ONCOGENE PROTEIN COEXPRESSION - VALUE OF HA-RAS, C-MYC, C-FOS, AND P53 AS PROGNOSTIC DISCRIMINANTS FOR BREAST-CARCINOMA

Objective A refinement of prognostic variables using traditional patho logic markers integrated with oncogene proteins, enzymes, and hormonal factors may enhance the ability to predict for recurrence or survival in patients with mammary carcinoma. Although various oncogenes and on cogene products have been identified in human breast carcinoma, their relationship to disease outcome remains controversial. Methods Using t he monoclonal antibodies cS93.1, 9E1.0, F235-1.7.1, and PAb 1801 again st each oncogene protein studied, the avidin-biotin complex immunopero xidase method provided immunohistochemical staining of bound oncogene protein for c-fos, c-myc, Ha-ras, and p53, respectively. Analyses were made on archival pathology tissues of 85 breast cancer patients (stag es I, IIA, and IIB). Forty patients (47%) had recurrence of disease; 4 5 remained free of local-regional or distant disease at mean follow-up of 48 months (range 6-180 months). Molecular biological data were mer ged with clinicopathologic demographics 1) to determine the frequency of single or co-expression of oncogenes in this patient population, 2) to evaluate the Value of these molecular protein markers to predict p robability of recurrence; and 3) to determine worth of the studied onc ogenes to correlate with traditional clinical pathologic parameters an d overall survival.Results In this study, oncogene expression had stat istical correlation for recurrence with increasing coexpression: one o ncogene 17.2%, two oncogenes 56.3%, three or four oncogenes, 100% (p = 0.001). Increasing oncogene or co-oncogene expression correlated with statistically significant reduction in disease-free and overall survi val; with no expression of oncogenes, disease-free survival was 30 (SE +/- 5.7) months and overall survival was 56.4 (SE +/- 4.57) months. W ith expression of three oncogenes, disease-free survival was 12 (SE +/ - 1.23) months (p = 0.0018) and overall survival was 23.4 (SE +/- 3.38 ) months (p = 0.0025). In univariate Wilcoxon analysis, oncogene expre ssion was the most significant variable to determine survival (p = 0.0 35); in multivariate analysis, age and oncogene co-expression each eme rged as the most significant variables for overall survival. For the p roportional hazards regression model, oncogene coexpression was signif icant (p = 0.0104, risk-ratio 1.914) and correlated with age and tumor size as significant variables. Ha-ras and c-fos both emerged as impor tant individual oncogene proteins to affect survival (p = 0.0925, risk -ratio 3.517 and p = 0.025, risk-ratio 4.214, respectively). The proto -oncogene c-myc and the antitumor suppressor gene p53 did not have sig nificant effects as individual oncogenes to influence survival. Conclu sions Approximately one fifth of the breast cancer patients in this an alysis (disease-free and recurrent) expressed only a single oncogene m arker (c-fos, c-myc, Ha-ras, or p53); one quarter of patients with rec urrent disease expressed only one oncogene protein. Single oncogene ex pression did not possess independent prognostic significance for predi ction of recurrence. Further, p53 mutations did not function as indepe ndent correlates for prognosis. The co-expression of the studied proto oncogenes (c-myc, Ha-ras) and the nuclear transcriptional protein (c-f os) functioned as a strong prognostic correlate for recurrence and sur vival; the effect of individual oncogenes to predict survival was grea test for Ha-ras and c-fos. Immediate or early co-expression of three o ncogene proteins in neoplastic transformation endowed cells of invasiv e carcinoma with an aggressive phenotype. This aggressive phenotype wa s evident in a small percentage of the studied population (11%) and pr edicted adverse disease-free and overall survival. These findings sugg est that oncogene co-expression possesses significant prognostic and p otential therapeutic value; incorporation of this molecular technology into future prospective randomized trials is advisable.