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Journal of Clinical Oncology, Vol 22, No 23 (December 1), 2004: pp. 4725-4729 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.06.134 Racial Disparity of Epidermal Growth Factor Receptor Expression in Prostate CancerFrom the Departments of Urology, Pathology, and Medical Oncology, New York University Cancer Institute; and Departments of Biostatistics and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Iman Osman, MD, New York University School of Medicine, 550 First Avenue, H-100, New York, NY 10016; e-mail: Iman.Osman{at}med.nyu.edu
PURPOSE: The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors.
PATIENTS AND METHODS: We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage RESULTS: EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003). CONCLUSION: Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.
The development of agents that target epidermal growth factor receptor (EGFR) as a treatment option for prostate cancer patients is based on evidence that increased EGFR signaling is crucial for prostate carcinogenesis.1 In addition to cellular proliferation, escape from apoptosis, and promotion of tumor cell invasion, both in vitro and in vivo studies have demonstrated that the EGFR signaling pathway is critical in the progression to androgen-independent disease.2,3 Moreover, studies have shown that EGFR inhibitors effectively hinder the growth of both androgen-dependent and androgen-independent prostate cancer xenografts.4-6 On the basis of these observations, phase I and II trials have been initiated to test the efficacy and toxicity of anti-EGFR agents as monotherapy and in combination with chemotherapy for prostate cancer patients.7-9 There have been considerable efforts to define factors that will help identify the patients most likely to benefit from EGFR inhibitor therapy.10-12 Although predictors of clinical response have not been elucidated fully,13,14 it has been shown recently by two independent groups that a subset of patients with non–small-cell lung cancer have specific mutations in the EGFR gene that correlate with clinical responsiveness to the tyrosine kinase inhibitor, gefitinib.15,16 In addition, several lines of evidence suggest that there are interethnic differences in response to EGFR inhibitor therapy. Preliminary data from approximately 17,000 patients with advanced non–small-cell lung cancer receiving gefitinib showed that Asian or Japanese ethnicity was associated with longer survival.17 In line with this observation, studies have demonstrated that there are major interethnic differences in the allelic distribution of a dinucleotide (CA) repeat polymorphism in intron 1 of the EGFR,18 and that the number of CA repeats (which ranges from 14 to 21) correlates with transcriptional activity.19,20 On the basis of the association between EGFR protein expression and the length of the CA repeat polymorphism, it has been suggested that genotypic background might contribute to the variability in EGFR expression and to the differential responses of patients to anti-EGFR agents.18,19 As multidisciplinary approaches, including systemic chemotherapy, prove to be increasingly valuable in the treatment of patients with localized prostate cancer, it is critical to understand the implications of alterations in potential therapeutic targets, such as EGFR, in clinically localized disease stages.21,22 We have shown previously that African American race is an independent predictor of poor outcome in prostate cancer patients.23 In this study, we attempt to reveal the impact of race on the expression of EGFR in prostate cancer.
Patient Characteristics Patients were identified through review of the Department of Urology database at the Veterans Administration Medical Center (VAMC) and New York University School of Medicine (New York, NY). This prospective database enrolled patients with prostate cancer from 1990 to the present, documenting patient demographics and characteristics, including racial background, stage, and grade of the primary tumor. After institutional review board approval, a review was performed to gather all relevant clinical and pathologic information including racial background, age at the time of diagnosis, tumor grade, stage, pretreatment prostate-specific antigen (PSA) values, PSA recurrence, and survival. Patient selection was based on adequate clinical follow-up and the availability of representative pathology specimens for immunohistochemical (IHC) analysis. We identified 226 patients who underwent radical prostatectomy at the VAMC. Formalin-fixed, paraffin-embedded primary tumor tissue blocks were available for 202 of the 226 patients. This cohort included 142 African American and 60 white men. Patients were classified as having either low Gleason score (< 7; n = 110) or high Gleason score (  7; n = 92), and as having either early organ-confined tumors (pT2; n = 130) or advanced tumors extending beyond the prostatic capsule (pT 3; n = 72).
