In this large study of African American and white women aged 35–64, we found that BMI at age 18 was associated with reduced risk of breast cancer. In premenopausal women, recent BMI was associated with reduced risk although the trend was not statistically significant. This association was not significantly modified by race. Among postmenopausal women, for recent BMI, associations in postmenopausal women differed depending on whether the cancer was receptor positive or not. For ER-PR- breast cancers, recent BMI was inversely associated with risk in both AA and white women. For ER+PR+ cancers, recent BMI was positively associated with risk in AA women but there was no association in white women.
The borderline significant protective effect of increasing adult (recent) BMI on the risk of breast cancer in premenopausal white women is supported by several (7
) but not all (23
) previous studies. The protective effect of adult overweight and obesity on premenopausal breast cancer risk has been found also in African American women (10
), although the findings are not consistent (8
We observed a borderline significantly reduced risk of premenopausal breast cancer associated with BMI of 25 or greater at age 18 among African American women, a finding consistent with a recent cohort study (10
). We further observed an inverse association between increasing BMI at age 18 and risk of ER+PR+ tumors in premenopausal African American women, but not in white women. The Nurses' Health Study reported that the protective effect of obesity at age 18 or 20 years (5
) was stronger for premenopausal ER+ tumors, although the study population was predominantly white (22
). However, in a study of breast cancer subtypes in white and African American women, Millikan et al reported a slight inverse association between BMI and the ER+ breast cancer subtype defined as “luminal A” in premenopausal women (31
We found no association between recent BMI and postmenopausal breast cancer overall, although there was a non-significant inverse association in white women. Most previous studies (23
) have found recent BMI to be associated with increased risk of postmenopausal breast cancer; only a few studies have reported no association (25
) or an inverse association (26
). In the WCRF/AIRC report, five of 19 cohort studies on postmenopausal women showed decreased risk of breast cancer by BMI, statistically significant in one of them (4
). Thus our results appear consistent with a minority of the previous studies. However, the age distribution of the Women's CARE study must be kept in mind. We limited the CARE study to women under age 65 years, resulting in a relatively young group of postmenopausal women. Further, CARE oversampled younger women to get uniform distribution of participants across the 5-year age groups (15
). A Dutch cohort study that did not find any association between BMI and postmenopausal breast cancer also included relatively young postmenopausal women, with median age of 58 years and upper age limit of 73 years at study entry (25
). One of the cohort studies that found a positive association between BMI and postmenopausal breast cancer, had mean baseline age less than 60 years, but included women 50-73 years (32
). Other studies that find a positive association and present the age of the postmenopausal women, have median age above 60 years (26
) or have the upper age limit of 79 years (34
). Thus, the postmenopausal women in the Women's CARE study were younger than in many of the previous studies. It is not clear exactly where in the menopausal transition BMI shifts from a protective factor to a risk factor for breast cancer, or how many years it takes (35
Few studies have assessed the effects of BMI on breast cancer risk among postmenopausal African American women, and in general results are more mixed. Two studies found a positive association between recent BMI and postmenopausal breast cancer in African American women (9
), although two other studies found non-significant inverse associations (10
). Perhaps the most marked difference between the two racial groups in our analyses was the heterogeneity of effect by ERPR status. Among postmenopausal African American women BMI was associated with increased risk of ER+PR+ tumors. This finding is consistent with prior studies of both white (36
) and African American women (10
). However, among white women in our study, the protective effect of BMI was greater on ER-PR- tumors. Although this latter finding was unexpected, it is consistent with results from a Swedish cohort study, which reported a negative association between BMI and PR- tumors (39
). A previous Surveillance, Epidemiology and End Results (SEER) study has reported that the proportion of receptor positive and negative tumors differed between postmenopausal white and African American cases (40
). This was also true in our study, with ER+PR+ tumors being more frequent in white cases and ER-PR- tumors more frequent in African American cases. We hypothesize that certain of these molecular subtypes of cancers (even within hormone receptor negative or receptor positive tumors) are more affected by BMI, and these subtypes might differ by race.
On the other hand, the few differences we observed by race and ERPR were not very impressive, and may not be causal differences, but could simply have been due to random fluctuations or chance in our data. Future studies of these associations should include more detail on breast cancer subtypes.
In our study the effects of BMI did not differ significantly by whether women had used HT. Specifically, we did not observe a positive association when limiting the analyses to never or non-current users of HT, as has been found in several other studies (26
Previous studies of the association between BMI at age 18 years and postmenopausal breast cancer risk have been predominantly conducted among white women, and have yielded inconsistent results. Most studies have reported no effect of obesity at 15–20 years of age (9
), although the Women's Health Initiative observational study (33
) and the Black Women's Health Study (10
) suggested a protective effect. Our results are consistent with these latter two studies, and suggest that BMI at age 18 might be associated with a reduced risk of postmenopausal breast cancer, with no significant difference between the races.
