The Ninth AACR American Cancer Society Award Lecture on Cancer Epidemiology and Prevention Diet and Cancer : One View at the Start of the Millennium 1

The large differences in cancer rates among countries, striking changes in these rates among migrating populations, and rapid changes over time within countries indicate that some aspect of lifestyle or environment is largely responsible for the common cancers in Western countries. Dietary fat has been hypothesized to be the key factor because national consumption is correlated with the international differences, but these correlations are potentially confounded by other aspects of Western lifestyles. Detailed analyses in large prospective studies have not supported an important role of dietary fat. Instead, positive energy balance, reflected in early age at menarche and weight gain as an adult, is an important determinant of breast and colon cancers, consistent with numerous studies in animals. Physical inactivity has also been shown to be a risk factor for these diseases, and in part accounts for the international differences in cancer rates. Although the percentage of calories from fat in the diet does not appear related to risk of colon cancer, greater risks have been seen with higher consumption of red meat, suggesting that factors other than fat per se may be important. In many case-control studies a high consumption of fruits and vegetables has been associated with reduced risks of numerous cancers, but recent prospective studies suggest these associations may have been overstated. Among the factors in fruits and vegetables that have been examined in relation to cancer risk, present data most strongly support a benefit of higher folic acid consumption in reducing risks of colon and breast cancers. These findings have been bolstered by an association between incidence of colon cancer and a polymorphism in the gene for methylenetetrahydrofolate reductase, an enzyme involved in folic acid metabolism. The benefits of folic acid appear strongest among persons who regularly consume alcohol, which itself is associated with risk of these cancers. Numerous other aspects of diet are hypothesized to influence the risks of cancers in Western countries, but for the moment the evidence is unclear. Two decades of effort in developing, evaluating, and refining methods of dietary assessment have laid the groundwork for further insights into the role of diet in cancer etiology that will emerge from the more than 30 large prospective studies that are currently underway. Diet and Cancer: One View at the Start of the Millennium A fundamental observation in cancer epidemiology during the last century was that cancer incidence and mortality rates vary dramatically across the globe (1). In addition, rates of cancer among populations migrating from lowto high-incidence countries change markedly; in most cases, they approximate the rates in the new region within one to three generations. These lines of evidence indicate that the primary determinants of cancer rates are not genetic factors, but rather environmental and lifestyle factors that could, in principle, be modified to reduce cancer rates in high-risk areas (2). During the last two decades, the primary factor of interest, apart from tobacco, has been dietary fat. The hypothesis that dietary fat is largely responsible for cancers of the colon, breast, and prostate in Western countries derives largely from the strong ecological correlations between national per capita fat consumption and rates of these major cancers (1). Although international comparisons provide fertile soil for the development of etiologic hypotheses, they are a treacherous basis for conclusions because of the major potential for confounding. In the case of breast cancer, the low-risk countries are primarily developing areas and traditional Eastern societies where almost all aspects of lifestyle have been markedly different than those in affluent Western countries. These include differences in reproductive behaviors, physical activity, body composition, and many aspects of diet other than fat consumption. Thus, more detailed studies are needed to control for variables that may seriously confound cross-national comparisons. For the most part, these will necessarily be casecontrol and prospective cohort studies, which should be interpreted in the light of animal and mechanistic experiments. Ideally, every dietary hypothesis related to cancer would be tested by multiple large randomized trials in human populations. However, for even a small number of hypotheses, this is likely to be impossible because of the large numbers of individuals required and the long and uncertain follow-up period. For example, the Women’s Health Initiative trial of fat reduction, conducted along with interventions related to hormone replacement therapy and calcium/vitamin D, will cost approximately $1 billion (3). Even so, it is not likely to provide a clear answer to the fat and breast cancer relationship because multiple dietary factors are being changed simultaneously (4) and a 10-year intervention period late in life may well be inadequate even if fat was an etiologic factor. In this brief overview, I will describe the general process Received 11/2/00; accepted 11/5/00. 1 Presented at the 91st Annual Meeting of the American Association for Cancer Research, April 5, 2000, San Francisco, CA. 2 To whom requests for reprints should be addressed, at Department of Nutrition and Epidemiology, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. 3 Vol. 10, 3–8, January 2001 Cancer Epidemiology, Biomarkers & Prevention on May 15, 2017. © 2001 American Association for Cancer Research. cebp.aacrjournals. org Downloaded from by which we have investigated diet and cancer relationships epidemiologically and will provide a short status report on some of the major issues addressed during the last 20 years. In addition to discussing cancer incidence, I will also mention important findings related to non-cancer outcomes, in particular, coronary heart disease. These non-cancer outcomes can be helpful in interpreting findings for cancer, especially when an association is seen with coronary heart disease but the same variable is not associated with cancer. In this case, the lack of association with cancer cannot be attributed to insufficient variation in the dietary factor or inability to measure it. Moreover, coronary heart disease is itself important, and in the end we eat one diet. Thus, any actual dietary decisions should be made in the light of not just cancer, but how these variables relate to cardiovascular disease and other important conditions. In the late 1970s, when interest in diet as a major determinant of cancer began to emerge, great skepticism existed about the potential for studies of human diets in relation to risk of disease. Two major concerns were raised: that “diets are homogeneous within populations,” and that “people can’t remember what they ate. ” Indeed, if either of these conditions was true, it would be impossible to conduct informative analyses of diet and cancer incidence within populations. However, at that time, we had reasons to believe that neither of these assertions was correct. First, even simple surveys within populations indicated that individuals vary widely in food choices so that diets would not likely be homogeneous. Second, the experience of epidemiologists investigating food-borne outbreaks indicated that individuals could indeed remember what they ate, even at some time well removed from the critical event. However, this experience suggested that individuals could more readily answer questions about what they usually would have eaten as opposed to what they actually ate at a specific time on a specific day. Fortunately from the standpoint of cancer incidence, it is usual diet rather than a single meal or intake for 1 day that is likely to be most important etiologically. Thus, during the late 1970s, we and several other groups embarked on prospective studies of diet in relation to cancer incidence. At that time, virtually all investigators converged on the concept that a food-frequency questionnaire would be the only practical means of investigating the effects of long-term dietary intake in large numbers of individuals. The major alternative, 24-h recall, has practical limitations because it requires a professional dietitian and is expensive. More importantly, detailed studies had shown that diet varies greatly from day to day for most individuals so that even perfect information about a 24-h period would not reasonably represent a person’s longer-term intake (5, 6). The food-frequency questionnaire that we initially developed included 61 foods that were carefully selected to provide the maximum information on intakes of nutrients hypothesized to influence cancer and cardiovascular disease risk (7). For each of these 61 foods, participants were asked about their average use over the past year and were offered a multiple choice of answers ranging from never to six or more times a day. In addition to collecting data over an extended period, from a practical standpoint the food-frequency questionnaire has tremendous advantages because it could be self-administered and thus used in large populations. In 1982, we developed and tested an optically scanned version of our food-frequency questionnaire, which was found to be highly acceptable. Importantly, this substantially reduced data-entry costs and errors, which allowed us to expand the questionnaire and to collect dietary data repeatedly over time in a large population. This approach has become standard in almost all large prospective studies of diet and cancer. A central concern in the study of diet and cancer is validity of the dietary assessment. We therefore conducted a series of detailed studies to address this issue using three methods to assess question of validity: comparison with a detailed quantitative method, comparison with biochemical indicators of diet, and ability to predict known disease relationships (7). In the first va