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Cancer Epidemiology Biomarkers & Prevention Vol. 14, 1557-1561, June 2005
© 2005 American Association for Cancer Research

Short Communication

Prediagnostic Plasma Vascular Endothelial Growth Factor Levels and Risk of Prostate Cancer

Haojie Li1, Philip W. Kantoff2, Jing Ma1, Meir J. Stampfer1,3 and Daniel J. George2

1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; 2 Lank Center for Genitourinary Oncology, Division of Solid Tumor Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute; and 3 Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts

Requests for reprints: Haojie Li, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Room 452, 181 Longwood Avenue, Boston, MA 02115. Phone: 617-525-2093; Fax: 617-525-2008. E-mail: haojie.li{at}channing.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Vascular endothelial growth factor (VEGF) plays important roles in endothelial cell proliferation, vascular permeability, and angiogenesis that may be critical to prostatic carcinogenesis and progression. Plasma VEGF levels were significantly greater in patients with metastatic prostate cancer compared with those with localized disease or healthy controls, and plasma VEGF level at prostate cancer diagnosis was an independent prognostic marker for survival in patients with hormone refractory prostate cancer. We therefore examined the association between prediagnostic plasma VEGF levels and risk of prostate cancer and disease phenotype. Using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, we conducted a nested case-control study among 504 men diagnosed with prostate cancer during 13 years of follow-up and 520 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression. Prediagnostic plasma VEGF levels were similar among cases and controls. Plasma VEGF concentration was not associated with subsequent risk of prostate cancer (third versus first tertile OR, 1.09; 95% CI, 0.80-1.49; Ptrend = 0.65). Furthermore, no association was observed among men with advanced (stage C or D) prostate cancer or among those who died of prostate cancer. Our results indicate that prediagnostic circulating VEGF levels are not associated with prostate cancer development and have limited value in predicting future risk of prostate cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
With the introduction of prostate-specific antigen (PSA) testing, prostate cancer is diagnosed on average 5 years earlier and relatively few patients now present with overtly metastatic tumors. Nonetheless, between 28% and 53% of patients with apparently organ-confined disease progress following prostatectomy (1), suggesting that microscopic metastasis occurs early in the disease process. Angiogenesis is critical for tumor growth and cancer progression and plays important roles in invasion of cancer cells into the circulation and growth of dormant micrometastasis over time (2, 3). Therefore, circulating growth factors that promote tumor angiogenesis are attractive candidate biomarkers in predicting prostate cancer development and progression.

Vascular endothelial growth factor (VEGF) is a pleiotrophic growth factor that promotes endothelial cell proliferation, vascular permeability, and angiogenesis (4, 5). VEGF is produced in many normal tissues, but one of the richest sources in humans is the prostate gland (6). Normal prostatic growth and survival is dependent on VEGF-mediated angiogenesis, and studies of castrated animals show that in the prostate, VEGF expression is androgen regulated (7, 8). Similar to the normal prostate gland, growth of prostate cancer also seems dependent on VEGF-mediated angiogenesis (9). These preclinical data suggest that VEGF-dependent angiogenesis may represent an important step in prostatic carcinogenesis and progression (10, 11).

Several clinical studies have examined the prognostic value of circulating VEGF levels in patients with prostate cancer. Two studies showed higher VEGF levels in circulation among patients with metastatic or hormone-escaped prostate cancer compared with patients with localized disease or healthy controls (12, 13). Among 197 men with hormone-refractory prostate cancer, we previously showed that plasma VEGF level at diagnosis was an independent prognostic factor for survival (14). We therefore conducted a nested case-control study within the Physicians' Health Study to prospectively assess the relationship of prediagnostic plasma VEGF levels with subsequent risk of prostate cancer and disease progression.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
The Physicians' Health Study was a randomized, double-blind, placebo-controlled trial of aspirin and ß-carotene in the primary prevention of cardiovascular disease and cancer among 22,071 healthy U.S. male physicians ages 40 to 84 years. At baseline in 1982, men were excluded if they had a history of myocardial infarction, stroke, transient ischemic attack, or unstable angina; cancer (except for nonmelanoma skin cancer); current renal or liver disease, peptic ulcer, and gout; or current use of platelet-active agents, vitamin A, or ß-carotene supplements. The participants were predominately Caucasians (94%). A detailed description of the Physicians' Health Study was published previously (15, 16).

