Abstract ES02-1: Pathology and biology of early breast lesions
Authors: Schnitt SJ 
Published: August 2014

Abstract
It has been almost three decades since Dupont and Page published their seminal study relating breast cancer risk to the histologic findings in benign breast biopsies. Their initial observation, that proliferative lesions without atypia are associated with a 1.5-2-fold increase in breast cancer risk whereas atypical hyperplasias are associated with a 4-5-fold increase in risk, has been confirmed by other groups, including the Breast Cancer Detection Demonstration Project, the Nurses’ Health Study and the Mayo Clinic, among others. In aggregate, these groups have evaluated the relationship between the findings in benign breast biopsies and breast cancer risk in over 15,000 women and have additionally shown that several clinical, epidemiologic and histologic factors such as patient age, menopausal status, family history, time since biopsy, type and extent of atypical hyperplasia, and even the extent of involution of normal breast lobules modify the breast cancer risk among women with benign breast disease. More recent studies have examined the expression of various biomarkers and molecular alterations to determine their impact on breast cancer risk among women with benign breast lesions. While the expression of some biomarkers (including ERa, ERβ, TGFβ receptor II, COX2, and Ki67) has been reported to further stratify risk among women with proliferative breast lesions with and without atypia, all of these studies are limited by small patient numbers, due in part to the difficulty in capturing the microscopic lesions of interest for biomarker analysis. Given these limitations, an alternative approach is to study expression of biomarkers and molecular alterations in histologically normal breast tissue since normal epithelium is typically more abundant in benign breast biopsies than is lesional tissue. Using this approach, one recent study suggested that cytoplasmic expression of IGF-1R in normal breast epithelial cells identifies woman with benign breast disease at a particularly high risk for the subsequent development of breast cancer. This raises the possibility that targeting the IGF-1 pathway could be a novel strategy for breast cancer risk reduction. Other studies evaluating gene expression in normal breast epithelium have identified signatures that distinguish histologically normal breast epithelium obtained from reduction mammaplasty specimens from that obtained from breast cancer patients and, further, that distinguish normal breast epithelium in breasts with ER-positive cancers from that in breasts with ER-negative tumors. Data such as these raise the possibility that there may be identifiable, subtype-specific changes in gene expression within normal breast epithelial cells before histologic abnormalities are evident. It is likely that an integrated approach that combines epidemiology, histopathology, biomarker analysis and evaluation of molecular alterations will permit refinement of breast cancer risk assessment beyond that currently available and will, in turn, lead to new risk reduction strategies.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES02-1.