EDITORIALS Biomarkers in Benign Breast Disease: Risk Factors for Breast Cancer

Benign breast diseases are both common and heterogeneous. Some types (usual and atypical hyperplasias) are weak but well-established risk factors (1) and probably precursors for breast cancer (2). Other types (e.g., sclerosing adenosis, papillomas, and fibroadenomas) also may be associated with a slightly el-evated risk, although the evidence is less compelling (3–5). These benign lesions are defined by their histologic features, which are insufficient to distinguish breast tissue destined to develop cancer. An article by Rohan et al. (6) in this issue of the Journal describes an interesting study that evaluates the abilities of cer-tain biomarkers to better discriminate risk in patients with be-nign breast disease. Using a nested case–control study design based on the Canadian National Breast Screening Study (NBSS), Rohan et al. evaluated p53 and c-erbB-2 abnormalities by im-munohistochemistry in benign breast tissue of patients who later developed breast cancer (cases; n 4 71) compared with matched patients who did not (controls: n 4 291 for c-erbB-2; n 4 288 for p53). Alterations of the p53 tumor suppressor gene and c-erbB-2 oncogene are very common in breast cancer (7,8), which was the rationale for focusing on these markers as potential risk factors in this study. Most p53 abnormalities in breast cancer are mis-sense point mutations resulting in nuclear accumulation of pre-sumably nonfunctional protein (9). Most alterations of c-erbB-2 are gene amplifications that are highly associated with overex-pression of the oncoprotein at the cell membrane (10,11). Im-munochemistry was well suited to screening for p53 accumula-tion and c-erbB-2 overexpression in the archival tissue samples available in the study by Rohan et al. (6). Evaluating the risk of a relatively rare disease (e.g., breast cancer) in a relatively healthy population (e.g., patients with benign breast disease) can be difficult for a number of reasons, and the nested case–control design used in the study by Rohan et al. was an effective strategy to compensate for some of these difficulties (12). By sampling controls matched to breast cancer cases from the entire cohort of all NBSS enrollees with benign breast disease, the study had power nearly equivalent to that of the entire cohort (n 4 4888) but evaluated far fewer subjects (