Genetic events in breast cancer and their clinical correlates.

The great heterogeneity of clinical breast cancer probably reflects heterogeneity of the mechanisms that are involved in its genesis and in disease progression. Genetic events that may be critical for tumor etiology, may determine tumor characteristics, and may contribute to tumor evolution should differ among individuals and among individual tumors and may distinguish subgroups with varying prognoses. We approach this problem from two viewpoints: one is based on population studies and the other on genetic events at the cellular level. 1. Population-based questions: What susceptibility factors are associated with individuals and groups who develop tumors? Inheritance patterns, familial aggregates, and associations with other tumors and other genetic diseases have been described for breast cancer. Bilateral and multifocal tumors may be examples of inherited predisposition, and their clinical and biological characteristics should be informative. Are there associations with tumor identifiers, such as histologic type and other tumor markers, for any of the "increased susceptibility" states? 2. Tumor-derived information: What types and frequencies of genetic alterations are found; do they relate to stage of tumor evolution, to morphologic classification, or to clinical evidence of comparative malignancy? Genetic evaluation depends upon cytogenetic and cytometric methods at the cellular level, and on detection of mutation, gene deletion, or amplification at the molecular level. We examine whether observed genetic alterations suggest mechanistic bases for morphologic distinctions among breast cancers and whether they assist in defining clinical phenotypes or steps in tumor progression. The general conclusions are that breast cancer comprises a complex set of neoplasms, that there is as yet little evidence to favor a final common pathway for its origin, and that a wide range of biological perturbations underlie its clinical course in the individual patient. An understanding of the basic mechanisms, their variety, and which of them apply in individual cases, is necessary as a rational basis for classification and for the development of strategies to interfere with tumor development in high-risk individuals.