Abstract
To explore if the expression of phosphorylated epidermal growth factor receptor (pEGFR) in nonmalignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients. We used formalin-fixed tissues obtained through the transurethral resection of the prostate from 259 patients diagnosed with prostate cancer after the transurethral resection of the prostate, and patients were then followed with watchful waiting. Tissue microarrays of nonmalignant and malignant prostate tissue were stained with an antibody against pEGFR. The staining pattern was scored and related to clinicopathologic parameters and to outcome. Low phosphorylation of EGFR in prostate epithelial cells, both in the tumor and surprisingly also in the surrounding nonmalignant tissue, was associated with significantly longer cancer-specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were added together with pEGFR to a Cox regression model. Tumor epithelial pEGFR immunoreactivity was significantly correlated to tumor cell proliferation, tumor vascular density, and nonmalignant epithelial pEGFR immunoreactivity. Patients with metastases had significantly higher immunoreactivity for tumor and nonmalignant epithelial pEGFR compared with patients without metastases. Low pEGFR immunoreactivity is associated with the favorable prognosis in prostate cancer patients and may provide information about which patients with Gleason score 6 and 7 tumors that will survive their disease even without treatment. Changes in the nonmalignant tissue adjacent to prostate tumors give prognostic information.
Highlights
Experimental Design: We used formalin-fixed tissues obtained through the transurethral resection of the prostate from 259 patients diagnosed with prostate cancer after the transurethral resection of the prostate, and patients were followed with watchful waiting
Tumor epithelial phosphorylated epidermal growth factor receptor (pEGFR) immunoreactivity was significantly correlated to tumor cell proliferation, tumor vascular density, and nonmalignant epithelial pEGFR immunoreactivity
Patients with metastases had significantly higher immunoreactivity for tumor and nonmalignant epithelial pEGFR compared with patients without metastases
Summary
Cutoffs obtained were used in the Kaplan-Meier analysis in a test set and in a validation set (one of three of the patients on watchful waiting; Fig. 2) These survival analyses showed that low pEGFR immunoreactivity in prostate epithelial cells, both in tumor cells and in surrounding nonmalignant luminal epithelial cells, were associated with significantly longer cancer-specific survival (Fig. 2). Patients with high nonmalignant luminal pEGFR TY845 had significantly shorter cancer-specific survival than patients with low nonmalignant luminal pEGFR TYR845 (15-year P-EFS was 48 ± 6% and 80 ± 5% in the two groups; Fig. 3). High nonmalignant luminal epithelial pEGFR in patients with GS 6 or 7 (15-year P-EFS, 53 ± 9%) and in patients with GS 6 (15-year P-EFS, 63 ± 11%) had significantly shorter cancer-specific survival than patients with low nonmalignant luminal pEGFR in the subgroups (15-year P-EFS of 77 ± 9% and P-EFS of 87 ± 9%, respectively; Fig. 3). Patients with high tumor pEGFR and high nonmalignant luminal pEGFR had a 3-fold excess risk of prostate cancer death compared with the added separate relative risks for patients identified as having high tumor pEGFR or high nonmalignant luminal pEGFR, respectively (interaction analysis P < 0.001)
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