Biomarkers in early breast neoplasia

Early breast neoplasia may be defined in many ways. Any non‐invasive or invasive but non‐metastatic breast cancer qualifies as early neoplasia in the sense that they are non‐lethal. Before we can prevent lethal breast cancer, we must gain a better understanding of the biological abnormalities underlying its development and progression. Many studies into the mechanisms of breast cancer evolution have evaluated potential precursor lesions (e.g., proliferative disease without atypia [PDWA], atypical ductal hyperplasia [ADH], and ductal carcinoma in situ [DCIS]) for genetic alterations known to occur in fully developed invasive carcinomas. This approach has shed some light on events which may be important in early malignant transformation, including the observations that overexpression of the c‐erbB‐2 oncogene and mutations of the p53 tumor suppressor gene are present in significant subsets of DCIS, but not PDWA or ADH. This approach is limited by our incomplete knowledge of cancer genetics. However, there is more to learn by evaluating known cancer‐associated genes in potential precursor lesions using established techniques such as immunohistochemistry and in situ hybridization. Until recently, technology could not detect unknown genetic abnormalities in microscopic lesions such as PDWA, ADH, or DCIS. Now, PCR‐based techniques have the theoretical ability to detect novel tumor promoter and suppressor genes in clinical samples of these very small lesions. For example, suppressor‐type genes may be deteted using comprehensive mapping probes to identify loss of heterozygosity in PCR‐amplified DNA extracted from a few hundred cells microdissected from either fresh or archival tissue. Differential display is another new technique with the potential to detect both tumor promoter and suppressor gene expression in very small samples. This PCR method uses short random primer pairs to amplify representative cDNA from microgram quantities of mRNA extracted from fresh tissue. Rapid progress is likely to result from applying these complementary approaches to the challenging problem of breast cancer evolution.