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High Levels of Circulating Insulin-Like Growth Factor-I Increase Prostate Cancer Risk: A Prospective Study in a Population-Based Nonscreened Cohort

From the Department of Surgery and Perioperative Sciences, Urology and Andrology, Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden; Hormones and Cancer Group, International Agency for Research on Cancer, Lyon, France; and Department of Clinical Chemistry, University Hospital of Helsinki, Finland

Address reprint requests to Pär Stattin, MD, Department of Surgery and Perioperative sciences, Urology and Andrology, Umeå University Hospital, 901 85 Umeå, Sweden; e-mail: par.stattin{at}urologi.umu.se

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Insulin-like growth factor-I (IGF-I) stimulates proliferation and inhibits apoptosis in prostate cancer cells, and IGF-I has been associated with increased prostate cancer risk in some, but not all, epidemiologic studies.

SUBJECTS AND METHODS: We extended our previous case-control study nested in the Northern Sweden Health and Disease Cohort, a population-based cohort from a region where little prostate specific antigen (PSA) screening is done. Levels of IGF-I and IGF binding protein-3 (IGFBP-3) were measured in prediagnostic blood samples from a total of 281 men who were subsequently diagnosed with prostate cancer after recruitment (median, 5 years after blood collection) and from 560 matched controls.

RESULTS: Logistic regression analyses showed increases in prostate cancer risk with increasing plasma peptide levels, up to an odds ratio (OR) for top versus bottom quartile of IGF-I of 1.67 (95% CI, 1.02 to 2.71; P _trend = .05), which was attenuated after adjustment for IGFBP-3 to an OR of 1.47 (95% CI, 0.81 to 2.64; P _trend = .32). For men younger than 59 years at recruitment, OR for top versus bottom quartile of IGF-I was 4.12 (95% CI, 1.01 to 16.70; P _trend = .002), which was significantly stronger than for men older than 59 years (P _interaction = .006). For men with advanced cancer, OR for top versus bottom quartile of IGF-I was 2.87 (95% CI, 1.01 to 8.12; P _trend = .10).

CONCLUSION: Our data add further support for IGF-I as an etiologic factor in prostate cancer and indicate that circulating IGF-I levels measured at a comparatively young age may be most strongly associated with prostate cancer risk.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Insulin-like growth factor-I (IGF-I) has been consistently shown to be an important factor for cancer development in in vitro and in vivo studies.^1,2 Proliferation of prostate cancer cells is stimulated and apoptosis is inhibited by IGF-I signaling.³ Transgenic mice expressing human IGF-I in the basal epithelium of the prostate showed a 50% cumulative incidence of prostate cancer.⁴ Circulating IGF-I and IGF binding protein-3 (IGFBP-3), the major plasmatic binding protein of IGF-I, peak during adolescent growth and then gradually decline with age.⁵ Most circulating IGF-I and IGFBP-3 originates from the liver, and the key stimulus for production of these polypeptides in the liver and in many other tissues is growth hormone.⁶ Circulating and tissue levels of IGF-I are decreased in the energy-restricted state that is also cancer-protective.^3,7 In addition, minimal levels of dietary protein intake are needed to sustain normal IGF-I levels.⁸ Besides nutritional and other lifestyle factors,^9,10 genetic factors seem to be important codeterminants of IGF-I and IGFBP-3.¹¹

Approximately a dozen studies have related serum or plasma levels of IGF-I to prostate cancer risk among cases and controls, and some of these studies,^12–20 but not others,^21–26 have shown a direct association between IGF-I and cancer risk. Most of the studies were relatively small; only eight studies included more than 100 cases, and only five studies had a prospective design. The first three prospective studies reported a significant association between IGF-I and risk,^14,16,17 and a meta-analysis of these and other studies published until 2001 demonstrated a modest but significant increase in relative risk of 1.47 (95% CI, 1.23 to 1.77).²⁷ However, in an extension of the study in Physician's Health Study, which is largest study to date (530 cases), IGF-I showed no association with overall prostate cancer risk²⁴ and only in subgroup analysis of advanced disease was IGF-I associated with increased risk. Another recent prospective study did not show any association with overall prostate cancer risk either.²⁵ Thus observed associations between circulating levels of IGF-I and risk have been inconsistent. This inconsistency may have been the result of between-study differences in subject characteristics, such as age at recruitment, lag time between blood sampling and diagnosis, tumor characteristics, or biochemical analytic methods.