IHC Analysis of EGFR Expression Membrane immunoreactivities for the EGFR protein were categorized as undetectable (zero) to +3. A score of zero was defined as undetectable staining or membrane staining in less than 10% of the tumor cells. A score of +1 was defined as faint, incomplete membrane staining in more than 10% of the tumor cells. A score of +2 was defined as weak to moderate, complete membrane staining in more than 10% of the tumor cells. Finally, a score of +3 was defined as strong, complete membrane staining in more than 10% of the tumor cells. EGFR protein expression was then classified as negative (scores 0 and 1) or positive (scores 2 and 3). We have used this scoring system previously in our study of HER-2 expression30 in prostate cancer, and other groups have used the same cutoff of complete membrane in more than 10% of tumor cells to define positive expression in published reports on EGFR in prostate cancer.31 Our primary objective was to study the association between EGFR and patients’ race. As a secondary objective, we also explored the association between EGFR and treatment outcome. The response variable for this secondary goal, time to PSA relapse, was defined as the time from radical prostatectomy to the time of the first detectable (nonzero) PSA. Three consecutive increases of PSA were required to confirm PSA relapse; however, the time of relapse was taken as the time of the first detectable PSA value.32-34 Nine patients who did not achieve undetectable PSA after radical prostatectomy were excluded from time to PSA relapse analysis. Investigators who performed the IHC assay were blinded to all patient data, including race.
Statistical Analyses
We determined EGFR expression in 202 of 226 patients from the Department of Urology database. Twenty-four patients had insufficient tumor for IHC evaluation. In this cohort, the median age at the time of diagnosis was 67 years and the median follow-up period was 4.5 years, during which time 32% of patients developed PSA recurrence. Normal prostate glands demonstrated strong membranous immunostaining of the basal cells (Fig 1A) and were considered internal positive controls for each patient case. Expression in tumors was evaluated according to the percent of invasive tumor cells with membrane immunoreactivity and the intensity of the signal. Negative expression was scored either as 0 (n = 87) or +1 (n = 40; Fig 1B). Positive expression was scored either as +2 (n = 49) or +3 (n = 26; Fig 1C). A total of 75 patients (37.1%) showed EGFR overexpression.
Table 1 summarizes the univariate analyses of the associations between EGFR expression and baseline characteristics of the patients. We observed a significant association between EGFR overexpression and African American race (45% African American v 18% white; P = .0006), higher pretreatment PSA (45% of PSA > 10 v 26% of PSA < 10; P = .02), and stage (49% of stage 3 v 31% of stage  2; P = .02), but not with Gleason score (41% of Gleason score 7 v 34% of Gleason score < 7; P = .33). Race (odds ratio, 3.1; 95% CI, 2.1 to 4.6; P = .003; baseline is white race) was associated with EGFR positivity in a multivariate logistic regression model (Table 2).
