Lobular involution: the physiological prevention of breast cancer.

It truly is a remarkable event when traditional pathologic observations lead to new ideas about the prevention of cancer. In this issue of the Journal , Milanese et al. (1) , through a histologic review of breast biopsy specimens, show that the extent of age-related lobular involution is strongly associated with a reduced risk of breast cancer. Breast cancer risk decreased with increasing extent of involution in both high-risk and low-risk subgroups defi ned by age, epithelial atypia, reproductive history, and family history of breast cancer. Beginning in the premenopausal period, lobular involution is a physiologic process that occurs over many years whereby the parenchymal elements in the breast progressively atrophy and disappear (2 , 3). The study reported by Milanese et al. represents a unique application of the Mayo Benign Breast Disease Cohort to investigate prospectively involution as a risk factor for breast cancer. It is the fi rst study, to our knowledge, to substantiate a hypothesis that is based on pathologic and epidemiologic considerations that delayed involution is a major risk factor for breast cancer (4 , 5). As for an explanation of the effect of lobular involution on breast cancer risk, it has been suggested that a reduction in mam-mary gland tissue that results from involution should lead to a reduction in breast cancer because a progressively smaller amount of epithelial tissue is available for malignant transformation (1 , 5). The result of involution, therefore, can be considered physiologically analogous to a partial prophylactic mastectomy, with a corresponding reduction in breast cancer risk. Although a reduction in mammary tissue is a plausible explanation , the underlying issue is one of aging or, more precisely, the failure of breast tissue to age normally. The aging process in the breast is under control of various hormones and does not follow the pattern seen in other organs or tissues. Pathologists have long commented on the possibility that persistent atypical lobules might be precursors of invasive breast cancer (6 , 7). It seems paradoxical that an organ that normally undergoes complete or near complete physiologic atrophy would be a site in which cancer rates steadily increase with age. The continuing increase in breast cancer risk with age is likely associated with the persistence of glandular epithelium beyond the time of normal involution, refl ecting an abnormal delay of the aging process in the breast (4 , 5). Except for morphologic observations …