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Clinical Cancer Research 13, 6579, November 15, 2007. doi: 10.1158/1078-0432.CCR-07-1257
© 2007 American Association for Cancer Research
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Human Cancer Biology

Clinical Significance of Epidermal Growth Factor Receptor Protein Overexpression and Gene Copy Number Gains in Prostate Cancer

Thorsten Schlomm1, Patrick Kirstein2, Liv Iwers2, Birte Daniel2, Thomas Steuber3, Jochen Walz3, Felix H.K. Chun3, Alexander Haese3, Jens Kollermann2, Markus Graefen1, Hartwig Huland1,3, Guido Sauter2, Ronald Simon2 and Andreas Erbersdobler2

Authors' Affiliations: 1 Martini-Clinic, Prostate Cancer Center, Department of 2 Pathology and 3 Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Requests for reprints: Thorsten Schlomm, Martini-Clinic, Prostate Cancer Center Hamburg-Eppendorf, Martinistr. 52, 22299 Hamburg, Germany. Phone: 49-40-42803-1314; Fax: 49-40-42803-1323; E-mail: tschlomm{at}uke.uni-hamburg.de.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: The epidermal growth factor receptor (EGFR) is a protein involved in the tumor progression of many cancer types and is an important therapeutic target. To determine its role in prostate cancer, we analyzed 2,497 prostate cancers on the DNA and protein level.

Experimental Design: Tissue samples from each tumor were brought into a tissue microarray and analyzed by immunohistochemistry and fluorescence in situ hybridization. A subset of cancers was also sequenced for EGFR exon 18 to 21 mutations.

Results: Detectable EGFR expression was found in 18% of cancers and was significantly associated with high grade, advanced stage, and high risk for prostate-specific antigen recurrence in univariate analysis (P < 0.0001, each). Fluorescence in situ hybridization analysis with a dual-labeling probe for centromere 7 and EGFR showed increased EGFR copy number in 3.3% of cases. EGFR copy number gains were mostly due to an overrepresentation of the entire chromosome and were associated with EGFR protein expression (P < 0.0001), high grade (P < 0.0001), and advanced stage (P = 0.0056). Only one cancer had a high-level amplification (>20 EGFR gene copies per cell). This amplification was heterogeneous, involving only ~30% of the cancer volume. EGFR mutations were not found in 35 of the cases analyzed.

Conclusion: Increased EGFR expression is often seen in prostate cancer and is associated with poor prognosis. The significant association of EGFR copy number gains with protein expression argues for the significant role of minimal gene copy number changes for protein expression. Although EGFR expression was not an independent prognostic variable, the potential utility of anti-EGFR medications might be worth further investigation in EGFR-expressing prostate cancer.

The epidermal growth factor receptor (EGFR) gene is located on chromosome 7p12 and codes for a 185 kDa transmembrane tyrosine kinase (1). EGFR is widely expressed in most epithelial tissues including basal cells of the prostate epithelium (2). Increased expression of EGFR has been described in many different tumor types (reviewed in ref. 3). In several tumor types, EGFR overexpression has been suggested as a prognostic factor (3). In prostate cancer, studies employing immunohistochemistry reported increased frequencies of EGFR expression between 1% and 100% (2, 4, 5). In addition, statistical associations were described between high EGFR expression and tumor progression or development of androgen independence in studies analyzing 74, 147, and 211 prostate cancers (5–7).

EGFR has recently gained considerable additional importance due to its role as a drug target. A variety of anti-EGFR drugs are currently Food and Drug Administration–approved or in clinical trials. These drugs include small inhibitory molecules such as Iressa or Tarceva, as well as antibodies such as Cetuximab (8). Most experience with anti-EGFR drugs has been collected in lung cancer. Here, the number of strong responders to anti-EGFR drugs seems to be relatively low. However, treatment response is substantial in some patients, most of which have exon 18 to 21 mutations of the EGFR gene (9). More recently, increased gene copy number has also been proposed as a predictor for response to anti-EGFR therapy (8).

