In this article we have focused on comparisons of generally accepted or suspected risk factors for breast cancer, including some characteristics measured both for adulthood and adolescence. Interestingly, cases and controls were strikingly similar for several factors known to influence breast cancer risk (such as family history of breast cancer, contemporary socioeconomic status, age at first birth, or use of hormone replacement therapy). For instance, although the overall rate of positive first-degree family history (19%) among cases is similar to that reported in other recent series [16
], the controls in this population had rates of family history comparable to those of the cases. One possible explanation for the homogeneity of cases with regard to these factors could be our focus on residents of a small, relatively homogenous, and affluent area, Marin County. The homogeneity of the Marin County population is supported by recent maps showing little variation in standardized incidence rate ratios for breast cancer among the census tracts within Marin County [18
Another explanation could involve preferential participation in the study by controls with these recognized breast cancer risk factors over those without these factors. This seems unlikely given the high participation rates among those found to be eligible on the basis of RDD, but it is possible that there was some selection bias in women or households who were willing to answer the telephone call screening for eligibility. Further studies with alternative control ascertainment methods would be necessary to resolve this issue. In addition, appropriately adjusted comparisons of these factors in this high-risk area versus geographic areas with lower breast cancer rates would be needed to answer the question of how much of the excess of breast cancer incidence in Marin County might be due to patterns of these risk factors. Such a study is currently underway. A study that uses risk factor prevalence data from this study and other sources is also underway to estimate the attributable proportions of breast cancer due to specific risk factors.
As mentioned above, selection bias due to differential participation by cases or controls with some risk factor of interest is always a potential concern in case-control studies. In attempts to minimize this problem, we sought an abbreviated interview for those cases and controls not able or willing to participate in the full interview. The preliminary age-adjusted analyses of individual risk factors used all women for whom information was available. There were not any notable differences in magnitude of the age-adjusted ORs that used all 657 participants and the multivariate results based on 571 subjects with complete information.
Despite homogeneity in current socioeconomic status, our study suggests that among women aged 50 years and older, breast cancer cases might have been more likely than controls to have grown up in more affluent families, although the results are largely due to the small proportion of subjects reporting their family's socioeconomic status as 'upper' before age 21 years. In contrast, for women under the age of 50 years, breast cancer cases were somewhat less likely than controls to have grown up in more affluent families. That an effect of pre-adult socioeconomic status existed in the women aged 50 and over that was independent of contemporary socioeconomic status as well as established reproductive, menstrual, and other factors such as body size and alcohol consumption suggests that further attention is needed to understand the relationship of childhood or adolescent socioeconomic factors and breast cancer.
Almost all women in this study had health insurance, and whereas women with breast cancer were more likely than controls to report having had four or more mammograms in the period 1990–94, they were about equally likely to report obtaining pelvic exams over the same period. This suggests that women who subsequently developed breast cancer might have had more mammograms than controls because they had more breast problems rather than because they were, in general, more regular users of cancer screening services than controls.
Interestingly, in both age groups, women who had given birth but had not breastfed had a higher risk for breast cancer than women who had never been pregnant, women who had been pregnant but not parous, and women who had been parous and breastfed, although the result was statistically significant only in those aged 50 years and older. In addition, among women under the age of 50 years, women who breastfed for 12 months or more had significantly reduced odds of breast cancer. This finding is consistent with a large collaborative study [19
] showing breastfeeding to be protective for breast cancer through hormonal or other mechanisms. That report suggested an urgent need to fully understand the mechanisms of the protective effect of breastfeeding so that some intervention mimicking breastfeeding could be developed and offered to women who have not breastfed.
It is also possible that inability to lactate or suppressing lactation after giving birth might have a deleterious effect on breast physiology [20
], but we did not request this information from subjects. Given the relatively late ages of first birth in this population, one might not expect to see a protective effect of having ever given birth, because the well-established protective effects of pregnancy seem to be reversed for first births at about age 30 years or later [21
]. This study had a higher percentage of nulliparous women (25% of cases and 26% of controls) than a recent study conducted in the Seattle area (13% of cases and 14% of controls) [17
]. However, the California Teachers Study cohort, with a similarly elevated rate of invasive breast cancer of 151 per 100,000 person years among non-Hispanic white women between 1995 and 1998, reported a similar percentage of nulliparous women (27%) among participants without breast cancer in 1995 [23
Consistent with previous findings [12
] was our observation that cases were more likely to be premenopausal than controls, suggesting a later age at menopause. Despite the absence of a strong difference in age at menarche between cases and controls in this group, those women who developed breast cancer had relatively later menopause, indicating a greater number of years of active menstruation. Starting menarche at age 11 years or earlier is considered an established breast cancer risk factor, and starting menarche at age 15 years or older is considered an established protective factor [12
]. In the present study, cases were somewhat less likely than controls to start menarche at age 15 years or older, but cases were not more likely than controls to have early menarche. A similar lack of association of age at menarche with breast cancer status was apparent in the large recent study by March-banks and colleagues [16
]. The distribution of age at menarche reported by control women in Marin County was similar to that observed for women in the California Teachers Study cohort [23
Disagreement remains in the literature on the direction and magnitude of effect, if any, of oral contraceptives on breast cancer risk [12
]. Despite large studies designed to address such differences, chance, selection factors, changes in formulations, patterns of use, and different background risk for breast cancer might account for some of the variation in findings. In this Marin County study, we found a rather strong and significant inverse association of oral contraceptive use and breast cancer. However, the lack of case-control differences by duration or latency of use argues against a causal connection and suggests that oral contraceptive use might be a surrogate for some other protective behavior or exposure. Given the very high rate of use of oral contraceptives in this population, an alternative explanation could be that factors or conditions contraindicating the use of oral contraceptives might increase the risk for breast cancer. In future studies it might be worthwhile to assess why women chose to use, or not to use, oral contraceptives.
