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Insulin-like Growth Factors, Their Binding Proteins, and Prostate Cancer Risk: Analysis of Individual Patient Data from 12 Prospective Studies

Andrew W. Roddam, DPhil; Naomi E. Allen, DPhil; Paul Appleby, MSc; Timothy J. Key, DPhil; Luigi Ferrucci, MD; H. Ballentine Carter, MD; E. Jeffrey Metter, MD; Chu Chen, PhD; Noel S. Weiss, MD; Annette Fitzpatrick, PhD; Ann W. Hsing, PhD; James V. Lacey Jr, PhD; Kathy Helzlsouer, MD; Sabina Rinaldi, PhD; Elio Riboli, MD; Rudolf Kaaks, PhD; Joop A.M.J.L. Janssen, MD; Mark F. Wildhagen, PhD; Fritz H. Schröder, MD; Elizabeth A. Platz, ScD; Michael Pollak, MD; Edward Giovannucci, MD; Catherine Schaefer, PhD; Charles P. Quesenberry Jr., PhD; Joseph H. Vogelman, DEE; Gianluca Severi, PhD; Dallas R. English, PhD; Graham G. Giles, PhD; Pär Stattin, MD; Göran Hallmans, MD; Mattias Johansson, PhD; June M. Chan, ScD; Peter Gann, MD; Steven E. Oliver, PhD; Jeff M. Holly, PhD; Jenny Donovan, PhD; François Meyer, MD; Isabelle Bairati, MD; and Galan, MD
[+] Article and Author Information

From University of Oxford, Oxford, United Kingdom; National Institute on Aging, Harbor Hospital, Johns Hopkins University, and Mercy Medical Center, Baltimore, Maryland; Fred Hutchinson Cancer Research Center, Health Sciences, and Collaborative Health Studies Coordinating Center, Seattle, Washington; National Cancer Institute, Bethesda, Maryland; International Agency for Research on Cancer, Lyon Cedex, France; German National Cancer Center, Heidelberg, Germany; Imperial College London, London, United Kingdom; Erasmus MC, Rotterdam, the Netherlands; Cancer Prevention Research Unit, Jewish General Hospital–Lady Davis Institute, Montreal, Canada; Centre de Recherche en Cancérologie, Université Laval, Québec, Canada; Harvard School of Public Health, Boston, Massachusetts; Kaiser Division of Research, Oakland, California; Orentreich Foundation for the Advancement of Science, Cold Spring, New York; Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia; Umeå University, Umeå, Sweden; University of California, San Francisco, San Francisco, California; Northwestern University, Feinberg School of Medicine, Chicago, Illinois; University of York, The Hull York Medical School, Heslington, York, United Kingdom; University of Bristol, Paul O'Gorman Lifeline Centre, Southmead Hospital, Bristol, United Kingdom; and UMR SMBH Université, Bobigny Cedex, France.


Grant Support: The central pooling and analysis of these data were supported by Cancer Research UK, London, United Kingdom.

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement:Study protocol and statistical code: Available from Dr. Roddam (e-mail, mailto:andrew.roddam@ceu.ox.ac.uk). Data set: Not available.

Requests for Single Reprints: Andrew W. Roddam, DPhil, Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom; e-mail, andrew.roddam@ceu.ox.ac.uk.

Current Author Addresses: Drs. Roddam, Allen, and Key and Mr. Appleby: Cancer Epidemiology Unit, University of Oxford, Richard Doll Building, Roosevelt Drive, Oxford OX3 7LF, United Kingdom.

Drs. Ferrucci and Metter: Clinical Research Branch, National Institute on Aging, Harbor Hospital, 3001 Hanover Street, Baltimore, MD 21225.

Dr. Carter: Johns Hopkins Hospital, Urology–Marburg 145, 600 North Wolfe Street, Baltimore, MD 21287.

Dr. Chen: Program in Epidemiology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024.

Dr. Weiss: Box 357236, Department of Epidemiology, 1959 NE Pacific Street, Health Sciences F-262D, Seattle, WA 98195.

