Genetic Causation for Mortality Disparity among Young African-American Men

Clinical and Genetic Evidence Support a Faster Growth Rate of Prostate Cancer among African American Compared to European American Men

Incidence by Ethnicity per 100,000 Men 2006 (SEER 2009 Data) Black239.8 Whites153.0 Hispanics133.4 American Indian 76.1 Asian/Pacific Islander 91.1

Mortality by Ethnicity per 100,000 Men 2006 (SEER 2009 Data) Black56.3 Whites23.6 Hispanics19.6 American Indian20.0 Asian/Pacific Islander10.6

We propose that a faster prostate cancer growth rate among AAM compared to EAM contributes significantly to the racial disparity of advanced disease at diagnosis and a 2 to 3 times greater mortality rate among AAM versus EAM. We examined our autopsy series, radical prostatectomy specimens and SEER data to study this issue.

Methods We evaluated entirely embedded prostate glands from 1,027 AAM and EAM who died from causes other than prostate cancer between 1993 and 2004 to document the prevalence of sub-clinical prostate cancers. We examined 736 radical prostatectomy specimen from 1991 to We reviewed data from the Detroit SEER registry supported by NCI on the incidence rates in AAM and EAM diagnosed with metastatic prostate cancer at early ages. We reviewed data from the BRFSS on insurance status and screening behaviors between AAM and EAM.

Autopsy Study of Latent Prostate Cancer Decades in YearsAAM EAM 20 – 29 (n=177)8%11% 30 – 39 (n=199)31% 40 – 49 (n=301)43%38% 50 – 59 (n=206)46%44% 60 – 69 (n=86)72%68% 70 – 79 (n=58)77%69%

Autopsy Study of Latent Prostate Cancer Age Group Number of Specimens Latent Prostate Cancer Mean Tumor Volume (cc) % of cases with Gleason score ≤6 AAMEAMAAMEAMAAMEAMAAMEAM 20 – %11% % 30 – % %100% 40 – %38% %100% 50 – %44% %93% 60 – %68% %87% 70 – %69% %84%

Autopsy Study of High Grade PIN Age Group Number of SpecimensHigh Grade PIN AAMEAMAAMEAM 20 – %8% 30 – %23% 40 – %29% 50 – %49% 60 – %53% 70 – %67%

Radical Prostatectomy Study Age Group Number of SpecimensMean Tumor Volume (cc) AAMEAMAAMEAM 40 – – – –

Post-operative stage

Post-op advanced stage

Gleason Grade for Prostate Cancer Cases who underwent RP, Years Age Range Gleason Grade WhiteBlackp value Ages or less58.3%48.4% 7 or higher41.7%51.7% Ages or less50.8%42.9% 7 or higher49.2%57.1%< Ages or less43.2%37.7% 7 or higher56.8%62.3% Citation : Surveillance, Epidemiology, and End Results (SEER) Program ( SEER*Stat Database: Incidence - SEER 9 Regs Limited-Use, Nov 2007 Sub ( ) - Linked To County Attributes - Total U.S., Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2008, based on the November 2007 submission.

Age Specific Incidence Rates for Distant PCa (Rates per 100,000 men) Age WhiteBlackWhiteBlack Citation : Surveillance, Epidemiology, and End Results (SEER) Program ( SEER*Stat Database: Incidence - SEER 9 Regs Limited-Use, Nov 2007 Sub ( ) - Linked To County Attributes - Total U.S., Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2008, based on the November 2007 submission.

Age-specific prostate cancer mortality rates for the years Age Group EAMAAM Rate Ratio 95% C.I. Ratio p-value Rate95% C.I.Rate95% C.I < < – 4.06< < < < <

Possible Contributing Factors for Racial Disparity of PCa Mortality 1.Socio-Economic Status 2.Non-financial barriers, delayed diagnosis 3.Treatment differences 4.Lack of Access to Care PSA testing Rate of Access to Insurance

Data from the BRFSS Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance System Survey Data. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Percentage of Men aged who reported having some type of insurance coverage ( ) YesNo White88.6%11.4% Black80.9%19.1% Percentage of Men aged 40+ who have had a PSA test White55.0%53.1%55.5% Black57.1%54.2%59.6%

Protein stop AA A AACU U UG GGG GGCCCCCG RNA Normal Coding Polymorphism Protein stop A AAAA CU UUG G G A GGCCCCCG RNA

Genetic/Biology Support Cytochrome P4503A4 (CYP3A4) is a protein. It is involved in the oxidative deactivation (breakdown) of testosterone to biologically less active metabolites. Inhibition of this transformation would result in increased bioavailability (activity) of testosterone. A germ-line genetic variant (SNP) of the CYP3A4 gene has been reported.

CYP3A4 Polymorphism Studies 1. Rebbeck et al in a study of EAM only, found the genetic variant (SNP) of CYP3A4 to be associated with a higher clinical grade and stage prostate cancer. (JNCI,1998) 2. Paris et al found that the variant A to G allele was much more common among AAM than EAM, Hispanic or Asian Americans. (Cancer Epi. Bio. Prev. 1999) 3. Powell et al reported a strong association between race and genotype (p= ) in that 8% of EAM and 83% of AAM had 1 or more copies of the variant G allele. A follow-up study reported that aggressive disease among AAM was strongly associated with the variant allele. (J. of Urol. 2004)

8q24 Single Nucleotide Polymorphism (SNP) 1. Recent studies have identified multiple SNPs at 8q24 and different racial/ethnic distributions of the SNPs associated with PCa. (Haiman, Nature Genetics 2007) 2.Haiman et al estimated risk associated with seven SNPs or variants and found that risk estimates among AAM were significantly higher than among EAM. (Haiman, Nature Genetics 2007) 3. It is controversial whether specific variants are associated with aggressiveness at 8q24 but Helfand et al in a cohort study reported that the presence of multiple risk alleles was significantly associated with high grade disease in the biopsy and prostatectomy specimens. (Helfand, J of Urol 2008)

Difference in Expression of Metastasis Genes Genes associated with invasion and metastasis demonstrated higher expression in primary tumors among African Americans compared with tumors of European Americans 1.MMP-9 (matrix metalloproteinase -9) (2.0 - fold) 2.AMFR (autocrine motility factor receptor) (1.5 - fold) 3.CXCR4 (Chemokine receptor 4) (1.8 – fold) Wallace T.A. et, Cancer Res. 2008; 68: (3).

Conclusion Prostate cancer that starts at the same time with no significant differences in proportions among AAM and EAM but reaches distant disease at a ratio of 3 to 1, supports the concept that PCa is growing faster among AAM than EAM. There is growing genetic and biologic evidence to support this conclusion.

Funding for future research To continue genetic and biologic research to identify biologic markers and targets for therapy for high risk populations (i.e. AAM) to eliminate outcome disparity. To decrease the cost of health care by decreasing the cost of advanced prostate cancer treatment and death from prostate cancer, both of which are more costly than diagnosing and treating early disease.

Genetic Causation for Mortality Disparity among Young African-American Men