We previously described the results of a case-control study nested within the Northern Sweden Health and Disease Cohort, which includes 149 incident cases of prostate cancer and 298 matched control patients with prediagnostic plasma concentrations of IGF-I and IGFBP-3.¹⁷ In the present article, we describe the results of an extension of this study, in which we sought to estimate risk of prostate cancer more precisely by subgroups of case and tumor characteristics.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The Northern Sweden Health and Disease Cohort Study
Men are recruited to the Northern Sweden Health and Disease Cohort study through the Västerbotten Intervention Project (VIP) and the Northern Sweden part of the WHO study for Monitoring of Trends and Cardiovascular Disease Study (MONICA).^28,29 VIP is an ongoing population-based intervention study initiated in 1985 that aims to decrease mortality resulting from cardiovascular disease and cancer by advocating a healthy diet and lifestyle to the general public. VIP invites all persons residing in the county of Västerbotten, Sweden, total population 260,000, to participate in a health survey when they reach the even decades of 30, 40, 50, and 60 years. MONICA includes 2,704 men, recruited in 1986, 1990, and 1994, who are also a population-based sample from the counties of Västerbotten and Norrbotten. In both projects, patients were asked to complete a self-administered questionnaire that included questions about demographic, medical, and lifestyle characteristics. In addition, we recorded the subjects' height and weight and drew a 20 mL blood sample from each subject at study entry. In July 2001, a total of 37,776 men had been recruited to the VIP and MONICA cohorts. Blood samples from the majority of study patients were obtained in the morning, and fasting time before blood sampling was more than 8 hours in 66% subjects in this study, 4 to 8 hours in 31%, and less than 4 hours in 3%. All participants gave written consent for use of their blood samples in future research projects, and the study was approved by the research ethical committee of Umeå University Hospital.

Case Identification and Case Ascertainment
Incident cases of prostate cancer and deaths were identified through linkage between the cohort and registries for cancer incidence and all-cause mortality using a national individual identification number as identity link. In our first study, 149 incident cases of prostate cancer with available plasma samples were identified.¹⁷ The present analysis includes 132 additional cases identified up to July 2001. Data on tumor characteristics were obtained from the Primary Prostate Cancer Registry of Northern Sweden at the Oncological Center at Umeå University Hospital, which has been in operation since 1992. This registry provides data on tumor characteristics and primary treatment on more than 99% of all incident prostate cancer cases in the region.³⁰ Data from medical charts in hospitals that provided diagnostic work-up and care for the cases were extracted by a research nurse, verified by the treating physician, and entered to the registry. Data in the registry includes date of diagnosis, mode of diagnosis, tumor-node-metastasis system classification, tumor differentiation, serum level of prostate specific antigen (PSA), and primary treatment. For cases diagnosed before 1992, data were extracted from medical charts and directly entered onto the study file. No formal screening program has been or currently is in operation in the catchment area of the cohort. Since 2000, the cause for work-up leading to the diagnosis of prostate cancer is registered in the registry, and for cases diagnosed before that date, the cause for work-up was extracted from medical charts. Approximately 10% of cases were detected in health check-ups of asymptomatic men, indicating relatively little exposure for opportunistic PSA screening for early detection of prostate cancer.

Tumor stage was evaluated according to the classification of the International Union Against Cancer.³¹ The presence of lymph node metastases was evaluated by histologic examination of obturator lymph nodes obtained by surgery, and the presence of bone metastases was evaluated by a bone scan. Data on tumor differentiation were based on grade reported from the histopathologic or cytologic examination of the core biopsy/aspirate that led to the diagnosis of prostate cancer. Until January 1, 2000, pathologic reports were based on the WHO grading system; after that date, the Gleason score system was used in all but a few cases.³² The two classification systems were merged as follows: WHO G1 and Gleason score 2 to 5, highly differentiated; WHO G2 and Gleason score 6 to 7, intermediate; and WHO G3 and Gleason score 8 to 10, poorly differentiated.