Dr. Fitzpatrick: Box 354922, Collaborative Health Studies Coordinating Center, 6200 NE 74th Street, Suite 310, Building 29, Seattle, WA 98155.

Dr. Hsing: Division of Cancer Epidemiology and Genetics, Executive Plaza South, Room 5024, National Cancer Institute, 6120 Executive Boulevard, MSC 7242, Bethesda, MD 20892-7335.

Dr. Lacey: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, MSC 7234, Bethesda, MD 20852-7234.

Dr. Helzlsouer: Prevention and Research Center, Mercy Medical Center, 227 Saint Paul Place, Baltimore, MD 21202.

Dr. Rinaldi: International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.

Dr. Riboli: Division of Epidemiology, Public Health and Primary Care, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom.

Dr. Kaaks: Division of Cancer Epidemiology, German National Cancer Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

Dr. Janssen: Erasmus MC, Department of Internal Medicine, 's Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands.

Dr. Wildhagen: Erasmus MC, Departments of Urology and Obstetrics & Gynaecology, 's Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands.

Dr. Schröder: Department of Urology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.

Dr. Platz: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E6132, Baltimore, MD 21205.

Dr. Pollak: Cancer Prevention Research Unit, Jewish General Hospital–Lady Davis Institute, Pollak Research Lab–E 423, 3755 Côte Ste Catherine Road, Montreal, Quebec H3T 1E2, Canada.

Dr. Giovannucci: Department of Nutrition and Epidemiology, Harvard School of Public Health, 655 Huntington Avenue, Building II Room 319, Boston, MA 02115.

Drs. Schaefer and Quesenberry: Kaiser Division of Research, 2000 Broadway, Oakland CA, 94612.

Dr. Vogelman: Orentreich Foundation for the Advancement of Science, Cold Spring, NY 10516.

Drs. Severi, English, and Giles: Cancer Epidemiology Centre, The Cancer Council Victoria, 1 Rathdowne Street, Carlton, Victoria 3053, Australia.

Drs. Stattin and Johansson: Department of Surgical and Perioperative Sciences Urology and Andrology, Umeå University, 901 85 Umeå, Sweden.

Dr. Hallmans: Department of Clinical Medicine and Public Health, Umeå University, 901 85 Umeå, Sweden.

Dr. Chan: Epidemiology & Biostatistics, and Urology, University of California, San Francisco, Box 1695, San Francisco, CA 94143-1695.

Dr. Gann: Northwestern University, Feinberg School of Medicine, Department of Preventive Medicine, 680 North Lake Shore Drive, Suite 1102, Chicago, IL 60611.

Dr. Oliver: Department of Health Sciences, University of York, The Hull York Medical School, Seebohm Rowntree Building, Heslington, York YO10 5DD, United Kingdom.

Dr. Holly: Department of Clinical Science at North Bristol, University of Bristol, Paul O'Gorman Lifeline Centre, Southmead Hospital, Bristol BS10 5NB, United Kingdom.

Dr. Donovan: Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Clifton, Bristol BS8 2PR, United Kingdom.

Drs. Meyer and Bairati: Centre de Recherche en Cancérologie, Université Laval, 11 côte du Palais, Québec G1R 2J6, Canada.

Dr. Galan: UMR U557 Inserm, U1125 Inra, Cnam, Paris 13, SMBH— Université Paris 13, 74 rue Marcel Cachin, 93017 Bobigny Cedex, France.

Author Contributions: Conception and design: A.W. Roddam, N.E. Allen, T.J. Key, C. Chen.

Analysis and interpretation of the data: A.W. Roddam, P. Appleby, T.J. Key, C. Chen, M. Pollak.

Drafting of the article: A.W. Roddam, N.E. Allen, P. Appleby.

