CONCURRENT ABNORMAL EXPRESSION OF ERBB-2, EGFR, AND P53 GENES AND CLINICAL-DISEASE PROGRESSION OF BREAST-CARCINOMA

Metastatic phenotype in human solid tumors is believed to follow stoch astic acquisition of structural genetic aberrations-so-called multiste p tumor progression. We tested this hypothesis in breast carcinoma by immunostaining 89 stage-heterogeneous cases for the products of three genes (p53, ERBB-2, and EGFR) which are frequently altered in this tum or system. Variable relationships were observed between advanced disea se stage and immunostaining for individual gene products (ERBB-2 - p = 0.05, EGFR - p = 0.02, p53 - p = 0.12, Chi Square test). Regional or distant metastases at presentation correlated with multiple oncogene/t umor suppresser gene expression abnormalities: node negative - 59% non e positive, 29% one positive, 12% two or more positive, vs. node posit ive - 37% none positive, 23% one positive, 39% two or more positive (p = 0.01). Only 2/12 (17%) of tumors with distant metastases at present ation were negative for abnormal expression of any of these gene produ cts, and 7/12 (58%) were positve for two or three. Among axillary node negative patients who developed recurrences, 67% exhibited staining f or at least one gene product, compared to only 27% of those without re currences (p = 0.02). All 5 cases with abnormal staining for each gene product had regional or distant metastases at presentation and recurr ed. In multivariate analysis, individual expression of p53 outweighed expression of ERBB-2 and EGFR in correlation with outcome. These data suggest clinical neoplastic progression of breast carcinomas correlate s with cumulative genetic events detectable by protein expression. Sho rt term recurrence, however, may correlate more closely with abnormal expression of p53 than with EGFR or ERBB-2.