difference in association of obesity with prostate cancer risk between us african- american and...

Difference in association of obesity with prostate cancer risk between US African-American and non-Hispanic white men in SELECT

July 20, 2015

Wendy E. Barrington, Jeannette M. Schenk, Ruth Etzioni, Kathryn B. Arnold, Marian L. Neuhouser, Ian M. Thompson Jr, M. Scott Lucia, Alan R. Kristal

Click to edit Master title styleEpidemiology of prostate cancer

Most commonly diagnosed non-skin cancer 2nd leading cause of death among U.S. men Estimated new cases in 2014: 233,000

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.

http://seer.cancer.gov/statfacts/html/prost.html

Click to edit Master title style

All Races

White

Black

Asian/Pacific Islander

American Indian/Alaska Native

Hispanic

0 50 100 150 200 250

# new cases per 100,000 persons

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.

Disparities in prostate cancer risk

http://seer.cancer.gov/statfacts/html/prost.html


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.

Association of race with risk of clinically advanced prostate cancer (6 SEER sites)

Click to edit Master title styleMechanisms need further study

Social factors– SES– Access to healthcare– Lifestyle behaviors

Biological differences– More aggressive tumor types– Earlier age at diagnosis

Proportion explained varies substantially across studies (17%-75%)


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

Racial differences in prostate cancer risk factors

Click to edit Master title styleObesity 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

Click to edit Master title styleObesity 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

Click to edit Master title styleObjective

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)

RaceProstateCancer

Obesity

RaceProstateCancer

Obesity

Moderation Mediation

Click to edit Master title styleSELenium, 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

SELenium and vitamin E Cancer prevention Trial (SELECT)

Click to edit Master title styleSELenium 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

Click to edit Master title styleProstate 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

Click to edit Master title styleStatistical 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

Click to edit Master title styleDemographic characteristics African-

AmericansNon-Hispanic

whitesP

valuea

Total No. 3,398 22,673 Age (y), mean ±SD 59.2 ±7.0 63.4 ±6.3 <0.000

1Education ,% <0.000

1≤High school 31.1 19.1 Some college 35.7 25.5 College graduate 19.3 29.2 Post-graduate 13.9 26.2

Diabetes, % 17.4 7.8 <0.0001

Current smoker, % 18.0 5.5 <0.0001

Body Mass Index (kg/m2), % <0.0001

18.0 to <25.0 18.8 20.1 25.0 to <27.5 22.0 27.1 27.5 to <30.0 20.3 22.7 30.0 to <35.0 26.4 22.5 35.0 to 50.0 12.5 7.6

Family history of prostate cancer, %

18.4 19.9 0.04

Trial arm, % 0.41Selenium+Vitamin E 24.1 25.3 Selenium+Placebo 25.2 24.9 Vitamin E+Placebo 24.5 24.6 Placebo+Placebo 26.2 25.2

aP values by t-test for continuous variables; P values by Chi-square test for categorical variables

Click to edit Master title styleClinical characteristicsAfrican-Americans Non-Hispanic

whitesP valuea

n CrudeRate

AdjRateb

n Crude Rate

Total prostate cancer 270 1565.1 1939.8 1453 1183.4 <0.0001

Clinical stage at diagnosis

Stage 0-1 207 1199.9 1505.9 1018 829.1 0.0002Stage 2-3 56 324.6 386.2 421 342.9 0.38Unknown 7 40.6 47.8 14 11.4 0.07

Gleason score at diagnosis

2-6 148 857.9 1038.3 898 731.4 <0.0001

7-10 88 510.1 657.8 441 359.2 <0.0001

Unknown 34 197.1 243.8 114 92.9 <0.0001

aP values by t-test for continuous variables; P values by Chi-square test for categorical variablesbRates per 100,000 person-years directly standardized by 5-year increments using non-Hispanic white men in SELECT as reference population; p-values generated via Wald test of 5-year age-adjusted incidence rate ratio comparing African-American and non-Hispanic white men


<25.0

25.0-<27.5

27.5-<30.0

30.0-<35.0

35.0 +

Black race and prostate cancer (SELECT)Total cancer

BMI

P=0.03

1.00

1.60

0.80

1.80

1.20

1.40

2.00

2.20Risk of African-American vs. White (non-Hispanic)


<25.0

25.0-<27.5

27.5-<30.0

30.0-<35.0

35.0 +

Black race and prostate cancer (SELECT)Cases with known grade only

Total

BMI

P=0.005 P=0.41

Grade 2-6

2.20

0.80

1.40

1.00

1.20

2.00

1.60

1.80

Grade 7-10

P=0.005

Risk of African-American vs. White (non-Hispanic)


<25.0

25.0-<27.5

27.5-<30.0

30.0-<35.0

35.0 +

Obesity and prostate cancer (SELECT)Total cancer

BMI

P=0.63

White (non-Hispanic)

1.00

2.00

0.80

1.40

1.80

1.60

1.20

African-American

P=0.03


<25.0

25.0-<27.5

27.5-<30.0

30.0-<35.0

35.0 +

BMI

P=0.61 P=0.05

Total

White (non-Hispanic)

Grade 2-6 Grade 7-10

African-American

Total Grade 2-6 Grade 7-10

P=0.02 P=0.004P=0.01 P=0.02

1.00

0.80

1.80

1.60

1.20

1.40

2.00

2.40

2.20

2.60

Obesity and prostate cancer (SELECT)Cases with known grade only

Click to edit Master title styleAttributable risks (per 100,000) of obesity in SELECT

Total <25.0 25.0 to <27.5

27.5 to <30.0

30.0 to <35.0

35.0 to 50.0

NHW 0.0 (ref) 28.1 9.9 -9.0 -14.8

AA 61.8 152.2 147.1 155.9 204.3

Race Effect

61.8 124.0 137.2 165.0 219.1

Graded <25.0 25.0 to <27.5

27.5 to <30.0

30.0 to <35.0

35.0 to 50.0

NHW 0.0 (ref) 29.4 7.2 -8.6 -9.2

AA -10.6 130.3 134.6 135.5 204.2

Race Effect

-10.6 100.9 127.5 144.1 213.4

Click to edit Master title styleAttributable risks (per 100,000) of obesity in SELECT

Low-grade

<25.0 25.0 to <27.5

27.5 to <30.0

30.0 to <35.0

35.0 to 50.0

NHW 0.0 (ref) 54.3 -0.8 -41.2 -61.0

AA -61.3 137.7 154.1 77.9 226.3

Race Effect

-61.3 83.4 154.9 119.2 287.3

High-grade

<25.0 25.0 to <27.5

27.5 to <30.0

30.0 to <35.0

35.0 to 50.0

NHW 0.0 (ref) 0.6 2.1 3.4 6.2

AA 5.6 16.9 15.6 27.8 25.0

Race Effect

5.6 16.3 13.5 24.4 18.9

Click to edit Master title styleSensitivity 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

Click to edit Master title styleSummary 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

Click to edit Master title styleFindings 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

Click to edit Master title stylePossible 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

Click to edit Master title styleStrengths 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

Click to edit Master title styleImplications 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

Click to edit Master title styleReferences

1. Mordukhovich I, 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.

2. Powell IJ, Bollig-Fischer A. Minireview: the molecular and genomic basis for prostate cancer health disparities. Mol Endocrinol. Jun 2013;27(6):879-891.

3. Discacciati A, 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.

4. 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.

5. 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.

6. Nemesure B, 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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