Critical revision of the article for important intellectual content: N.E. Allen, T.J. Key, C. Chen, N.S. Weiss, S. Rinaldi, R. Kaaks, J.A.M.J.L. Janssen, M.F. Wildhagen, E.A. Platz, E. Giovannucci, C. Schaefer, C.P. Quesenberry, J.H. Vogelman, G. Severi, D.R. English, G.G. Giles, P. Stattin, M. Johansson, J.M. Chan, P. Gann, S.E. Oliver, J.M. Holly, F. Meyer, I. Bairati.

Final approval of the article: A.W. Roddam, N.E. Allen, P. Appleby, T.J. Key, H.B. Carter, C. Chen, N.S. Weiss, A. Fitzpatrick, S. Rinaldi, R. Kaaks, J.A.M.J.L. Janssen, M.F. Wildhagen, E.A. Platz, M. Pollak, E. Giovannucci, C. Schaefer, C.P. Quesenberry, J.H. Vogelman, G. Severi, D.R. English, G.G. Giles, P. Stattin, M. Johansson, J.M. Chan, P. Gann, S.E. Oliver, J.M. Holly, J. Donovan, F. Meyer, I. Bairati.

Provision of study materials or patients: N.E. Allen, T.J. Key, C. Chen, N.S. Weiss, A. Fitzpatrick, S. Rinaldi, R. Kaaks, J.A.M.J.L. Janssen, M.F. Wildhagen, E.A. Platz, E. Giovannucci, C. Schaefer, C.P. Quesenberry, J.H. Vogelman, G. Severi, D.R. English, G.G. Giles, P. Stattin, M. Johansson, J.M. Chan, P. Gann, S.E. Oliver, J.M. Holly, J. Donovan, F. Meyer, I. Bairati.

Statistical expertise: A.W. Roddam, N.E. Allen, P. Appleby, D.R. English.

Obtaining of funding: A.W. Roddam, N.E. Allen, T.J. Key, C. Chen, N.S. Weiss, S. Rinaldi, R. Kaaks, J.A.M.J.L. Janssen, E.A. Platz, E. Giovannucci, C. Schaefer, C.P. Quesenberry, J.H. Vogelman, G. Severi, D.R. English, G.G. Giles, P. Stattin, M. Johansson, J.M. Chan, P. Gann, S.E. Oliver, J.M. Holly, J. Donovan, F. Meyer, I. Bairati.

Administrative, technical, or logistic support: A. Fitzpatrick, G. Severi.

Collection and assembly of data: A.W. Roddam, P. Appleby, H.B. Carter, C. Chen, N.S. Weiss, S. Rinaldi, R. Kaaks, J.A.M.J.L. Janssen, M.F. Wildhagen, E.A. Platz, E. Giovannucci, C. Schaefer, C.P. Quesenberry, J.H. Vogelman, G.G. Giles, P. Stattin, M. Johansson, J.M. Chan, P. Gann, S.E. Oliver, J.M. Holly, F. Meyer, I. Bairati.


Ann Intern Med. 2008;149(7):461-471. doi:10.7326/0003-4819-149-7-200810070-00006
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Table 1 shows the characteristics of the studies. The 12 prospective studies included approximately 3700 case patients with prostate cancer and 5200 control participants. Insulin-like growth factor I and IGFBP-III measurements were available for all and 3600 case patients, respectively. However, IGF-II and IGFBP-II measurements were available for only 379 and 419 case patients, respectively (Table 2). Mean age at blood collection was 61.5 years (range, 55 to 73 years). Data on race were available for most studies; however, we did not explore associations by race because more than 95% of participants were white. The median concentration of IGF-I was higher in case patients than in control participants in 9 of 12 studies; the picture is less clear for IGFBP-III, and 5 of 11 studies showed lower concentrations in case patients than in control participants (Table 2). Insulin-like growth factor II and IGFBP-II concentrations were similar between case patients and control participants. On average, case patients received a diagnosis 5 years after their blood was drawn, were age 67 years at diagnosis, and received the diagnosis after 1995 (Table 3). When data were available, most case patients had localized disease (range across studies, 70% to 80%) and most were low-grade lesions (range across studies, 60% to 80%).