Control Selection
For each prostate cancer case, two controls were selected randomly among all study subjects who were alive and free of any cancer history at the time of diagnosis of the index case; these control patients were matched with the index case according to age (± 6 months) and date (± 2 months) at recruitment. In two sets, only one control was available. Sampling was done without replacement. Nine of the controls in our previous study had become cases, these were kept in the original case-control triplets, and for five of these controls, an additional plasma sample was available for inclusion in a new case-control triplet in which the subject was treated as case in statistical analysis.

Biochemical Analyses
The assays used in the extension of the study analyzed in February 2002 were the same as used previously.¹⁷ IGF-I and IGFBP-3 were measured by immunoradiometric assays from Immunotech (Marseille, France). The protocol for the IGF-I assay included an acid-ethanol extraction step to release IGF-I from its binding proteins. The coefficients of variation (CVs) for the additional part of the study reported here were very similar to those in the original part. Globally, intra- and interbatch CVs for IGF-I measurements were 11.0% and 13.8%, respectively, for a concentration of 60 ng/mL, and 8.6% and 15.2%, respectively, for a concentration of 110 ng/mL. For IGFBP-3 measurements, intra- and interbatch CVs were 4.9% and 6.9%, respectively, for a concentration of 2,600 ng/mL, and 3.6% and 5.9%, respectively, for a concentration of 3,500 ng/mL. The detection limits for IGF-I and IGFBP-3 measurements were 3 ng/mL and 50 ng/mL, respectively. The baseline PSA levels were determined by time-resolved immunofluorometric assays (Prostatus PSA; Wallac, Turku, Finland). The analytic detection limit of the assay was 0.01 ng/mL. For quality control, all batches included three control samples containing known amounts of analyte. Case-control triplets were always analyzed together in the same batch (ie, on the same day and with the same immunoassay kit). The laboratory personnel were blinded to the case-control status of the samples. Serum levels of PSA in blood drawn shortly before the diagnostic biopsies had been determined by either the Tandem-R PSA assay (Hybritech Inc, San Diego, CA) or with the use of the IMx PSA assay (Abbot Laboratories, Abbott Park, IL), and values had been recorded in the Primary Prostate Cancer Registry. The coefficient of correlation between the two assays was 0.990 (IMx value = [1.22 x tandem value] – 2.80).³³

Statistical Analysis
Pair-wise t tests were used to test mean differences between anthropometric indices or hormone levels of the cases and the average values of matched controls. Odds ratios (ORs) for disease were calculated by conditional logistic regression for quartile levels of IGF-I and IGFBP-3. Quartile cutoff points were determined on variable distributions of cases and controls combined. CIs (95%) were computed using the SEs of the pertinent regression coefficients, assuming a normal probability distribution for the estimated coefficients. Likelihood ratio tests for linear trends in risk with increasing peptide concentrations were performed using original data as a continuous variable. Heterogeneity between subgroups was tested by ² tests using continuous values. Evidence for heterogeneity was regarded to exist if the difference between these models was significant. All statistical tests and corresponding P values were two-sided. The logistic regression analyses were performed using the PHREG procedure for proportional hazards regression of the Statistical Analysis System (SAS Institute, Cary, NC).³⁴

	RESULTS

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Baseline Characteristics of Cases and Controls
Baseline characteristics for cases and controls are listed in Table 1. Compared with the control subjects, cancer cases had statistically significantly higher mean plasma levels of IGF-I: 218 ng/mL (standard deviation [SD] = 78.1) versus 208 ng/mL (SD = 78.3; P = .04). Cancer cases also had higher mean plasma levels of IGFBP-3: 2,442 ng/mL (SD = 548) versus 2,360 ng/mL (SD = 555; P = .03). Spearman's correlation between IGF-I and IGFBP-3 levels was strong (r = 0.55, cases and controls combined) and similar for cases and controls separately.