To evaluate the significance of EGFR alterations in prostate cancer and to investigate the potential utility of anti-EGFR drugs in this cancer type, we analyzed EGFR expression and gene copy number changes in more than 2,000 prostate cancers with clinical follow-up data. The results suggest a role for EGFR in prostate cancer progression.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients. Radical prostatectomy specimens were available from 3,261 patients treated at the Department of Urology, University Medical Center Hamburg-Eppendorf between 1992 and 2005 (Table 1 ). Follow-up data were available for 2,385 patients, ranging from 1 to 144 months (mean, 34 months). All prostatectomy specimens were surface-inked and processed using serial transverse sections at 3-mm intervals according to the Stanford protocol (10). Pathologic stage was defined according to the 2002 American Joint Committee on Cancer staging classification. Prostatectomy specimens were histologically graded according to the Gleason grading system. All patients are scheduled for an annual follow-up visit at our institutional outpatient clinic. Information about external posttreatment prostate-specific antigen (PSA) testing (usually done every 6 months) is added to the institutional database. Tumor recurrence (biochemical recurrence) was defined as postoperative levels of total PSA ≥ 0.1 ng/mL and rising after initial undetectable total PSA. None of the patients received adjuvant therapy prior to evidence of cancer recurrence.


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  		Table 1. Clinical and pathologic characteristics of 3,261 patients who underwent radical prostatectomy and of 2,385 patients with available follow-up data

 
All H&E-stained histologic sections from all prostatectomy specimens were reviewed for the purpose of this study, and the index tumors, as defined by the largest tumor focus and/or the focus with the worst Gleason grade, were marked on the slides. One 0.6-mm-thick tissue core was punched out from the index tumor of each case, and transferred in a tissue microarray (TMA) format as described before (11). The 3,260 cores were distributed among seven TMA blocks each containing 129 to 522 tumor samples. From the resulting TMA paraffin blocks, serial histologic sections were taken. The first set of sections was routinely H&E-stained, whereas subsequent sections served for EGFR immunostaining, EGFR fluorescence in situ hybridization (FISH), and immunostaining for high–molecular weight cytokeratins (34ßE12), which labels basal cells in normal prostate glands. For internal controls, each TMA block also contained various control tissues, including normal prostate tissue, other normal tissues, and a set of tumor tissues, among the latter including several EGFR-positive lung cancers.

Immunohistochemistry. Freshly cut TMA sections were analyzed in 1 day in one experiment for each antibody. The antibody "EGF receptor" (Zymed 20.005) was used for EGFR protein detection. Slides were deparaffinized and treated with Pronase type XIV for 15 min at 37°C. Optimal staining was achieved at 1:100 antibody dilution. The antibody was omitted for negative controls. Bound primary antibody was visualized using the Vectastain Elite ABC kit (Vector Laboratories). Only membranous EGFR staining was considered. For each tumor sample, the fraction of positive cells was estimated and the staining intensity was judged as 0, +, ++, or +++. Tumors were subsequently categorized as negative (no membranous staining), strongly positive (≥50% 2+ or ≥30% 3+), or weakly positive. Weakly positive was defined as some positivity without reaching the above criteria selected for our definition of strongly positive.

FISH analysis. A 4 µm TMA section was used for two-color FISH. For proteolytic slide pretreatment, a commercial kit was used (paraffin pretreatment reagent kit; Vysis). A Spectrum Orange–labeled EGFR probe was used together with a Spectrum Green–labeled centromere 7 probe (PathVysion; Vysis). Before hybridization, TMA sections were deparaffinized, air-dried, and dehydrated in 70%, 85%, and 100% ethanol followed by denaturation for 5 min at 74°C in 70% formamide-2 xSSC solution. After overnight hybridization at 37°C in a humidified chamber, slides were washed and counterstained with 0.2 µmol/L of 4',6-diamidino-2-phenylindole in an antifade solution. For each tumor, the average gene and centromere copy numbers were estimated. Based on these numbers, a tumor was considered amplified if the EGFR/centromere 7 ratio was ≥2.0.

Technical issues in immunohistochemical and FISH analyses on TMAs. As in all TMA studies, a fraction of tissue samples were noninformative due to complete lack of tissue samples or absence of unequivocal cancer tissue in the corresponding 34BE12-immunostained TMA section. The percentage of noninterpretable samples was 22.5% for EGFR immunohistochemistry and 28.1% for EGFR FISH.

EGFR mutation analysis. Genomic DNA was extracted from 35 tumors according to standard procedures. Sequenced cancers included all strongly immunohistochemistry positive and EGFR gene amplified cancers. Genomic DNA was extracted according to standard procedures. "Macrodissection" with a scalpel was carried out on tissue sections to ensure a high content (>80%) of tumor cells in the tissue samples. Genetic analysis of the EGFR gene was done by PCR amplification of exons 18, 19, 20, and 21 with subsequent sequencing of the PCR products exactly following the protocol of Lynch et al. (9).