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Figures

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Figure 1.
Association of prostate cancer risk with increasing quintiles of insulin-like growth factors (IGFs) and their main binding protein concentrations.

IGFBP = insulin-like growth factor binding protein.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI.

† Chi-square statistic for linear trend, calculated by replacing the categorical variables with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1.

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Figure 2.
Association of prostate cancer risk with insulin-like growth factor I concentration, by study.

For expansion of study names, see Table 1.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The OR is the estimate of the linear trend for insulin-like growth factor I obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all-studies OR.

† Heterogeneity between studies was assessed by using the chi-square statistic, which tested whether the study-specific results statistically significantly differed from the overall result. The P value for statistical significance of the chi-square statistic is 2-sided. Heterogeneity was also quantified by using the H and I2 statistics.

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Appendix Figure 1.
Association of prostate cancer risk with insulin-like growth factor II concentration, by study.

For expansion of study names, see Table 1.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The OR is the estimate of the linear trend for insulin-like growth factor II obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all-studies OR.

† Heterogeneity among studies was assessed by using a chi-square statistic that tested whether the study-specific results statistically significantly differed from the overall result. The P value for statistical significance of the chi-square statistic is 2-sided. Heterogeneity was also quantified by using the H and I2 statistics.

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Appendix Figure 2.
Association of prostate cancer risk with insulin-like growth factor binding protein II concentration, by study.

For expansion of study names, see Table 1.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The OR is the estimate of the linear trend for insulin-like growth factor binding protein II obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all-studies OR.

† Heterogeneity among studies was assessed by using a chi-square statistic that tested whether the study-specific results statistically significantly differed from the overall result. The P value for statistical significance of the chi-square statistic is 2-sided. Heterogeneity was also quantified by using the H and I2 statistics.

Grahic Jump Location
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Figure 3.
Association of prostate cancer risk with insulin-like growth factor binding protein III concentration, by study.

For expansion of study names, see Table 1.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The OR is the estimate of the linear trend for insulin-like growth factor binding protein III obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all-studies OR.

† Heterogeneity between studies was assessed by using the chi-square statistic, which tested whether the study-specific results statistically significantly differed from the overall result. The P value for statistical significance of the chi-square statistic is 2-sided. Heterogeneity was also quantified by using the H and I2 statistics.

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Figure 4.
Association of prostate cancer risk with insulin-like growth factor I concentration, by tumor and participant characteristics.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The OR is the estimate of the linear trend for insulin-like growth factor I obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all-studies OR.

P value from a chi-square test for heterogeneity to assess whether the OR estimates for each characteristic differ from each other.

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Appendix Figure 3.
Association of prostate cancer risk with insulin-like growth factor II concentration, by tumor and participant characteristics.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment).The OR is the estimate of the linear trend for insulin-like growth factor II obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all-studies OR.

P value from a chi-square test for heterogeneity to assess whether the OR estimates for each characteristic differed from each other.

Grahic Jump Location
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Appendix Figure 4.
Association of prostate cancer risk with insulin-like growth factor binding protein II concentration, by tumor and participant characteristics.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The OR is the estimate of the linear trend for insulin-like growth factor binding protein II obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all-studies OR.

P value from a chi-square test for heterogeneity to assess whether the OR estimates for each characteristic differed from each other.

Grahic Jump Location
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Appendix Figure 5.
Association of prostate cancer risk with insulin-like growth factor binding protein III concentration, by tumor and participant characteristics.

* All odds ratios (ORs) are unadjusted except for factors controlled for by stratification (study, age, and year of recruitment). The OR is the estimate of the linear trend for insulin-like growth factor binding protein III obtained by replacing the categorical variable with a variable that was scored as 0, 0.25, 0.5, 0.75, and 1. The position of each square indicates the magnitude of the OR, and the area of the square is proportional to the amount of statistical information available (inverse of the variance of the logarithm of the OR). The horizontal line indicates the 95% CI. The dashed line represents the all- studies OR.

P value from a chi-square test for heterogeneity to assess whether the OR estimates for each characteristic differed from each other.

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