Even rare serious side effects can preclude the use of chemopreventive agents in primary prevention, where large numbers of otherwise healthy adults must be treated for many years to prevent disease in a relatively small subgroup. Although aspirin is the most likely candidate among NSAIDs for chemoprevention, due to its established cardiovascular benefit and safety profile, it has not yet been proven that the benefits of long term prophylaxis exceed the risks. A study coauthored by Thun and Eric Jacobs suggests that daily use of adult strength aspirin (approximately 325 mg) for five or more years may reduce risk of all cancers combined by approximately 15%. If this can be replicated, it could influence the recommended dose of prophylactic aspirin to prevent heart disease and/or the indications for prophylactic use.
In the mid-1990s, Thun was drawn into tobacco research and the controversy about whether design changes in cigarettes had changed their pathogenicity. A comparison of lung cancer death rates during the first six years of CPS-I (1959-66) and CPS-II (1982-88) showed that the death rate in smokers doubled in men and increased more than fivefold in women over this 20-25 year interval, adjusting for measured differences in duration and intensity. In contrast, no change was observed in the lung cancer death rate among never-smokers. The increased risk in smokers occurred even though most had shifted from unfiltered, very high “tar” yield brands to filter-tip products marketed as having lower “tar” yield, as measured by smoking machines.
Direct evidence that the "tar" rating of cigarettes allowed by the Federal Trade Commission (FTC) bore little relationship to lung cancer risk came from a collaborative study of CPS-II with Jeffrey Harris of MIT. This study, published in the British Journal of Medicine, compared lung cancer risk in people who smoked very low tar cigarettes (< 7mg), low tar cigarettes (8-14 mg), filter-tip regular tar cigarettes (15-21 mg) and unfiltered very high tar cigarettes (> 22mg). The first two categories correspond roughly to “light” and “ultralight” categories. No difference in lung cancer risk was observed between smokers of “regular” filter tar cigarettes (15-21 mg) and those who smoked “light” or “ultralight” brands. Lung cancer risk was significantly lower only among people who had quit smoking compared to those who continued. The highest risk was in smokers of unfiltered, very high tar cigarettes (>22mg). Supporting these results were biomarker studies that showed little correlation between machine measured “tar” or nicotine ratings of cigarette brands and the amount of tobacco smoke taken up by smokers. Based on this collective evidence, the FTC rescinded its approval of machine measured smoking as a reliable measure of product yield. Subsequently the Food and Drug Administration (FDA) banned use of the terms “light”, “ultralight”, and “mild”. Because of Thun’s major research contributions on the adverse health effects of tobacco use, he has served on three working group on tobacco for the International Agency for Research on Cancer, most recently chairing the subgroup on active and passive smoking for Monograph 100E.
Cancer incidence and death rates are now decreasing in both sexes in the United States. The death rate from all cancers combined decreased by approximately 19 percent in men and 11 percent in women from 1991 to 2005. What is less well recognized is that approximately 40 percent of this decrease in men can be attributed to the reduction in death rates from smoking related cancers in men, due to widespread smoking cessation since the 1950s. Thun is a vocal advocate of cancer prevention, which despite its successes maintains a considerably lower profile than either treatment or basic research. Cancer prevention relies on effective advocacy to remind the public of the essential value of prevention and to build social, physical, and economic environments that facilitate healthy behaviors for the entire population.