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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 8 2744-2747
Copyright © 2000 by The Endocrine Society

Original Studies

Insulin-Like Growth Factor I Is Not a Useful Marker of Prostate Cancer in Men with Elevated Levels of Prostate-Specific Antigen1

Patrik Finne, Anssi Auvinen, Hannu Koistinen, Wan-Ming Zhang, Liisa Määttänen, Sakari Rannikko, Teuvo Tammela, Markku Seppälä, Matti Hakama and Ulf-Håkan Stenman

Departments of Clinical Chemistry (P.F., W.-M.Z., U.-H.S.), Obstetrics and Gynecology (H.K., M.S.), and Urology (S.R.), Helsinki University Central Hospital, FIN-00029 Helsinki, Finland; STUK–Radiation and Nuclear Safety Authority (A.A.), FIN-00881 Helsinki, Finland; Finnish Cancer Registry (A.A., L.M., M.H.), FIN-00170 Helsinki, Finland; and School of Public Health, University of Tampere (M.H.), and Division of Urology, Tampere University Hospital (T.T.), FIN-33521 Tampere, Finland

Address all correspondence and requests for reprints to: Patrik Finne, M.D., Department of Clinical Chemistry, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 Helsinki, Finland. E-mail: patrik.finne{at}hus.fi


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
High serum levels of insulin-like growth factor I (IGF-I) and low levels of IGF-binding protein-3 (IGFBP-3) have been shown to correlate with increased prostate cancer risk. To evaluate this, IGF-I, IGFBP-3, and prostate-specific antigen (PSA) were measured in serum from 665 consecutive men (179 with prostate cancer), aged 55–67 yr, with elevated serum prostate-specific antigen (PSA; >=4 µg/L) in a screening trial. Men in the highest quartile of IGF-I levels had an odds ratio (OR) for prostate cancer of 0.50 [95% confidence interval (CI) 0.26–0.97] when adjusting for serum IGFBP-3. IGFBP-3 itself was not significantly associated with prostate cancer risk (OR, 1.24; 95% CI, 0.68–2.24). Prostate volume was larger in men without than in those with prostate cancer (P < 0.001), and after adjustment for prostate volume, the negative association between serum IGF-I and prostate cancer risk was no longer significant (OR, 0.57; 95% CI, 0.28–1.16). In screen-positive men with elevated serum PSA, serum IGF-I is not a useful diagnostic test for prostate cancer, but it may be associated with benign prostatic hyperplasia and enlargement.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PROSTATE CANCER is the most common malignancy in men in industrialized countries, excluding nonmelanoma skin cancer (1). Serum prostate-specific antigen (PSA) is a sensitive marker of prostate cancer, but its positive predictive value is low, as prostate cancer is detected in only a third of the men whose PSA level is elevated above 4 µg/L. Moderately elevated PSA values are usually due to benign prostatic hyperplasia (2). Although the cancer specificity of PSA can be improved by measurement of the two major forms of PSA, free PSA and the complex between PSA and {alpha}1-antichymotrypsin (3), further improvement is needed.

Insulin-like growth factors (IGF-I and IGF-II) are mitogenic peptides (4) that have been related to the pathogenesis of prostate cancer (5, 6, 7) and benign prostatic hyperplasia (8). In particular, the association between IGF-I and prostate cancer has received much attention. In serum, most of IGF-I is bound to the major IGF-binding protein, IGFBP-3 (9). The serum levels of IGF-I and IGFBP-3 are regulated by GH, nutritional status, age, pregnancy, and chronic disease (9). The affinity of IGFBP-3 for IGF-I is reduced by proteases that cleave the binding proteins (10), and this is thought to cause local growth stimulation by increased activity of free IGF-I. PSA is a serine protease that cleaves IGFBP-3; thus, it may modulate the activity of the IGFs (11).

