Apparent continuing increases in the incidence of breast cancer have stimulated interest in gaining a greater understanding of the development of this disease so that it may be possible to prevent it. At present, considerable attention is being focused on the inherited genetic changes that play important roles in perhaps 10% of cases of breast cancer among American women. Although investigation of the functional implications of these changes should provide useful information about broad developmental processes in breast cancer, a more general focus on our emerging understanding of this process is critical to addressing the ultimate public health goal of breast cancer prevention: the reduction of the incidence of breast cancer in the entire American population.
A broad strategy to address this goal is clear: to identify, understand, and act broadly on manipulable causes of breast cancer. Pursuit of this strategy requires that the following challenges be addressed:
- Identification of (new) specific manipulable causes. For example, dietary factors and exercise appear to be important causes, but exactly which dietary constituents are important and when in the developmental causal sequence these constituents and exercise exert their effects are unknown.
- Greater understanding of the developmental causal sequence. More inclusive, more comprehensive models are needed, along with targeted studies to explain how apparent causes (eg, lactation, alcohol(Drug information on alcohol)) fit these models. This understanding is critical to manipulating usual physiology to prevent clinical cancers.
- The development of sound biologic, behavioral, and social data as bases for broad action.
This article will explore each of these challenges in turn.
A discussion of manipulable factors associated with the development of breast cancer serves to introduce and emphasize the importance of hormonal physiology in the pathogenesis of this disease and especially in its prevention.
Known manipulable risk factors--in particular, three that act as initiators--are relevant for a minority of the population. Specifically, inherited genetic susceptibility appears to be important in approximately 10% of cases, and thus, manipulation of these changes and their functions (when defined) is likely to be of limited benefit in the general population. For example, the extreme intervention of prophylactic mastectomy is acceptable only in genetically at-risk individuals.
Radiation is a second well-described initiator of breast cancer, and limitation of exposure, particularly of the prepubertal breast through judicious use of therapeutic radiation for malignancy, is an important preventive strategy. Again, however, this strategy can be applied to only small numbers of women. Nevertheless, there remains the possibility that excess sensitivity to lower doses of diagnostic radiation may be an important initiator of breast cancer in larger numbers of women.
Finally, cigarette smoking seems to be a likely initiator. For many health reasons, major efforts to reverse the upward trend in smoking among younger female age groups are well justified.
More Recently Identified Associations
Four more recently identified associations have potentially greater application to populations. Lactation for total periods of more than 6 months appears to be associated with a reduced risk for premenopausal breast cancer. This association has obvious widespread application, and is particularly intriguing because of its physiologic mechanism of action (discussed further below).
It appears likely that the basis for the associations of alcohol and exercise with breast cancer is hormonal modulation, whereas the possible basis for the association of fresh fruits and vegetables with breast cancer is uncertain. There appear to be broad health benefits and risks of both alcohol and exercise, and thus, the specifics of how these factors work in breast cancer are more important. The possibility that certain dietary constituents (fruits and vegetables) are protective is also of significant interest because of their direct applicability to public health. Although these associations (for alcohol, exercise, and fruits and vegetables) are not strong (twofold increased risk for high alcohol intake and a halving of risk for exercise and for high fruit and vegetable consumption), they are worthy of attention because they can be altered.
There has been a long-standing emphasis on the observation that many breast cancers in individual Western women occur in the absence of attributable risk factors. Recently, for example, Brinton suggested that only half of the disease can be explained on the basis of widely accepted risk factors. This perspective has left the impression that little is known about the development of breast cancer, and this impression has been reinforced by the fact that comprehensive models have rarely been presented or discussed.
Despite these circumstances, it is becoming clearer that we do have a broad understanding of the major physiologic factors in breast cancer, which provides a sound basis for prevention strategies. The initiation, promotion, progression model from skin carcinogenesis experiments appears to be a less useful model for breast cancer than is a physiologic model. The basic skin-derived model, however, is useful in emphasizing the multistep nature of malignancy development and the prolonged multiyear nature of the process.
There now appear to be two key physiologic variables in breast cancer: breast lobular maturation and hormone exposure of breast tissue. Together, these variables provide a rational model that can account for many epidemiologic observations (Table 1) and that can form the basis for prevention strategies. Although the importance of lobular maturation and hormonal exposure has been recognized increasingly over the last 20 years, there remains the perception that these variables (and their associated risk factors) do not provide a complete or satisfying explanation for the disease.
Perhaps the major reason for this perception is the fact that, in a majority of breast cancer cases, no exposure can be identified that is considered critical in initiating the malignant transformation of breast epithelia. Inherited genetic changes, radiation, and perhaps cigarette smoking, described earlier, may each represent such exposures or act as initiators, but together they appear to play a role in only a minority of cases. (Clearly, the details and extent of impact of these factors deserve further intense study.) This unidentified exposure-cause may not be as critical numerically as has been suggested. Some experts suggest that, together with spontaneous mutation rates, these exposures provide adequate explanation for observed rates.
The first critical physiologic variable--lobular maturation--was so recognized by Russo and Russo in animal studies. The supporting observation in humans, however, preceded this laboratory work by a decade. Based on international data, MacMahon et al clearly laid out the powerful relationship of age at first full-term pregnancy and breast cancer risk later in life (Figure 1). How powerful a risk factor this age is found to be clearly depends on the referent group. In Figure 1, a relative risk of 1.0 is assigned to nulliparous women. Note that a woman completing her first pregnancy at age 15 has approximately 25% the risk of a similar woman who completes her first pregnancy at age 35.
Perhaps the obvious occurrence of significant hormonal perturbations during and after pregnancy (which do have a recognizable impact on breast cancer risk) has detracted from an appreciation of the explanation for this strong relationship recognized by the Russos.[6,13] In elegant work following the suggestion that lobular maturation and permanent differentiation of breast terminal end-bud cells were critical events in susceptibility to breast malignancy in animals, the Russos studied the process in human tissues (Table 2). The coherent picture suggested by their work is very compelling. Four types of breast lobules are seen in human breasts. Lobule 1, which is the dominant type in women before a pregnancy (and in nulliparous women throughout their premenopausal years), is an undifferentiated structure with only several ductules. Cells in these lobules appear to exhibit increased sensitivity to malignant transformation, and appear to be the cells of origin of the most common breast cancers of the ductal type.
The hormonal proliferative stimulation of menstrual cycles causes some type 1 lobule cells to begin to differentiate; prior to pregnancy, young women have a mixture of types 1 and 2 lobules, but the majority are type 1. The profound and sustained hormonal stimulation of a full-term pregnancy results in differentiation of the cells in most breast lobules to semidifferentiated (lobule 2) or fully differentiated (lobule 3) states. Although lobular structures with the appearance of types 1 and 2 are seen in postmenopausal women, these are, in fact, terminally differentiated structures without the sensitivity to malignant transformation of these types seen in younger women.
This theory of lobular development clearly suggests that a full-term pregnancy is a defining event for breast cancer risk expressed perhaps 2 decades later. It is noteworthy that during the 10 to 20 years following a first pregnancy, breast cancer risk is first greater and then lower than that for nulliparous women (Figure 2); consequently, for premenopausal women, age at first full-term pregnancy is not an obvious risk factor.