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July 20, 2015

Difference in association of obesity with prostate cancer risk between US African-American and non-Hispanic white men in SELECT. Wendy E. Barrington , Jeannette M . Schenk, Ruth Etzioni, Kathryn B. Arnold, Marian L. Neuhouser, Ian M. Thompson Jr , M. Scott Lucia, Alan R. Kristal.

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July 20, 2015

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  1. Difference in association of obesity with prostate cancer risk between US African-American and non-Hispanic white men in SELECT Wendy E. Barrington, Jeannette M. Schenk, Ruth Etzioni, Kathryn B. Arnold, Marian L. Neuhouser, Ian M. Thompson Jr, M. Scott Lucia, Alan R. Kristal July 20, 2015

  2. Epidemiology of prostate cancer • SEER 9 Incidence 1975-2011 & U.S. Mortality 1975-2010, All Races, Males. Rates are Age-Adjusted. SEER Cancer Statistics Factsheets: Prostate Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/prost.html Accessed: 6/9/14. Most commonly diagnosed non-skin cancer 2nd leading cause of death among U.S. men Estimated new cases in 2014: 233,000

  3. Disparities in prostate cancer risk • SEER 18 2007-2011.Rates are Age-Adjusted. SEER Cancer Statistics Factsheets: Prostate Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/prost.html. Accessed: 6/9/14.

  4. Association of race with risk of clinically advanced prostate cancer (6 SEER sites) • Hoffman RM, Gilliland FD, Eley JW, et al. Racial and ethnic differences in advanced-stage prostate cancer: the Prostate Cancer Outcomes Study. J Natl Cancer Inst. 2001;93(5):388-395.

  5. Mechanisms need further study Proportion explained varies substantially across studies (17%-75%) • Social factors • SES • Access to healthcare • Lifestyle behaviors • Biological differences • More aggressive tumor types • Earlier age at diagnosis

  6. Racial differences in prostate cancer risk factors • No evidence1: • Alcohol intake • Tobacco use • Family history of prostate cancer • Inconsistent findings: • Physical activity • Diet • Obesity: findings not stratified by grade • Emerging2: • Molecular mechanisms (e.g. androgen receptor status) • Genetic polymorphisms • Epigenetic processes

  7. Obesity may be salient mediator of racial disparities • Is associated with genetic and environmental factors • Is more prevalent among African Americans • Affects biological processes associated with cancer initiation and progression • May affect sensitivity of prostate-specific antigen (PSA) screening

  8. Obesity and prostate cancer risk • Whites3-4 • Reduced risk for low-grade (Gleason <7) • Increased risk for high-grade (Gleason 7+) • Blacks5-6 • Increased risk for both low- and high-grade • Studies among African-Caribbean men • Confirmation of findings in U.S. black men needed

  9. Objective Obesity Obesity Race Race Prostate Cancer Prostate Cancer Moderation Mediation To test whether association between obesity and risk of grade-specific prostate cancer varies by race. To evaluate the mediating role of obesity in racial disparities in prostate cancer risk using a causal mediation framework (in progress)

  10. SELenium and vitamin E Cancer prevention Trial (SELECT) SELenium, vitamin E, and Calcium Trial (SELECT) • Randomized, placebo-controlled trial • 4 treatment groups (S+E; E+P; S+P; P+P) • 427 sites across U.S., Canada, Puerto Rico • Eligibility: • 50+ years (blacks only) • 55+ years (all other men) • No history of prostate cancer • PSA <= 4 nm/ml and normal DRE • Total randomized: 35,533 • July 2001- May 2004 • Trial discontinued October 2008

  11. SELenium and vitamin E Cancer prevention Trial (SELECT) • Exclusions: • Race other than black or white (2641) • Prior prostate cancer (9) • Error in randomization (14) • Registration at alternate site (619) • Only study visit was at registration (10) • Missing data: education, smoking status, BMI, family history (476) • BMI<18 and BMI>50 (67) • Total sample: 31,697 • Screened subsample: 26,071 • 3,398 AA • 22,673 NHW

  12. Prostate cancer outcome • Most detected by PSA and/or DRE • Most reviewed centrally for pathology and grading using Gleason system(91.4%) • Low-grade tumors: Gleason 2-6 • 1,046 of 1,723 • High-grade tumors: Gleason 7-10 • 529 of 1,723 • Ungraded: • 148/1,723