In a nested case-control study based on a serum bank with 152 prostate cancer patients and 152 controls, a 4-fold risk of prostate cancer was found to be associated with the highest quartile of plasma IGF-I levels compared with the lowest one (5). Adjustment for IGFBP-3 strengthened the association. Two case-control studies of newly diagnosed patients have shown that the serum concentrations of IGF-I are higher among men with prostate cancer than in controls with or without benign prostatic hyperplasia (6, 7). These results suggest that serum IGF-I is a risk factor and a possible marker for prostate cancer. However, no significant differences have been found in other studies (12, 13, 14), and in a recent study of clinically diagnosed patients, IGF-I was not found to be a useful marker (15). However, the lack of correlation in these studies can possibly be related to the limited number of cases and controls.

We evaluated whether serum IGF-I and IGFBP-3 can supplement PSA in prostate cancer screening by using samples from 665 screen-positive men with a serum PSA level of 4 µg/L or more (16).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The subjects were identified from the Finnish prostate cancer screening trial in which 15,036 men, aged 55–67 yr, were randomized to the screening arm by 1997 (16). The participation rate was 68%, and informed consent was obtained in writing from the participants. Of the 910 men whose serum PSA concentrations were elevated (>=4.0 µg/L), 665 had undergone transrectal ultrasound guided sextant biopsies of the prostate by March 1998 and were included in this study. Of them, 179 were diagnosed with prostate cancer, 268 had normal histology, 174 had benign prostatic hyperplasia, and 44 had other nonmalignant diagnoses, such as prostatitis and prostatic intraepithelial neoplasia. Of the 179 patients with prostate cancer, WHO grading was available for 178, Gleason score for 154, and complete clinical staging (including metastatic status) for 163.

Serum samples

The serum samples were kept frozen at -80 C until tested. They were thawed once for analysis of total PSA and immediately refrozen. For this study, the samples were rethawed 2–18 months after sampling and were analyzed in random order and blinded with regard to case-control status.

Laboratory methods

Total serum IGF-I was measured by a sandwich-type immunoassay (Active IGF-I ELISA, DSL-10–5600, Diagnostics Systems Laboratories, Inc., Webster, TX). The assay uses acid-ethanol extraction to dissociate IGF-I from its binding proteins. The intraassay coefficient of variation (CV) was 8.0%, and the interassay CV was 8.6% at a level of 130 µg/L and 11.8% at a level of 280 µg/L.

Serum IGFBP-3 was measured by an immunofluorometric assay, using monoclonal antibodies (1B6/5C11) against recombinant IGFBP-3 (17). The intraassay CV was 3.6–6.2%, and the interassay CV was 4.9–11.0%. The assay detects only intact IGFBP-3 and shows no cross-reaction with the other human IGFBPs or IGFs. IGF-I and IGF-II do not interfere with the assay (17). Total PSA was determined by a dual label immunofluorometric assay (Prostatus PSA, EG&G-Wallac, Inc., Turku, Finland).

Prostate volume

Prostate volume was determined by transrectal ultrasound in 649 of the 665 men and was estimated according to the formula: ({Pi}/6) x (transverse diameter x antero-posterior diameter x cephalo-caudal diameter) (18).