Study participants completed two mailed questionnaires before randomization. Additional questionnaires were mailed at 6 and 12 months and annually thereafter. Blood samples were collected at baseline, as described previously (17). We received specimens from 14,916 (68%) of the randomized physicians; >70% of the specimens were received between September and November in 1982. During 13 years of follow-up, >99% of surviving participants were still reporting morbidity events; by 2003, vital status for cases diagnosed between 1982 and 1995 was ascertained for 100%.

Selection of Prostate Cancer Cases and Controls
When a participant reported a diagnosis of prostate cancer, we requested hospital records and pathology reports for review by study physicians from the End Point Committee. For each case, one to three controls were selected from those who had provided blood, had not had a prostatectomy, and had not reported a diagnosis of prostate cancer at the time the diagnosis was reported by the case. Controls were individually matched to cases by age (±1 year; ±5 years for men ages >55 years) and smoking status (never, former, or current). Of all cases diagnosed between 1982 and 1995 who had provided blood sample at baseline, 504 cases had samples sufficient for analysis. The lack of sufficient blood samples for 30% of participants is unlikely to have introduced a bias; case participants with and without adequate blood sample were not substantially different with respect to baseline lifestyle characteristics. In addition, it is unlikely that physicians who did or did not provide a sample would differ significantly in terms of the potential relationship between baseline plasma VEGF levels and subsequent diagnosis of prostate cancer.

Severity of Disease
Physicians, unaware of the VEGF assay results, reviewed the medical records (including pathology reports) for each case patient to determine the tumor stage, the tumor grade, and the Gleason score (17). Stage was determined according to the modified Whitmore-Jewett classification scheme (18). Cases without pathologic staging were classified as indeterminate stage unless there was clinical evidence of distant metastases.

Laboratory Assessment
Matched case-control pairs or sets were handled together and identically. Samples for each case and matched control(s) were analyzed in random order, with the case status unknown to the laboratory personnel. Plasma VEGF level for each case or control was assayed in duplicate using a microplate luminescence detection system (Dynex Technologies, Chantilly, VA) and a human VEGF immunoassay Quantiglo kit (R&D Systems, Minneapolis, MN). Aliquots from the pooled standard specimens were used as quality controls and were analyzed in duplicates (n = 22 pairs) with the study samples. We calculated the average plasma VEGF level from the duplicate measurements for each man and each quality control sample. The median coefficient of variation for the quality control samples was 22.8%. VEGF levels under 30 pg/mL are difficult to measure accurately and are considered physiologically normal. We identified 108 men (11% of the total samples) and six quality control samples with mean VEGF level of >30 pg/mL and coefficient of variation (between the replicate measurements) of >50%. These data were designated as less precise and thus were analyzed with caution. After excluding the less precise data, the median coefficient of variation for the quality control samples was 15.0%.

Total PSA level from the same baseline samples for cases and controls was analyzed previously using the Tandem-R immunoradiometric assay (Hybritech, Inc., San Diego, CA). Additional details on the quality and reproducibility of the assay are described elsewhere (19, 20).

Statistical Analysis
Baseline plasma VEGF levels for 504 cases and 520 controls were available for analysis; among these, 484 cases and 503 controls were matched by age and smoking status at baseline. The nonparametric Wilcoxon signed rank sum statistic was employed to compare the distribution of plasma VEGF levels of cases and controls. We assessed the correlation of plasma VEGF levels with age at baseline, body mass index, baseline PSA levels, Gleason sum, disease stage, and smoking status.