We also examined the association between EGFR expression and recurrence after surgery. In this cohort, we noted a trend of increased recurrence among the subset of patients with EGFR-positive tumors (41% v 27% for EGFR negative) that did not reach statistical significance (P = .07). As reported previously in this cohort, race, tumor stage and grade, and pretreatment PSA were predictors of recurrence both in univariate and multivariate models.23
We investigated EGFR protein expression in a well-characterized cohort of prostate cancer patients who presented to the VAMC in New York and had equal access to care and follow-up. Our study reveals that EGFR overexpression in prostate cancer is significantly more common in African American than in white patients after controlling for potential confounding factors. This observation suggests that race contributes significantly to variability of EGFR expression in prostate cancer, and that it may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents. Despite the plethora of publications evaluating EGFR expression in various solid tumors, there are limited data available regarding its clinical relevance in prostate cancer. Two independent groups have shown increased expression of EGFR in androgen-independent, metastatic prostate cancer.36,37 More recently, another study has demonstrated that EGFR expression increased after androgen ablation.31 However, there is a paucity of studies that have examined EGFR expression in localized prostate cancer specifically. Our data are in agreement with two published studies, which showed that EGFR overexpression was a common event in primary untreated prostate cancer, with a frequency of approximately 40%.38,39 Although one group reported no correlation between EGFR expression and racial background,39 their conclusion was based on a relatively small number of African American patients (n = 16) compared with our study, which included a larger number of African Americans (n = 142). Our analyses reveal an association between EGFR overexpression and poor prognostic criteria (stage and higher pretreatment PSA; Table 1). However, the association between EGFR overexpression and prostate cancer recurrence after surgery did not reach statistical significance (P = .07). We did not confirm the strong association between EGFR overexpression and recurrence after surgery that was reported in a recently published study.37 That report, however, included patients who received neoadjuvant hormone treatment before their radical prostatectomies, which is known to influence the time to PSA relapse after surgery. In contrast, our study was based on a more homogenous population of patients who were primarily hormone-naive at the time of surgery, and included a larger sample size with longer follow-up. In this regard, our observation that EGFR expression is not strongly associated with clinical outcome in primary prostate cancer has been reported by two independent groups.31,39 Although the results of our study clearly demonstrate that ethnic heterogeneity of EGFR alterations exists in prostate cancer, the functional significance of EGFR overexpression in African American patients remains abstruse. Previous studies have revealed that populations of various ethnic origins have differential distribution of a dinucleotide (CA)n repeat polymorphism in intron 1 of the EGFR gene.18,40 Specifically, they found that the longer allele, consisting of 21 repeats, is significantly more common in Asian individuals18 and is associated with an 80% reduction in EGFR protein expression compared with the shorter allele of 16 repeats.19 Moreover, a survey of the distribution of alleles among people of different ethnic backgrounds showed that the longer allele, associated with decreased EGFR transcription, was less common in African Americans compared with whites. Additional investigations are needed to better characterize the relationship between these genotypic variations, EGFR gene mutational status, differential expression of EGFR, and response to anti-EGFR agents.18 Our study has several limitations. First, our postulate that the difference in EGFR expression might be related to the differences in the allelic frequency of (CA)n repeats in intron 1 of the EGFR gene18 will require an additional prospective study of a sufficient cohort of patients from whom blood or tissue samples are available. Furthermore, our assumption that the difference in EGFR expression among prostate cancer patients with different ethnic backgrounds might affect their response to EGFR inhibitors awaits confirmation via prospective studies in prostate cancer. Such trials have been conducted only in patients with lung or colon cancer.41,42 In conclusion, the results of our study demonstrate significant ethnic heterogeneity in the expression of EGFR in prostate cancer, and suggest that race may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.
The authors indicated no potential conflicts of interest.
Supported by National Institutes of Health/National Cancer Institute grants CA-01713 (I.O.). Supported in part also by the use of facilities at the Manhattan Veterans Administration Medical Center, New York, NY. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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40. Chi DD, Hing AV, Helms C, et al: Two chromosome 7 dinucleotide repeat polymorphisms at gene loci epidermal growth factor receptor (EGFR) and pro alpha 2 (I) collagen (COL1A2). Hum Mol Genet 1:135, 1992 41. Kuwanda SK, Scaife CL, Kuang J, et al: Effects of trastuzumab on epidermal growth factor receptor-dependent and independent human colon cancer cells. Int J Cancer 109:291-301, 2004[CrossRef][Medline]
42. Cappuzzo FGV, Rossi E, Cancellieri A, et al: Gefitinib in pretreated non–small-cell lung cancer (NSCLC): Analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J Clin Oncol 21:2658-2663, 2003 Submitted June 18, 2004; accepted September 16, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Variables were subsequently evaluated in a multivariate logistic regression model. In the secondary analysis, which examined the association between EGFR and clinical outcome, EGFR was treated as a baseline variable, and the outcome was PSA relapse–free survival. The association between EGFR and outcome was examined using a competing risk regression approach,
