In this large prospective study, greater body fatness at young ages, particularly during adolescence, was associated with a substantial decrease in breast cancer risk. The inverse association was fairly linear, with no apparent threshold. Similar associations were observed for premenopausal and postmenopausal breast cancer, and both were independent of current BMI. The associations were stronger for women who weighed less than 8.5 pounds at birth and for past and current postmenopausal hormone users but did not vary significantly by other factors. Inverse associations were observed for all tumor subtypes, although they appeared stronger for ER− tumors than for ER+ tumors and possibly stronger for HER2-positive (HER2+) tumors than for HER2-negative (HER2−) tumors.
Our findings confirm those from previous studies that have shown inverse associations between body fatness at young ages and risk of premenopausal breast cancer (11
). Results for postmenopausal breast cancer are not as well-documented but are consistent with several prior studies (13
). When we adjusted for current BMI, the inverse associations for postmenopausal breast cancer became stronger and more similar to those for premenopausal breast cancer, providing further evidence that greater body fatness at young ages may confer a lasting protective effect.
The mechanisms by which greater body fatness during childhood and adolescence may reduce breast cancer risk are not understood. Girls who are overweight at young ages may experience slower pubertal growth and sexual maturation (13
), despite having earlier menarche; rapid adolescent growth has been associated with increased breast cancer risk (13
). Obesity in preadolescent and adolescent girls also is associated with higher levels of insulin (34
) and androgens (35
), greater frequency of anovulatory cycles (35
), and reduced fertility later in life (37
). In previous analyses in the NHS and NHS II, higher BMI at age 18 years was associated with increased risk of irregular and long menstrual cycles between ages 18 and 22 years and increased risk of ovulatory infertility (38
). However, a recent study in NHS II found that these factors were unlikely to explain the relation between BMI in early adulthood and premenopausal breast cancer (19
). Similarly, in the present study, the associations of body fatness with risk of all breast cancers and with risk of ER+ and ER− tumors separately were unchanged after adjustment for menstrual cycle patterns between ages 18 and 22 years, suggesting that other factors may be involved.
Girls who are heavier at young ages might experience earlier differentiation of breast tissue due to higher levels of estrogens and other sex hormones (36
), and terminally differentiated cells are less susceptible to malignant transformation (40
). Experiments in rats have shown that prepubertal or pubertal administration of sex hormones leads to differentiation of cells of the mammary gland and a reduction in the incidence of mammary tumors (41
). However, a longitudinal study in girls showed no differences in estrogen or progesterone concentrations according to BMI between ages 8 and 10 years (36
), and body fatness at ages 5 and 10 years was not associated with levels of sex hormones among premenopausal women in the NHS (8
). Body fatness during childhood and adolescence could act through other hormonal pathways, such as IGF-I/IGF binding protein 3 (7
), although this merits further exploration.
Few studies have had sufficient power to examine whether the inverse association for body fatness at young ages is modified by other factors. In 1 study, women with above-average weight at age 12 years who were relatives of breast cancer cases were at increased risk of breast cancer, whereas the association was inverse among women not related to the cases (25
). In contrast, a prospective analysis of postmenopausal breast cancer among participants in the Iowa Women's Health Study found no interaction between relative weight at age 12 years and family history (12
), similarly to our study.
Our findings suggest that the inverse association for adolescent body fatness may be restricted to women who weighed less than 8.5 pounds at birth. To our knowledge, this is the first study to have documented such an interaction. Birth weight has been positively associated with risk of breast cancer, especially premenopausal breast cancer, in multiple studies (44
). Greater birth weight also has been linked to elevated levels of IGF-I and decreased levels of IGF binding protein 3 in premenopausal women (7
). Women with greater birth weight may be at higher breast cancer risk due to permanent reprogramming of the growth hormone/IGF axis (45
) or genetic variation in the IGF pathway (46
). As a result, greater body fatness at later ages may no longer be protective among these women.
The observed interaction between adolescent body fatness and postmenopausal hormone use, with a stronger inverse association among past and current users than among never users, was unexpected and possibly due to chance. Previous studies of adult BMI and weight gain in the NHS have shown stronger positive associations for postmenopausal breast cancer among women who have never used postmenopausal hormones (47
). We did not observe this for adolescent body fatness, providing further evidence that the mechanism does not operate through current BMI and probably is not mediated by sex hormones, at least in postmenopausal women.
To our knowledge, only 1 prior study has examined associations between body fatness at young ages and risk of different breast cancer tumor subtypes. In this study, which included only postmenopausal women (2,503 cases), the inverse association for relative weight at age 12 years was strongest for PR-negative (PR−) tumors and weakest for PR-positive (PR+) tumors, although no formal tests of heterogeneity were conducted (12
). In contrast, we observed a stronger inverse association for ER− tumors than for ER+ tumors, with significant heterogeneity, while PR status did not seem to be important. Both our study and the previous study, however, indicated that the association for body fatness at young ages was not stronger for risk of ER+/PR+ breast cancer as compared with other subtypes, again suggesting a pathway not mediated by sex hormones.
In addition, although the test for heterogeneity was not significant at the 0.05 level, our data suggest that the inverse association may be stronger for tumors that overexpress HER2 than for those that do not. To our knowledge, this has not been explored in previous studies, although Borgquist et al. (48
) found differences in the associations of adult BMI and other anthropometric characteristics with HER2+ and HER2− tumors. In future studies, researchers should explore the relation between body fatness at young ages and risks of different breast cancer molecular subtypes that incorporate expression of ER, PR, and HER2, as well as other markers.
This study had several important strengths. By combining data from the NHS and NHS II and including premenopausal and postmenopausal women, we were able to examine higher levels of body fatness, interactions with other factors, and variation by tumor characteristics. In addition, we had detailed information on many breast cancer risk factors, permitting careful adjustment for these factors. A limitation is that we relied on participants’ recall of their body fatness at young ages, although the somatotype pictogram used has been validated (27
) and has been associated with risk of breast cancer (11
) and other related endpoints (49
) in this population. In the analysis of HER2+ and HER2− tumors, we could not include cases diagnosed before the 1998/1999 follow-up cycles because HER2 status was not assessed in earlier years. Future studies in this population that utilize tissue microarrays to evaluate marker expression will help address these issues.
In summary, this study showed strong and significant inverse associations between body fatness during childhood and adolescence and risk of breast cancer throughout life. These findings confirm those from previous studies, and they suggest that body fatness at young ages acts through a biologic pathway that is not mediated by adult BMI or endogenous sex hormones. Elucidating the mechanisms that explain the inverse relation of body fatness at early stages of life with risk of breast cancer may contribute to understanding of the causes of this important disease.