We examined the association of prediagnostic plasma VEGF concentration with risk of overall prostate cancer and refitted models for men who died from prostate cancer or within subgroups categorized by tumor stage at diagnosis (i.e., stage A or B, C, or D). Cases (n = 79) were excluded from the subgroup analyses by stage if they had unknown disease stage. We did both conditional (matched) and unconditional (unmatched) logistic regression analyses. Because results were similar, we primarily reported results from unconditional logistic regression, adjusted for age at baseline, smoking status, and duration of follow-up, accounting for the case-control selection criteria and matching. Unconditional logistic regression model allows us to include all control subjects in each model, especially those in the subgroup analyses, to maximize statistical power; thus, the results are more robust. The duration of follow-up for cases was calculated in years between baseline (1982) and year at diagnosis; for a control subject, the follow-up duration was considered the same as the matched case. We used tertile cut points from the control subjects to assign each study participant to a tertile and calculated the odds ratios (OR) and 95% confidence intervals (95% CI) for each tertile, using the lowest tertile as the reference category. Tests for trend were conducted using median levels of the tertiles. We also used various cutoff points (e.g., quartiles) when analyzing these data; results were similar. We did all these analyses among all subjects and among those after excluding the 108 subjects with less precise data; because results were similar, results from all data are shown below. All statistics were calculated by using SAS (version 8.12; SAS Institute, Inc., Cary, NC) with a significance level of 0.05 (two sided).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline characteristics of 504 prostate cancer cases and 520 controls are presented in Table 1. The average interval from baseline in 1982 to diagnosis was 9 years (range, 1-13). Of the 504 incident cases, 304 were localized (stage A or B) and 121 were advanced (stage C or D) cases; we were unable to classify 79 men because of insufficient information. The median plasma VEGF level among control subjects was 48.9 pg/mL. Case subjects did not differ significantly from controls for any variable presented in Table 1, including the baseline plasma VEGF concentration.


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  		Table 1. Baseline characteristics of prostate cancer cases and controls in the Physicians' Health Study

 
We observed no correlations of prediagnostic plasma VEGF levels with age at baseline (Spearman correlation coefficient, r = –0.04), body mass index (r = –0.004), smoking status (never, former, and current), or other disease status (e.g., hypertension or diabetes) among control subjects; these patterns were similar among cases (data not shown). Furthermore, among cases, plasma VEGF level was unrelated to Gleason score (r = 0.02) or baseline PSA levels (r = –0.06). Although nonsignificant, men who presented with more advanced clinical stage prostate cancer (stage C or D) tended to have lower prediagnostic plasma VEGF levels, compared with men who presented with localized disease (stages A and B) or controls (Fig. 1; Wilcoxon signed rank sum statistic; P = 0.16).



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  		Figure 1. Baseline plasma VEGF levels (median and the 25th-75th percentile) among control subjects and prostate cancer cases in the Physicians' Health Study. VEGF, vascular endothelial growth factor. Plasma VEGF Levels for cases are presented by clinical stage; cases (n = 79 out of 504) whose disease status was unknown were excluded from this analysis. Wilcoxon signed rank sum statistics, P = 0.16.

 
Table 2 shows the association of plasma VEGF levels with subsequent prostate cancer risk. Overall, prediagnostic plasma VEGF levels were not associated with risk of prostate cancer (unmatched analysis, third versus first tertile OR, 1.09; 95% CI, 0.80-1.49; Ptrend = 0.65). Results from unmatched and matched analyses were similar.


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  		Table 2. Associations between prediagnostic plasma VEGF levels and risk of total prostate cancer

 
We then examined the association of plasma VEGF levels with subsequent risk of prostate cancer by severity of disease (Table 3). Prediagnostic plasma VEGF levels were not associated with risk of prostate cancer among stage A, B, and C cases. We observed a tendency towards an inverse trend of prediagnostic plasma VEGF levels with prostate cancer risk among stage D cases; compared with those in the lowest tertile, the OR for men with VEGF levels in the highest tertile was 0.56 (95% CI, 0.23-1.34; Ptrend = 0.14). Among the 67 men who died of prostate cancer, we found a tendency towards a positive association between prediagnostic plasma VEGF levels and risk of prostate cancer. Of these deaths, 38 men were diagnosed with stage A, B, or C (non-stage D) tumors and 29 men had stage D tumors. Because stage D deaths are the truly aggressive cases, whereas disease aggressiveness for non–stage D deaths may depend on the duration between diagnosis and death, we further examine these relationships for non–stage D and stage D deaths, separately. We found a positive trend between plasma VEGF levels and risk of prostate cancer for non–stage D deaths, similar to those for all deaths; however, a tendency towards an inverse trend was observed for stage D deaths. Because preclinical disease at baseline or latent tumor may influence baseline plasma VEGF level thus alters its relation with prostate cancer, we repeated all above analyses excluding cases diagnosed within the first 2 years after baseline; results were similar.