There was virtually no difference in mean IGF-I levels between men younger and older than 59 years (210 ng/mL [SD = 81.3] v 211 ng/mL [SD = 76.4]; P = .9), whereas IGFBP-3 levels were significantly higher group of younger men (2,545 mg/mL [SD = 540] v 2,345 ng/mL [SD = 545]; P < .0001). Mean IGF-I levels were significantly higher for cases than for controls among men younger than 59 years of age but not in men older than 59 years (Table 1). In contrast, there was virtually no difference in IGFBP-3 levels between young cases and controls, whereas among older men, cases had slightly higher levels than controls. For controls, mean levels of IGF-I were somewhat higher for subjects that were part of our previous study (219 ng/mL [SD = 62]) than for the newly added subjects whose plasma samples were analyzed more recently (202 ng/mL [SD = 92]). A similar difference was observed for IGFBP-3 (2,536 ng/mL [SD = 554] v 2,221 ng/mL [SD = 504]). Because controls were on average slightly younger in the additional group (58.1 years) than in the original group (58.9 years), these differences cannot be accounted for by a difference in age but are more likely caused by changes in the performance of the immunoassays. Plasma levels of PSA at baseline were significantly higher among cases than among controls (P < .0001), and 86% of the case patients had a PSA level higher than 2 ng/mL, compared with 28% of the controls (Table 1).

Case Characteristics at the Time of Diagnosis
Lag-time between blood sampling and diagnosis was longer for cases younger than 59 years than for case patients older than 59 years (6.1 years [SD = 2.9] v 4.6 years [SD = 2.8]; P < .0001), reflecting the increase in prostate cancer incidence with increasing age. However, the proportion of cases detected through opportunistic screening was low (approximately 10%) and virtually the same for young as compared with older cases (Table 2). The majority of tumors were rather small and localized, but almost half of the cases had a serum PSA level greater than 10 ng/mL at the time of diagnosis, a level which we defined as an indicator of significant disease based on the fact that patients with prostate cancer with serum PSA greater than 10 ng/mL have significantly worse prognosis than patients with serum PSA less than 10 ng/mL.^35,36 The local stage of the tumors was mostly nonpalpable (48%) or localized (38%). A few cases had lymph node metastasis (4%), bone metastasis (10%), or poor tumor differentiation (11%; Table 2). Young cases tended to have somewhat less advanced tumors, and they had a lower median PSA level at baseline than older men (3.6 ng/mL [25th to 75th percentile, 2.1 to 5.6 ng/mL] v 5.0 ng/mL [25th to 75th percentile, 3.0 to 9.0 ng/mL]; P = .29).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
In this extension of our prospective cohort study, we found a statistically significant association between increasing plasma levels of IGF-I and prostate cancer risk, which was significantly stronger in younger men compared with older men. Our data thus add further support to the hypothesis that elevated IGF-I is an etiologic factor for prostate cancer. The association with cancer risk was strongest for IGF-I levels measured at a relatively young age.

Pituitary growth hormone secretion, plasma IGF-I levels, and the IGF-I/IGFBP-3 ratio all peak during adolescence and then gradually decline with age,⁵ and risk according to levels of IGF-I was significantly higher in younger compared with older men, with a four-fold increase in risk for the highest versus the lowest levels of IGF-I in men younger than 59 years. We speculate that prostate cancer risk is specifically increased in men who have elevated IGF-I levels at a young age and whose IGF-I levels subsequently show a stronger age-related decline than those in men with initially lower IGF-I levels and who also have lower cancer risk. Interestingly, bone density, which may be marker of cumulative exposure to IGF, androgens, and calcium, was recently shown to be positively associated with prostate cancer risk.³⁷ Possibly, the same age pattern may also be present in breast cancer, as one study reported a strong increase in risk for breast cancer for high levels of IGF-I in premenopausal women younger than 50 years, whereas no increase was found in older, postmenopausal women.³⁸

The prospective design of our study ensured identical handling of samples from cases and controls, which may be crucial given that the difference between cases and controls in mean levels of IGF-I was only 5% in the full study group. Another strength of our study is the precise and almost complete description of tumor characteristics from the Primary Prostate Cancer Registry of Northern Sweden, including concentrations of serum PSA. This allowed us to perform analyses of specific subgroups. Finally, only 10% of cases were detected by screening with PSA testing, and almost half of the tumors were significant as estimated by PSA levels (> 10 ng/mL) at the time of diagnosis,^35,36 in contrast to some other populations (eg, in the United States), where the widespread use of PSA screening has resulted in a drastic increase in the number of small, indolent tumors.^39,40 We speculate that this difference in case mix may at least partly explain why we found a significant association between IGF-I and prostate cancer risk, whereas no such association was found overall in an extension of the Physician's Health Study,²⁴ a United States cohort of male physicians where PSA testing is likely to have been highly prevalent during the last decade.

