ABSTRACT
OBJECTIVE: To determine the relative prognostic value of p53, cyclin D1, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) expression in patients with oral and oropharyngeal squamous cell carcinoma. DESIGN: Retrospective cohort study. PATIENTS: Fifty-six patients with oral and oropharyngeal squamous cell carcinoma referred to the Department of Therapeutic Radiology at Yale-New Haven Hospital (Conn) between 1981 and 1992 who were treated with gross total surgical resection and postoperative external beam radiotherapy. RESULTS: Archival tumor tissue was stained with monoclonal antibodies directed against these 4 oncoproteins and scored for staining intensity and percent distribution by a pathologist blinded to the patients' clinical outcomes. Frequency of marker expression was 48% for p53, 20% for cyclin D1, 64% for EGFR, and 41% for VEGF. In multivariate analysis, EGFR positivity was protective against locoregional relapse (relative risk [RR], 0.27; 95% confidence interval [CI], 0.11-0.66; P =.002). In contrast, advanced N stage predicted poor locoregional relapse-free survival (RR, 1.94; 95% CI, 1.03-3.66; P =.04). Predictors of poor overall survival in multivariate analysis included VEGF positivity (RR, 3.53; 95% CI, 1.75-7.13; P<.001) and black race (RR, 2.48; 95% CI, 1.05-5.85; P =.04). Cyclin D1 and p53 expression were not significantly associated with prognosis in this cohort. CONCLUSIONS: In oral and oropharyngeal squamous cell carcinoma treated with surgery and postoperative radiotherapy, VEGF and EGFR expression may influence clinical outcome. If confirmed, these results have potential implications for the determination of patient prognosis and the development of biologically based pharmacotherapies.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/genetics , ErbB Receptors/genetics , Oropharyngeal Neoplasms/genetics , Adult , Aged , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/radiotherapy , Carcinoma, Squamous Cell/surgery , Cohort Studies , Combined Modality Therapy , Cyclin D1/genetics , Endothelial Growth Factors/genetics , Female , Gene Expression Regulation, Neoplastic/physiology , Humans , Lymphokines/genetics , Male , Middle Aged , Neoplasm Staging , Oropharyngeal Neoplasms/pathology , Oropharyngeal Neoplasms/radiotherapy , Oropharyngeal Neoplasms/surgery , Prognosis , Retrospective Studies , Tumor Suppressor Protein p53/genetics , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
PURPOSE: We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples. MATERIALS AND METHODS: Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables. RESULTS: Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2-negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with > or = 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2-positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high (> or = 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2-positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup. CONCLUSION: PN2A immunostaining identified a subset (approximately 12% of ErbB-2-positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression (> or = 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.
