The number of genetic alterations seen in breast cancer makes the task of constructing a model of genetic progression daunting. In general, the cUnician pays little attention to any given genetic factor and bases patient management primarily upon tumor size, stage, and hormone receptor status. It is imperative that we decipher the accumulating genetic data in breast cancer in order to apply this information in optimizing patient care.
Patterns of LOH and gene expression in cancer as well as in experimental cell models support the notion that breast cancer can develop from a number of pathways of interdependent genetic changes. Thus, it is possible that future studies will allow the construction of several complementation groups that lead to breast cancer. The groups are likely to be degenerative such that one gene defect may be involved in a number of pathways. Other defects may be specific to one group and thus occur relatively rarely.
Depending upon the complementation group, prognoses may vary. A number of prognostic studies have sought to use multiple markers and multivariate analysis to identify such genetic groups in breast cancer.
In the same way, we may be able to identify early precursor lesions, based on the particular patterns of genetic alterations that are very likely to progress to aggressive cancers. It may be possible to stratify patients with atypical hyperplasia into groups with much higher risk than four- to fivefold and groups with very little increased risk. Once these genes that are associated with early stages of breast disease are identified, we may begin formulation of complementation groups combining these with genetic alterations seen in later stages of breast cancer.
Patterns of concurrent genetic alterations may identify complementation groups, but other clues to the role of different genetic aberrations in proliferative breast disease and cancer are provided by the incidence of individual genetic lesions at different stages of progression.
For example, if a genetic alteration predisposes a cell to progression following the additional genetic event(s), that first alteration should appear in a greater proportion of the precursor lesions than in the subsequent stage of progression, whereas a genetic event that precipitates progression to a more advanced stage should appear more frequendy in the advanced lesion than in the precursor. This suggests ihaipSS, erbB-2, and PRADl, all of which are frequently detectable in CIS, may precipitate progression to CIS because expression at precursor stages are rare.
For those genetic events that may participate in multiple complementation groups, these arguments have limitations and one can not be dogmatic in application of these principles. The case of erbB-2 overexpression suggests that erbB-2 precipitates progression to DCIS but predisposes DCIS to progression to invasive cancer because erbB-2 is rarely overexpressed in PBD, frequently expressed in DCIS, and less frequently overexpressed in invasive cancer.