Statistical analysis

The concentrations of total PSA in serum and prostate volume showed a log-normal distribution and were therefore logarithmically transformed. The concentrations of the other analytes were normally distributed. The Mann-Whitney U test was used to compare the distribution of age, IGF-I, IGFBP-3, total PSA, and prostate volume between prostate cancer cases and benign controls (all 486 subjects without prostate cancer). Correlations between serum analytes and prostate volume were assessed using partial correlation to adjust for age. IGF-I and IGFBP-3 values were divided into quartiles based on their distribution among the subjects with normal prostate histology. To evaluate the validity of IGF-I and IGFBP-3 as diagnostic tests in the PSA screen-positive men, receiver-operating characteristic (ROC) curves were drawn, and the area under the curve (AUC) was calculated according to the method of Hanley and McNeil (19). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by unconditional logistic regression (20) to evaluate prostate cancer risk for the second, third, and fourth quartiles of the variable compared to that for the first quartile. The binary response variable in the logistic regression model was the presence or absence of prostate cancer in biopsy. IGF-I and IGFBP-3 were also evaluated as continuous variables; ORs and CIs were calculated for a 2 SD increase in the variables. This corresponded to 160 µg/L for IGF-I and 2400 µg/L for IGFBP-3 when the SD was calculated for the subjects with normal prostate histology. ORs were adjusted for age, total PSA, and prostate volume as continuous variables in the logistic regression analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
After adjustment for age, a positive correlation between serum IGF-I and IGFBP-3 was found (r = 0.60; P < 0.001). IGF-I showed a weak positive correlation with prostate volume (r = 0.09; P = 0.021) and was unrelated to PSA. Both IGF-I and IGFBP-3 decreased slightly with age (r = -0.16; P < 0.001 and r = -0.20; P < 0.001, respectively). No significant difference in the age distribution was observed between cases and controls (Table 1Go). Prostate volume (28 vs. 38 mL; P < 0.001) was lower, and serum PSA (8.3 vs. 5.7 µg/L; P < 0.001) was higher among the cases than the controls. Serum levels of IGF-I were slightly, but not significantly, lower in the prostate cancer cases than in the controls (P = 0.09). IGFBP-3 did not differ between cases and controls.


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  		Table 1. Mean and SE for age, prostate volume, and serum markers

 
After adjustment for age and serum PSA, serum IGF-I showed an inverse association with prostate cancer risk (OR, 0.63; 95% CI, 0.41–0.96/160 µg/L increment of IGF-I), whereas serum IGFBP-3 did not (OR, 1.11; 95% CI, 0.76–1.61/2400 µg/L increment of IGFBP-3). When the effects of both IGF-I and IGFBP-3 were taken into account simultaneously, the associations with prostate cancer risk were stronger for both a low IGF-I (OR, 0.51; 95% CI, 0.30–0.86; Table 2Go) and a high IGFBP-3 (OR, 1.38; 95% CI, 0.88–2.17). When comparing the highest and the lowest quartiles, the highest quartile of IGF-I was associated with a lower prostate cancer risk (OR, 0.50; 95% CI, 0.26–0.97). The risk of prostate cancer was not significantly different between the highest and the lowest quartiles of IGFBP-3 (OR, 1.24; 95% CI, 0.68–2.24). After adjustment for prostate volume, the inverse association between serum IGF-I and prostate cancer risk was weaker (OR, 0.57; 95% CI, 0.28–1.16) and was no longer statistically significant (Table 2Go). The association between serum IGF-I and prostate cancer risk was not affected by WHO grade, Gleason score, or clinical stage.


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[in this window]
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  		Table 2. OR of prostate cancer in relation to continuous increase and quartiles of serum IGF-I concentration

 
The validity of IGF-I as a marker for prostate cancer was also evaluated by ROC analysis. The AUC was 0.55 for IGF-I and 0.50 for IGFBP-3. The AUC represents the probability that the IGF-I level would be lower and the IGFBP-3 level higher in a randomly selected cancer patient than those in a randomly selected control (Fig. 1Go). These results show that serum concentrations of IGF-I and IGFBP-3 do not distinguish between prostate cancer patients and controls with elevated PSA values.



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  		Figure 1. ROC curves showing the validity of IGF-I and IGFBP-3 as screening tests for the detection of prostate cancer in men with serum PSA levels of 4 µg/L or more.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We could not confirm the findings of a correlation between elevated serum IGF-I and prostate cancer risk (5, 6, 7). By contrast, we found an inverse correlation. This could at least partially be explained by differences in study design. Our study reflects the situation in a PSA-based screening, focusing on screen-positive men. Thus, both the cases and the controls had elevated PSA levels. Not unexpectedly, the controls had a larger prostate volume than the cases, and although the correlation was weak, serum IGF-I was associated with prostate volume. Interestingly, a strong association between high IGF-I levels, and benign prostatic hyperplasia and enlarged prostate volume was recently observed in acromegaly patients with elevated serum concentrations of GH and IGF-I, whereas successfully treated patients had normal prostate volume, and GH-deficient cases had reduced prostate volume (21). Another recent study has shown that IGF-I stimulates the proliferation of benign prostatic hyperplasia-derived stromal cells grown in a tissue culture (22). Taken together, these findings suggest that IGF-I is a risk factor for benign prostatic hyperplasia and prostatic enlargement.