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  		Table 3. Associations between prediagnostic plasma VEGF levels and risk of prostate cancer by severity of disease

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found no association between prediagnostic plasma VEGF levels and subsequent risk of prostate cancer; this association did not differ by severity of disease. To our knowledge, this is the first large report evaluating the correlations of variables such as age, body mass index, smoking status, and some disease status (e.g., hypertension and diabetes) with plasma VEGF levels. We observed no significant correlation of baseline plasma VEGF levels with any of these preexisting conditions among cases and controls. Moreover, we found no correlation of baseline plasma VEGF with Gleason sum or baseline PSA levels among cases; plasma VEGF levels were slightly lower among men presenting with advanced stage prostate cancer (stage C or D) compared with those who had localized diseases and controls (Fig. 1).

We are unaware of previous reports on the association of prediagnostic plasma VEGF levels with risk of prostate cancer. Previous findings were mainly from clinical studies; one major limitation is that VEGF levels might be influenced by preexisting tumors or treatments in those patients. In the current study, we collected blood samples from healthy men at the baseline (i.e., 1-13 years before prostate cancer diagnoses). Thus, this may explain the inconsistence of our findings with those of previous studies.

Our findings that prediagnostic plasma VEGF levels were not associated with risk of prostate cancer and disease progression suggest that VEGF has no direct role in the early development and progression of prostate cancer. However, further investigations are warranted. Alternatively, perhaps tissue VEGF levels are important but plasma VEGF may be an inadequate surrogate for prostatic VEGF or angiogenesis. Microvessel density is a prognostic factor for prostate cancer disease progression and survival (21, 22). VEGF expression in primary prostate specimens has been correlated to microvessel density and to prognosis (23). Future studies of the correlations of plasma VEGF levels with prostate VEGF expression and microvessel density will help to address this distinction.

Limitations of the current study are recognized. Plasma VEGF levels were based on a single blood specimen collected in 1982, which may not adequately represent the subjects' average VEGF level over time. In addition, VEGF may not be stable in storage over a long period of time. However, levels of plasma VEGF of control subjects in the current study are similar to those of others. Although we have no data to assess the long-term reproducibility of plasma VEGF levels over time, we have shown from previous analyses that other plasma markers such as insulin-like growth factors and steroid hormones are relatively stable over time and were predictors of prostate cancer risk (24, 25). These findings indicate that the quality of these Physicians' Health Study samples is still adequate after almost two decades of storage. One study suggests that to measure VEGF concentration in platelet-poor plasma may be the most reliable method to assess circulating VEGF (26). Although participants of the Physicians' Health Study cohort are not a random sample of U.S. men, it is unlikely that the biological relations to be examined among these Physicians differ from U.S. men in general.

To summarize, although both experimental and clinical studies indicate that VEGF is an important determinant of angiogenesis and VEGF expression is associated with metastatic capability, our findings suggest that high plasma VEGF level is not a risk factor for prostate cancer development and progression. However, these findings should be evaluated in other prospective studies. In addition, to determine whether plasma VEGF is a valid indicator of prostate VEGF, future studies could assess the association between circulating VEGF levels with tissue microvessel density or VEGF expression from prostectomy specimens.


   Acknowledgments
 
We thank all the participants of the Physicians' Health Study for their cooperation.


   Footnotes
 
Grant support: NIH/National Cancer Institute grants CA90381, CA42182, CA58684, and CA90598.

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.

Received 6/18/04; revised 3/ 9/05; accepted 3/17/05.


   References
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 Abstract
 Introduction
 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
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online