Statistics. Statistical calculations were done with PRISM 2.01 software (GraphPad). Contingency tables were calculated with the {chi}2 test and Fisher's exact test. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Cox regression was used to assess the independence of preoperative variables and EGFR status to predict PSA recurrence after radical prostatectomy.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Immunohistochemistry. A positive EGFR immunostaining could be observed in 448 of our 2,497 interpretable prostate cancers (18%). Representative images are given in Fig. 1 . EGFR staining was considered weak in 415 (17%), and strong in 33 (1%) of the cases. According to our predefined criteria, EGFR immunostaining was strongly associated with advanced tumor stage (P < 0.0001), high Gleason grade (P < 0.0001), and preoperative PSA (P = 0.0002). The association did not reach statistical significance for nodal status (P = 0.0563) and positive surgical margin status (P = 0.0867; Table 2 ). The EGFR protein expression level was significantly associated with patient prognosis (Fig. 2 ). However, this was not independent of grade and stage as described in detail below.


Figure 1
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  		Fig. 1. Examples of EGFR immunostainings. A, benign prostate gland showing strongly EGFR-positive basal cell layer. B, prostate cancer almost EGFR-negative adjacent to benign prostatic glandular epithelium with EGFR positivity strictly confined to the basal cell layer. C, prostate cancer strongly positive for EGFR.

 

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  		Table 2. EGFR immunohistochemistry and FISH results

 

Figure 2
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  		Fig. 2. EGFR expression and biochemical recurrence in patients with prostate cancer.

 
EGFR FISH. A total of 2,446 cancers were successfully analyzed by FISH and showed countable red EGFR and green centromere 7 signals. Amplification according to our predefined definitions was seen in 6 of 2,446 cases (0.25%). One of these cases was massively amplified with more than 20 EGFR signals per cell. To evaluate the heterogeneity of EGFR amplification, all available conventional large sections from this highly amplified cancer were then also analyzed. This analysis showed that only ~30% of the tumor mass showed amplification whereas the remaining cancer had two to four centromere 7 and two to four EGFR copies per cell (Fig. 3 ).


Figure 3
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  		Fig. 3. Heterogeneity of EGFR amplification in prostate cancer. FISH analysis of EGFR (red) and centromere 7 (green) copy numbers revealed areas with EGFR amplification (A) and with normal EGFR copy numbers (B) within the same patient sample.

 
Most cancers with increased EGFR copy numbers had a parallel increase of the centromere 7 counts, indicating chromosome 7 polysomy. With respect to the absolute centromere count, 2,365 cancers had two copies, 63 cancers three to four copies, 15 cancers five to six copies, and a single cancer had more than six copies per cell on average. Polysomy of chromosome 7 was associated with high preoperative PSA (P = 0.0127), advanced stage (P = 0.0056), and high Gleason grade (P < 0.0001; Table 2). A significant association with PSA recurrence could not be confirmed, however (data not shown). Chromosome 7 polysomy was strongly associated with elevated EGFR protein expression (P < 0.0001). EGFR immunostaining was observed in 16.6% of 2,338 cancers with two EGFR signals per cell, in 41.3% of 63 cancers with three to four, in 84.6% of 13 cancers with five to six, and in 50% of six cancers with more than six copies per tumor cell (P < 0.0001).

EGFR mutations. No exon 18 to 21 mutations were found in 35 sequenced cancers.

Multivariate analysis at prognostic markers. Follow-up data with respect to biochemical recurrence were available for 2,397 patients, ranging from 1 to 144 months (mean, 34 months). Cox regression analysis showed that high Gleason grade (P < 0.0001), advanced pT stage (P < 0.0001), positive surgical margins (P = 0.0001), and high preoperative PSA (P = 0.0027) were strongly linked to PSA recurrence in this patient subset. In a multivariate Cox regression analysis including preoperative PSA, pT stage, Gleason score, and positive surgical margin, neither EGFR expression nor EGFR copy numbers were independent predictors of PSA recurrence (P = 0.10 and P = 0.23; Table 3 ).