We did not observe any association between weight change from age 18 years to recently and breast cancer risk in premenopausal women. This is consistent with studies both among white (6
) and African American (9
) premenopausal women. The only reported effect of weight change on premenopausal breast cancer risk was observed in an Asian population (42
). In postmenopausal women, there is strong and consistent evidence that weight gain is associated with breast cancer risk, at least in white women (6
). Few studies, especially with convincing data, exist on African American women (9
). Most of the reported effect has been limited to non-users of HT (6
) or ER+PR+ cancer (6
The mechanisms by which obesity may protect against breast cancer in young women have not been completely elucidated. It has been suggested that any protective effect of high BMI in young women is because of higher prevalence of menstrual irregularities or anovulatory cycles in women with high BMI, and thus lower exposure to ovarian sex steroids (44
). One proposed mechanism is that obese premenopausal women have a higher number of anovulatory cycles, resulting in decreased estradiol and progesterone levels (44
), which causes reduced risk of breast cancer (45
). We found a higher proportion of women with irregular menstrual cycles to be overweight compared with women who had regular cycles. This is consistent with data from earlier studies (46
). However, the protective effect of overweight in our study was not restricted to women reporting irregular menstrual periods. We recognize, though, that self report of irregular menstrual periods 20–40 years ago may not be a good measure of frequency of anovulatory cycles in the post-pubertal period (47
An intriguing alternative mechanism for the protective effect of early obesity is that body fat at young age influences the histological constituents of the breast tissue. Evidence from a subset of women in this study suggests that adipose tissue in the breast may be protective. In a study of mammographic density among Los Angeles Women's CARE study participants, women with larger breast size (who tended to also be heavier), had less absolute mammographic density, and both percent and absolute density were weaker risk factors for breast cancer in this group than in women with smaller breasts (48
The exact age that obesity is most protective against premenopausal breast cancer is not clear. High body fat percentage at age 20 years was observed as a strong protective factor for premenopausal breast cancer among women in the Nurses Health Study II, independent of later BMI (5
). It has been suggested that body size in early adulthood is inversely associated with premenopausal breast cancer risk only as it predicts adult body size (7
). Our results among premenopausal women weakened when we adjusted for recent BMI in the statistical model.
As women pass through menopause, the protective effect of obesity on breast cancer risk is replaced by an increased risk. This change in the effect of obesity is possibly due to peripheral adipose tissue becoming an important source of estrogen, as this is where androstenedione is aromatized and converted to estrogen (49
It is unclear how long it takes for this transition to take place (i.e., for BMI being a protective factor to it being a risk factor for breast cancer). Pike et al. have modeled this effect, and argue that it takes a decade for a BMI of 30 kg/m2
in a premenopausal woman (at age 50, relative risk (RR) of 0.75) to become a risk factor (RR of 1.20 at age 62) (35
). It is, therefore, possible that the reason that we found no increased risk for postmenopausal breast cancer in white women with high BMI might be partially explained by the relatively young age of the postmenopausal women in our study. One explanation for our findings could be that the timing of the transition might vary between white and African American women. In our study white women had a later age at menopause than African American women; thus, it is possible that this transition took place at a younger age among African American women in general.
Strengths and Limitations of the Study
Our BMI measures were made on the basis of self-reported measures of weight and height. We cannot exclude the possibility that some women might have misreported their weight. However, we expect any such misclassification to have been non-differential with respect to case status, and therefore, if anything, to have biased the results towards the null.
The interview was conducted after the cases had been diagnosed, but within 18 months after diagnosis. Current weight could have possibly biased recall of previous weight. However, if anything, women with breast cancer tend to gain weight (51
), so that any such bias would have resulted in overestimation of weight in cases, not in controls. This implies that the inverse results we observed would be either nonexistent or underestimated. Small sample size of stratified analyses is a limitation in this study. The only positive association we found is for ER+PR+ breast cancer among African American women. Although we cannot exclude the possibility, we find it unlikely that the finding for this specific subtype of cancer was because of such recall bias.
The upper age limit in this study population was 64 years old, and only about one third of the postmenopausal women were above 60 years old. The lack of older women may partly explain why we do not have stronger findings on the risk associated with BMI among postmenopausal women, and why our results are similar to those seen in studies restricted to premenopausal women.
We unfortunately did not have waist and hip circumferences as measurements for central obesity. It has been suggested that central obesity measured as waist-hip ratio might be a risk factor for premenopausal breast cancer, independent of BMI (52
). However, we observed no differences in breast cancer risk by areas on the body where women tended to gain weight, or by bra size. Therefore, the data collected might not confirm the effect of central obesity among our study population.