The positive correlation between serum IGF-I and prostate cancer risk found in some earlier studies has been interpreted to indicate a causal relationship (5, 6, 7), but it has also been suggested that this association is caused by differences in prostate volume between cases and controls (8). Before the PSA era, prostate cancer was frequently detected because of symptoms of benign prostatic hyperplasia (23). Indeed, in the eighties, when two of the earlier studies were conducted (5, 7), there were centers in which more than 40% of the newly diagnosed prostate cancers were discovered when benign prostatic hyperplasia was treated by transurethral resection (24). Thus, it is possible that the prostate cancer patients identified on the basis of symptoms, on the average, had a larger prostate volume than the controls, but due to lack of data on prostate volume this explanation remains speculative (8). It should be noted that other studies have not shown any significant correlation between IGF-I and prostate cancer risk (12, 13, 14, 15). Interpretation of the causes of these discrepancies is not possible because of lack of data for PSA, prostate volume, or both. The present study, in which all of these parameters were determined for a large population, shows that elevated IGF-I carries no increased risk of prostate cancer in a PSA-based screening.

We also considered whether patient age and stage or grade of the disease could affect the results, but no effect was observed in the present study, and as far as we can judge, these factors have not affected the results of earlier studies either. The lack of an influence of stage and grade suggest that prostate cancer as such did not cause a reduction of serum IGF-I. Furthermore, the median serum PSA levels in our study (8.3 µg/L) and in that of Chan et al. (3–4 µg/L) (25) suggest that the average tumor volume was small (~2 and 1 mL, respectively) at the time of sampling (26). We furthermore determined sex hormone-binding globulin, testosterone, free testosterone, and free PSA (not shown), but adjustment for these did not affect the OR of IGF-I for prostate cancer.

In conclusion, our results demonstrate a negative association between IGF-I and prostate cancer risk in asymptomatic men with serum PSA values above 4 µg/L. However, the association is weak, and IGF-I is not a useful marker for prostate cancer screening. Our findings could be explained by a larger prostate volume in screen-positive men without prostate cancer. Together with recent data from acromegaly patients (21, 27), these results support the idea that a high serum IGF-I level is associated with benign prostatic hyperplasia and prostatic enlargement.


   Acknowledgments
 
We thank Ms. Anne Ahmanheimo and Ms. Anu Harju for expert technical assistance.


   Footnotes
 
1 This work was supported by the Cancer Society of Finland, the Academy of Finland, the Finska Läkaresällskapet, Helsinki University Central Hospital Research Funds, the Tampere University Hospital Research Fund, and the Foundation of K. Albin Johansson. Back

Received December 7, 1999.

Revised April 10, 2000.

Accepted April 13, 2000.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  11. Cohen P, Graves HC, Peehl DM, Kamarei M, Giudice LC, Rosenfeld RG. 1992 Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J Clin Endocrinol Metab. 75:1046–1053.[Abstract]
  12. Cohen P, Peehl DM, Stamey TA, Wilson KF, Clemmons DR, Rosenfeld RG. 1993 Elevated levels of insulin-like growth factor-binding protein-2 in the serum of prostate cancer patients. J Clin Endocrinol Metab. 76:1031–1035.[Abstract]
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S. M. Harman, E. J. Metter, M. R. Blackman, P. K. Landis, and H. B. Carter
Serum Levels of Insulin-Like Growth Factor I (IGF-I), IGF-II, IGF-Binding Protein-3, and Prostate-Specific Antigen as Predictors of Clinical Prostate Cancer
J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4258 - 4265.
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