Abstract IA11: Life course epidemiology and breast cancer: translating risk into prevention

Molecular histology may be conceptualized as the microscopic and molecular characteristics of normal tissues that are required for physiologic function. Over the life course, the molecular histology of the breast changes in response to physiological alterations, imparting spatial and temporal heterogeneity within the breasts of individuals and among women. These transitions contribute to the enormous range and imprecisely defined limits of what pathologists consider normal. Appreciation that molecular histology may reflect the cumulative influence of prior exposures linked to breast cancer risk, and may provide information about risk of developing breast cancer in the future, has stimulated interest in this topic. Unlike the study of breast cancer or its precursors, which represents a focal pathophysiologic deviation from normal, molecular histology, if assessable, would represent the state of the entire at-risk organ, based upon examination of a small tissue sample. The adult breast is characterized by well-developed terminal duct lobular units (TDLUs), which comprise the functional unit of milk production and represent the source of nearly all breast cancer precursors. Physiological changes in human breasts are likely driven by paracrine mechanisms, suggesting that tissue context and cellular topography are critical elements in physiology and pathophysiology. The breast undergoes profound changes with completion of childbearing and aging. Age-related TDLU involution may be conceptualized as a protective mechanism that lowers breast cancer risk following completion of childbearing, and in this context, delayed or incomplete involution is a breast cancer risk factor. With aging, the percent of the breast comprised of fibroglandular tissue declines, which is associated with a reduction in mammographic density, a strong breast cancer risk factor. Mammographic density is also imperfectly correlated with epithelial content in the breast. Women with benign breast disease whose surrounding normal breast tissue does not undergo age-appropriate TDLU involution are at increased risk of developing breast cancer, and both breast density and TDLU involution are independent markers of breast cancer risk. However, an important challenge is to understand the markers and mechanisms that underlie breast involution with aging, including both the epithelial and non-epithelial components, and to learn why both density and TDLU content decline with aging as breast cancer incidence rises. The thesis of this presentation is that understanding the amount of epithelium at-risk, the insults it sustains and the mechanisms that lead to its elimination, persistence or expansion may provide a window into the development of integrative biomarkers of risk that can translate into improved screening and prevention. However, progress towards this goal is quite early. Citation Format: Mark E. Sherman. Life course epidemiology and breast cancer: translating risk into prevention. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr IA11.