Title: Early-life Origins of Breast Development and the Implications for Breast Cancer Risk
Description: Breast cancer incidence, particularly late-stage disease, is increasing in U.S. women under 40 years of age, pointing to the importance of exposures acting early in the life course to increase breast cancer risk. Earlier onset of breast development has recently been identified as an independent risk factor for breast cancer. Thus, identifying modifiable factors that can delay the onset of breast development may provide an opportunity for breast cancer primary prevention starting early in life. This dissertation examined the influence of the early-life environment on the age at onset of breast development through: 1) a systematic review of the literature relating maternal pre-pregnancy body size, gestational weight gain (GWG), birth size, and infant growth to the timing of breast development and menarche; 2) analyses assessing the associations between these factors and the onset of breast development in a pubertal cohort enriched for breast cancer family history (BCFH); and 3) a pilot study assessing whether these factors are associated with serum levels of insulin-like growth factor(IGF)-1 and insulin-like growth factor binding protein(IGFBP)-3 during puberty.

Our systematic review identified 96 studies, the majority of which examined the association between birthweight and age at menarche. Although low birthweight is often cited as a risk factor for early menarche, the majority of studies (40/73 total) that examined this association did not observe a statistically significant association. Differences in exposure assessment, inadequate control for confounders, and differences in postnatal growth across studies may drive inconsistencies in the birthweight literature. In contrast, higher maternal body mass index (BMI) prior to pregnancy, GWG in excess of recommended guidelines and faster rates of weight gain between birth and 2 years of age were consistently associated with earlier age at breast development and menarche. We used data from the LEGACY Girls Study, a prospective cohort of girls primarily ages 6-13 years at baseline in which approximately 50% of girls had a family history of breast cancer, to examine the relations between maternal factors, birth size and infant growth and the onset of breast development, defined as a maternal report of breast Tanner stage 2 or greater.

Daughters of women with a pre-pregnancy BMI of 25 or greater and who gained 30lbs or more during pregnancy experienced breast development at an earlier age than daughters of women with a pre-pregnancy BMI less than 25 and who gained less than 30lbs. This association was similar in girls with and without a BCFH. Birthweight and birthlength were not associated with the timing of breast development. In a subset of LEGACY girls with height and weight data during infancy available from medical records, we examined the associations between changes in weight-for-age and length-for-age Z-scores from birth to 1 year of age and the onset of breast development. We observed a modest association between faster rates of weight gain from 0-12 months and earlier age at breast development. When we examined smaller age intervals within infancy, faster weight gain from 2-4 months and 6-9 months were each associated with an earlier age at breast development. A similar pattern was observed for growth in length, and these associations did not vary by BCFH.

In our pilot study including 109 girls with available serum samples between 6-17 years of age at the LEGACY New York site, rapid weight gain from 0-12 months was associated with higher mean levels of IGF-1 relative to IGFBP-3. Although not statistically significant, girls with a maternal pre-pregnancy BMI≥25 and GWG≥30lbs also had higher mean levels of the IGF-1/IGFBP-3 ratio. Since serum IGF-1 and IGFBP-3 are objective measures that are known to increase rapidly during puberty, the results of our pilot study support that the maternal BMI, GWG and rapid infant weight gain are associated with biological changes in the girls. Our findings suggest that measurement error in outcome assessment or confounding did not drive the associations that we observed between these factors and earlier onset of breast development. In conclusion, we identified higher maternal pre-pregnancy BMI, excess GWG and rapid growth during infancy as modifiable factors associated with earlier onset of breast development in girls across the spectrum of familial risk for breast cancer.

While this suggests that modifying these factors may decrease breast cancer risk later in life, further research should consider additional and potentially opposing pathways, such as childhood body size, through which the early-life environment affects breast cancer risk.