In addition, there was no indication of large differences in hormone replacement therapy use among cases and controls, which was similar to a recent Seattle case-control study [17
], although any use of hormone replacement therapy was somewhat higher in the Marin population (55–56%) than in the women in the Seattle study (49–51%). In addition, the specificity of questions about types of hormone replacement therapy used and the sample size of this Marin study is insufficient to rule out the small increased risk (25–30%) observed in larger studies [25
] or to examine in detail different hormone replacement therapy regimens, duration, or age of use. Appropriately adjusted comparisons of rates of hormone replacement therapy use in this area and geographic areas with lower breast cancer rates would be informative regarding the relationship of hormone replacement therapy use to the elevated breast cancer incidence in Marin County.
Many studies have examined breast cancer in relation to body weight, height, and overall body size (as measured by body mass index). The general consensus has been that increased height might be associated with increased risk for breast cancer, and that obesity might increase risk in women aged 50 years or over or who are post-menopausal but might decrease risk in women under the age of 50 years [27
]. Highest adult body mass index was strongly inversely related to breast cancer status both in women under the age of 50 years and, unexpectedly, in those aged 50 years and older. The average highest body mass indexes reported in this study (24.9 and 26.5 kg/m2
for cases and controls, respectively) were in the same range reported for subjects' body mass index 5 years previously in a recent large US study (25.5 and 25.8 kg/m2
for cases and controls, respectively) [16
] and participants in the California Teachers Study in 1995 (24.8 kg/m2
One explanation for the finding could be that mechanisms of weight maintenance might have contributed to the association. Because we did not ask about adult or recent physical activity in the interview, we cannot assess the impact of these factors on the body size results. In the Nurses' Health Study cohort, Huang and colleagues [31
] reported that among postmenopausal women, weight gain was consistently associated with an increased risk for breast cancer only among women who had not used hormone replacement therapy. We found that cases had lower highest body mass index than controls both among women who had used hormone replacement therapy and among women who had not. It is possible in this affluent community that perimenopausal and postmenopausal women who are not taking prescribed hormone replacement therapy could be eating foods or taking herbal or other non-prescribed supplements to ameliorate menopausal symptoms that might simulate the effects of hormone replacement therapy. Unfortunately we did not collect the data to test this possibility, but such questions should be included in future studies.
Alcohol use has been increasingly associated with both premenopausal and postmenopausal breast cancer risk [32
], including a report from the California Teachers Study, showing that recent alcohol consumption increases risk for breast cancer [34
]. We found that although women with breast cancer were less likely than controls to have begun drinking alcohol before age 21 years, they were much more likely than controls to consume two or more drinks per day on average as adults. That the ORs for alcohol consumption in this study were generally higher than those reported in other studies suggests a possible interaction of alcohol consumption with other factors that have a high prevalence in this population.
Cigarette smoking has not been consistently associated with breast cancer risk [12
]. The elevated OR observed in this study for the highest quartile of pack-years smoked might be due to differential participation by controls with a lower pack-year history or differential reporting of smoking history by cases and controls. It is also possible that smoking history was confounded by factors not measured in this study, such as physical activity.
For women under the age of 50 years, women with breast cancer were much more likely than controls to have been born or lived before age 21 years in the Northeastern or Great Lakes regions of the USA, regions that were in the upper deciles of breast cancer mortality both for the period 1950–69 and for the period 1970–94 [15
]. Geocoding and other refinements of residence information might help to clarify which areas of first or early life residences might be associated with later risk for breast cancer.
The similar average ages of first residence and total years lived in Marin for cases and controls do not support (but cannot completely rule out) the hypothesis that there is some agent specific to Marin County, such as a particular water source, that might increase the risk for breast cancer. These findings do not imply that environmental factors are unimportant in breast cancer causation. On the contrary, our and others' findings of increased risk with frequency of alcohol consumption show that a woman's personal environment can strongly influence her breast cancer risk. In addition, our result of higher risk among women under the age of 50 years who lived in the Northeast or Great Lakes regions before age 21 years might suggest a role of early environmental factors.
Because control women in this study had such high rates of health insurance and use of basic screening services, it seems likely that they truly did not have breast cancer at the time of interview. This was despite a higher proportion of controls with established breast cancer risk factors such as family history and nulliparity than observed in control subject groups in other recent studies. Given this observation, a further intensive study of this or other similarly high-incidence populations might reveal factors proximate to breast cancer diagnosis that could enrich our understanding of breast cancer etiology in a high-incidence population. Some provocative clues from this first analysis suggest that some as yet unidentified correlate of oral contraceptive use might be protective and that consuming two or more alcoholic drinks per day might be deleterious for women in this high-incidence population. We were unable to examine the effects of other provocative exposures previously proposed by others, including exposures to light at night [35
] and polycyclic aromatic hydrocarbons [36
]. The observed early socioeconomic differences combined with a lack of differences in age at menarche or early body size also suggest that attention might be turned to patterns of early infection (or lack of infection) and immune response [37
This study is among the first reported in which community advocates took part in all aspects of the research process, from formulating questions of interest and questionnaire design to monitoring progress of subject recruitment and data analysis and interpretation at regular meetings. This study provides important information for planning additional studies to understand reasons for breast cancer in this or other high-risk geographic areas characterized by a socioeconomically affluent population.