In that extension, Chan et al²⁴ reported a relative risk of approximately 5.0 for advanced cancer between top and bottom quartiles of IGF-I, and we also found a stronger relative risk for advanced compared with localized disease. The stronger association for advanced cancer suggests that IGF-I stimulation may be especially important in the late growth phase of tumor development. We do not think that the stronger association with advanced cancer reflects production of IGF-I by the tumor, because no increase in the validity for IGF-I in prediction of prostate cancer was found as the time between blood sampling and diagnosis became shorter. In support of this idea, a follow-up study showed that men who underwent prostatectomy and subsequently experienced relapse did not have higher serum levels of IGF-I at the time of relapse than men who did not experience relapse.⁴¹ In contrast, a recent study including longitudinally collected samples reported that IGF-I levels were higher in samples taken close to the time of diagnosis than in those drawn at baseline.²⁵ If indeed the role of IGF-I is most important in the early development of tumors that are more aggressive at the time of diagnosis, this would reconcile our findings (ie, that risk is significantly higher in young men with a long lag time) with those of Chan et al (ie, that risk is more strongly associated with IGF-I in men with advanced tumors and in cases with long lag time). We suggest that men with tumors diagnosed in an advanced stage may, already in an early phase of development, have higher IGF-I levels than men with more indolent tumors, which is in line with findings from studies on dietary and genetic risk factors, which often have also shown strongest associations with advanced disease.^42,43 In summary, the relationship between etiologic factors such as IGF-I and cancer risk is likely to be best demonstrated in prospective cohort studies in which blood has been sampled from study subjects at a relatively young age and which contain a large proportion of cases who have significant tumors at the time of diagnosis.

Plasma levels of IGFBP-3 were only weakly and nonsignificantly associated with risk in our study, as it has consistently been in our studies where IGFBP-3 was measured using the immunoradiometric assay from Diagnostic Systems Laboratories (Webster, TX). Several studies that used an enzyme-linked immunosorbent assay from the same company showed either no relationship or a mildly inverse relationship between IGFBP-3 and cancer risk.^14,38,44 We previously speculated that such inconsistencies in the relationship between IGFBP-3 and cancer risk may reflect differences in assay specificity.⁴⁵ IGFBP-3 exists in a variety of phosphorylated and glycosylated forms and undergoes proteolytic cleavage by specific proteases. Patients who are at increased cancer risk might have more elevated hepatic synthesis and blood levels of IGFBP-3, possibly as a reflection of altered circulating growth hormone, but lower levels of intact (uncleaved) forms of IGFBP-3, possibly due to higher proteolysis. Thus it is possible that the Diagnostic Systems Laboratories enzyme-linked immunosorbent assay method measures mostly specific intact forms of IGFBP-3, whereas other assays (eg, Diagnostic Systems Laboratories immunoradiometric assay) might detect more or different forms combined.

In conclusion, in this population-based cohort of patients with little exposure to PSA screening, we found circulating levels IGF-I to be significantly associated with risk of prostate cancer, particularly so for IGF-I measurements made at a comparatively young age and for advanced disease.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Pär Stattin, GlaxoSmithKline.

	Acknowledgment

 
We thank Åsa Ågren, data manager of the Medical Biobank of Umeå University Hospital; Charlotte Ingri, who extracted clinical data from patient records for the Primary Prostate Registry; and Björn Tavelin, who performed linkage and prepared the study file.

	NOTES

 
Supported by the Swedish Cancer Society (grant 01 0614) and Lions Cancer Foundation, Umeå, Sweden.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted October 14, 2003; accepted May 3, 2004.

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