Drs. King and Schottenfeld have provided an interesting review of the literature in their attempts to relate changes in breast cancer incidence over time to secular changes in postulated risk factors.
As discussed, numerous attempts have been made to assess the extent to which screening might explain recent recorded increases in breast cancer incidence. These studies generally conclude that screening probably explains most of the observed increase, although other factors might play a residual role. Difficulties in disentangling screening effects from other predictors of disease occurrence have led some investigators to focus exclusively on mortality data. This provides less evidence for an "epidemic" of disease; in fact, recent data show striking downward trends over time, which are mirrored by the latest available incidence data.
The authors note a recent study showing that established risk factors account for only 41% of breast cancer cases in the United States. As indicated, this percentage might have been higher had speculative risk factors also been taken into account. King and Schottenfeld describe many of these speculative factors, including physical activity, obesity, diet, alcohol(Drug information on alcohol) consumption, exogenous hormone use, and organochlorines. Relationships with these factors have been difficult to reconcile, although several recent findings may be useful in guiding our future research directions.
Physical Activity/Dietary Factors
The authors correctly indicate that future research regarding the effects of physical activity requires validated approaches for assessing energy expenditure, particularly in conjunction with exposures relevant to caloric intake. The relationship of dietary factors may benefit from a focus on nutritional factors other than the traditionally investigated dietary fat, especially given recent evidence of a possible etiologic role for vitamins A and C [1,2], fiber , and olive oil(Drug information on olive oil) . Studies assessing combined effects of various nutritional factors (eg, diets high in fat and low in micronutrients) may be particularly informative. Although studies have conventionally focused on recent diet, evidence that adolescence is a vulnerable period for breast cancer risk supports the need for a consideration of effects of exposures earlier in life . In fact, it has been proposed that even in utero exposures may be important , including factors that determine initial growth patterns. Of further note is the consistency with which alcohol has emerged as a predictor of breast cancer risk, although the biologic rationale for the association remains elusive. Further studies are needed to clarify biologic mechanisms underlying alcohol associations, including effects of different consumption patterns on endogenous hormone levels .
In terms of defining anthropometric associations, studies showing that breast cancer risk is most affected by recent weight are important , especially given obvious preventive implications. Further, this observation may explain the apparent contradictory results regarding body size derived from case-control and prospective studies. Studies that carefully consider effects of body size over time are therefore needed. Also, studies which include an assessment of predictors of height could provide important etiologic information, especially given the consistency of this association in recent studies and the lack of apparent explanation for the association in well-nourished populations .
The Role of Hormones and Oral Contraceptives
As pointed out in the article, clarification of the role of exogenous hormones has been complicated. The authors stress the need for future studies to address the relationship of risk to combined hormone replacement therapy, which is important given the large numbers of women who are taking estrogens(Drug information on estrogens) for prevention of other chronic diseases.
Although oral contraceptives have not been consistently identified as being responsible for increasing risk in any subgroup of women, there is accumulating evidence that such usage may be a factor in women with early-onset cancers . Whether this represents a cohort effect associated with unique usage patterns or specific tumor effects has yet to be determined. Of particular importance will be future studies addressing effects of specific pill types and relationships with tumor characteristics. Studies addressing the relationship of exogenous hormones to hormone receptor status may be especially helpful in clarifying trend patterns, since the largest increase in breast cancers in recent times has been in estrogen receptor-positive tumors .
Although the King/Schottenfeld article discusses many speculative risk factors for breast cancer, a few additional factors merit attention. No mention is made of the possible etiologic role of environmental factors other than organochlorines. Electromagnetic radiation has been the cause of much concern, because of its effects on pineal melatonin(Drug information on melatonin) production  and observations of increased rates of male breast cancer among electrical line workers . Investigators are also now studying occupational exposures in women, especially as more women enter the workforce. This may affect other lifestyle factors, including breastfeeding and childbearing practices (including the incidence of induced abortions), factors whose relationships to breast cancer remain controversial.
The authors speculate that future studies of the interactions of speculative factors with genetic factors may provide important etiologic clues, but they limit their discussion to genetic markers such as BRCA1, BRCA2, and p53, which affect only a small proportion of the general population. Given the recent identification of a variety of more common genetic susceptibility markers, such as the P450 mono-oxgenases, N-acetyltransferase, glutathione S-transferase, and alcohol dehydrogenase, it may be more informative to explore their interactions with various environmental factors-especially since many of these markers could clarify mechanisms underlying various postulated risk factors.
Further clarification of the etiologic role of suggested risk factors for breast cancer may achieve a greater understanding of the causes of breast cancer and provide more appropriate preventive measures. Ultimately, however, disease prevention programs will depend on our developing a better understanding of the biology of the disease, which is still poorly defined. Although recent trends indicate that breast cancer may no longer be an "epidemic" in the classic sense, it remains all too common an occurrence. Hopefully, future etiologic research efforts will lead to more effective preventive approaches, especially since most of the established risk factors are not readily amenable to change.