  13. Statistical analysis • Cox proportional hazards • Covariates: age, education, diabetes, family history, smoking status, treatment arm • Sensitivity analyses: • Random assignment of grade to ungraded cases • Competing risks • Race-specific effects of diabetes on prostate cancer risk • Censoring at date of study protocol noncompliance • Using all men regardless of screening status • Tests for multiplicative interaction between race and obesity • Joint effects models to facilitate health disparities interpretation

  14. Demographic characteristics

  15. Clinical characteristics

  16. Black race and prostate cancer (SELECT)Total cancer Risk of African-American vs. White (non-Hispanic) 2.20 2.00 BMI 1.80 1.60 1.40 1.20 1.00 P=0.03 0.80

  17. Black race and prostate cancer (SELECT)Cases with known grade only Risk of African-American vs. White (non-Hispanic) Grade 7-10 Grade 2-6 Total 2.20 2.00 BMI 1.80 1.60 1.40 1.20 1.00 0.80 P=0.005 P=0.005 P=0.41

  18. Obesity and prostate cancer (SELECT)Total cancer White (non-Hispanic) African-American 2.00 BMI 1.80 1.60 1.40 1.20 1.00 0.80 P=0.03 P=0.63

  19. Obesity and prostate cancer (SELECT)Cases with known grade only White (non-Hispanic) African-American Total Grade 7-10 Grade 2-6 Grade 2-6 Grade 7-10 Total 2.60 2.40 2.20 BMI 2.00 1.80 1.60 1.40 1.20 1.00 0.80 P=0.61 P=0.02 P=0.004 P=0.02 P=0.01 P=0.05

  20. Attributable risks (per 100,000) of obesity in SELECT

  21. Attributable risks (per 100,000) of obesity in SELECT

  22. Sensitivity analyses • Random assignment of grade: • Excess risk for AA vs. NHW men with BMI<25 kg/m2 increased • Change larger for low-grade cancers • Results did not differ when: • Censoring men at date of non-compliance • Allowing for race-specific effect of diabetes • Modeling death as competing risk • Including all AA and NHW men

  23. Summary of findings • Obesity acts as effect modifier in relationship between race and prostate cancer • Especially low-grade • Among AA men: BMI >=30 vs. <25 kg/m2 • Total PCa: • AR: 414.2 cases /100,000 person years • AR%: 28.6% • Effect of obesity on risk of low-grade prostate cancer differs by race • Obesity reduces risk for NHW men • Obesity increases risk for AA men • Effect of obesity on risk of high-grade not significantly different for AA and NHW men

  24. Findings consistent with published findings 58% increased risk for PCa among AA vs. NHW men Lower risk of low-grade PCa among NHW men associated with obesity Higher risk of high-grade PCa among NHW and men of African ancestry associated with obesity

  25. Possible mechanisms to explain findings • Biological effects of obesity may be stronger in AA vs. NHW men • Distribution of adipose tissue • Systemic inflammation • Insulin secretion • Interaction with genetic risk alleles • Detection differences • PSA higher in AA men • Associations of obesity with PSA

  26. Strengths and limitations • Strengths: • Large sample size • Standardized assessment of height and weight • Consideration of detection bias due to screening • Limitations: • Small number of cases by grade and BMI category • Possible remaining detection bias if differential biopsy follow-up

  27. Implications and future directions • Reinforces the importance of obesity prevention among AA men • Further research needed: • Differential effect of inflammation and insulin secretion in AA vs. NHW men • Interaction of obesity with candidate genetic markers • Effect of obesity on prostate cancer death in AA vs. NHW men

  28. References MordukhovichI, Reiter PL, Backes DM, et al. A review of African American-white differences in risk factors for cancer: prostate cancer. Cancer Causes Control. Mar 2011;22(3):341-357. Powell IJ, Bollig-Fischer A. Minireview: the molecular and genomic basis for prostate cancer health disparities. MolEndocrinol. Jun 2013;27(6):879-891. DiscacciatiA, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer--a dose-response meta-analysis of prospective studies. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. Jul 2012;23(7):1665-1671. Gong Z, Neuhouser ML, Goodman PJ, et al. Obesity, diabetes, and risk of prostate cancer: results from the prostate cancer prevention trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Oct 2006;15(10):1977-1983. Jackson MD, Walker SP, Simpson CM, et al. Body size and risk of prostate cancer in Jamaican men. Cancer Causes Control. Jun 2010;21(6):909-917. NemesureB, Wu SY, Hennis A, Leske MC, Prostate Cancer in a Black Population Study G. Central adiposity and Prostate Cancer in a Black Population. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. May 2012;21(5):851-858.

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