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  		Table 3. Multivariate analysis (Cox regression model)

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Detectable EGFR expression was observed in 18% of the 2,497 patients analyzed in this study. Although only one tissue sample measuring 0.6 mm in diameter was analyzed per patient, 18% is well in the range of previous studies. In 11 previous studies, the mean rate of EGFR positivity was 35% with a range spanning from 1% to 86% (2, 6) for localized cancers and 16% to 100% (2, 5) for metastases. The data for this study, analyzing mostly localized and locally advanced tumors, suggests the close association of EGFR protein expression with grade, stage, and patient prognosis. This result is also consistent with several of the previous studies describing correlations between EGFR expression and prostate cancer progression (4–6, 12). These findings provide further evidence for the utility of TMAs for analyzing molecular features in prostate cancer. Using the same TMA, we also recently identified the strong prognostic relevance of p53 alterations, HER2, and high Ki67 labeling index in prostate cancer.4

EGFR gene copy number changes were infrequent in prostate cancer. Most altered tumors had only a low-level EGFR copy number increase (three to four copies), which was found in 2.7% of prostate cancers. The simultaneous increase of centromere 7 copy number in virtually all of these cases suggests that a gain of the entire chromosome 7 (polysomy 7) caused most EGFR copy number gains. The clear-cut association of such low-level gene copy number gains with EGFR protein expression emphasizes the strong effect of minimal DNA copy number changes on EGFR gene expression. This is in line with data from a rapidly increasing number of studies comparing CGH array and RNA expression screening data (13). In these studies, significant RNA overexpression is regularly found for most of the genes that are mildly overrepresented on the DNA level (14). An increasing number of reports suggesting a predictive role of minimal EGFR gene copy number changes for response to anti-EGFR drugs in lung and brain cancer suggests a potential clinical significance of such minor EGFR copy number gains (15–18). In contrast to low-level gene copy number gains due to polysomy, gene amplifications typically reflect a much higher level gene copy number increase. However, only ~0.7% of all prostate cancers have four or more EGFR copies in ≥40% cells. It will be interesting to see whether prostate cancers with EGFR gene copy number changes could benefit from anti-EGFR therapies.

The importance of high-level gene amplification as a mechanism for EGFR overexpression is highly variable between different cancer types. For example, gene amplification causes EGFR overexpression in almost 100% of EGFR-positive glioblastomas and the vast majority of EGFR-positive esophageal squamous cell carcinomas (19, 20). In many other tumor types, such as lung cancer for example, EGFR amplification is a rare cause for overexpression. Also in prostate cancer, EGFR amplification is obviously rare and occurs at low levels in most cases. Only one of six prostate cancers that were amplified according to our predefined criteria had "classic" high level amplifications with clustered EGFR signals. Based on the reported high response rates of EGFR-amplified lung cancers to anti-EGFR drugs (16), EGFR-amplified prostate cancers might represent candidates for evaluating anti-EGFR drugs in a new indication. To further analyze the potential utility of anti-EGFR therapy in this cancer, we analyzed the entire tumor mass of our massively amplified prostate cancer, which had previously been completely embedded, for EGFR amplification. Remarkably, EGFR amplification was heterogeneous in this cancer and could only be found in ~30% of the tumor volume.

Heterogeneous amplification might be a substantial obstacle for targeted cancer therapy. An inhomogeneous distribution of a therapeutic target in a primary tumor might lead to variable findings in corresponding metastases and consecutive therapy failures. Heterogeneity of the expression (or amplification) of therapeutic targets has only rarely been examined in recent years. This is perhaps because of the very high frequency of completely homogeneous findings for HER2 amplification in breast cancer, the currently best-established drug target in solid tumors. It is possible, however, that heterogeneity might be much more frequent for other target genes and in other organs. It could be speculated that such heterogeneity could cause more than currently expected problems for the future development and use of targeted cancer drugs.

In summary, increased EGFR expression is frequent in prostate cancer and is associated with a high risk of PSA recurrence. High-level EGFR expression is often caused by EGFR polysomy, a feature associated with increased likelihood of response to Iressa in lung cancer. Although EGFR gene mutations were not found in 35 analyzed cancers and the only high-level EGFR gene amplification was inhomogeneous, the potential utility of anti-EGFR medications in prostate cancer might be worth further investigation.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

4 Unpublished data. Back

Received 5/23/07; revised 8/ 6/07; accepted 8/30/07.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
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