- Email: [email protected]
Prostate Cancer Screening Guidelines for African American Veterans: A New Perspective
Prostate Cancer Screening Guidelines for African American Veterans: A New Perspective Arthi Reddy, B.S., Russell Roberts, M.D., Divya Shenoy, M.D., Satyaseelan Packianathan, M.D., Ph.D., Shankar Giri, M.D., Srinivasan Vijayakumar, M.D.
Declarations of interest: There are no interests to declare. Disclosure statement for authors: 1. Ownership: No authors own or have an equity position in a health-care-related company who product or category of products is mentioned in the article. 2. Patents: No authors hold any patents for a health-care-related product or category of products named in the article. 3. Participation.a. No authors are paid consultants to health-care-related companies whose product or category of products is mentioned in the article.b. No authors have ongoing relationships (advisory board membership, research grant, speaker’s program, etc.) with a health-care-related company whose product or category of products is mentioned in the article. Abstract: Background: Prostate cancer is the most common form of cancer, other than skin cancers, in American men and the second leading cause of cancer deaths. In 2012, the US Preventative Task Force recommended against the prostate specific antigen-based screening for prostate cancer, regardless of race or age, due to overtreatment of low-risk disease and lack of impact on disease outcomes. In African-American men, however, the incidence of prostate cancer is almost 60% higher and the mortality rate is two- to three-times greater than that of Caucasian men. In the subpopulation of African-American veterans, many have been exposed to chemicals that increase incidence of high-risk prostate cancer. The yearly total number of veterans with prostate cancer based on quantification is 3471.9, and the total number of annual prostate cancer deaths is 556. Considering these facts, we examine whether or not it is appropriate to screen African-American veteran males for prostate cancer. Previously, we reviewed data on African-Americans in the general population. We concluded that new guidelines needed to be implemented for screening AfricanAmericans. Here we review the pertinent issues related to African-American veterans. Methods: We performed a PubMed and Google Scholar search using the keywords: African-American veteran, prostate cancer, mortality, PSA density, molecular markers, and Agent Orange. The articles that were relevant to the clinical, molecular, social, and health policy aspects of the diagnosis and treatment of prostate cancer in African-American veterans were analyzed. The data was then summarized. Results: After surveying the literature, we found several areas where the AfricanAmerican veteran population differed from their Caucasian counterparts. These areas were incidence, clinical course, social differences, PSA levels, mortality rate, and molecular markers. A subset of the veteran population was also exposed to Agent Orange, which has been shown to increase the incidence of aggressive forms of prostate cancer. Lastly, the current USPTF guidelines recommending against prostate cancer screening were based on patient cohorts containing disproportionately low numbers of African-Americans, limiting their extension to the African-American veteran population. Conclusion: After reviewing and summarizing the literature, we contend that a need exists to develop and implement more targeted prostate cancer screening guidelines for African-American veterans. Abbreviations: AUA, American Urological Association; ERSPC, European Randomized Study of Screening for Prostate Cancer; PIVOT, Prostate cancer Intervention Versus Observation Trial; PLCO, Prostate, Lung, Colorectal, and Ovarian cancer screening trial; PSA, Prostate Specific Antigen; SNP, Single Nucleotide Polymorphism; UCLA, University of California, Los Angeles; USPSTF, US Preventative Services Task Force; VA, Veterans Affairs; VHA, Veterans Health Administration Keywords: Prostate cancer screening-PSA-African american-Veteran
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Author affiliations: Arthi Reddy, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Russell Roberts, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Divya Shenoy, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Satyaseelan Packianathan, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Shankar Giri, G.V. (Sonny) Montgomery VA Medical Center Radiation Oncology, 1500 E Woodrow Wilson Ave, Jackson, MS 39216; Srinivasan Vijayakumar, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA Correspondence: Srinivasan Vijayakumar, email: [email protected] ª 2018 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jnma.2018.10.010
BACKGROUND
P
rostate cancer is the most common form of cancer, other than skin cancers, in American men and the second leading cause of cancer deaths.1 AfricanAmerican men have the highest incidence of prostate cancer and are more likely than Caucasian men to be diagnosed with an advanced form of prostate cancer.2 In 2016, there are estimated to be 180,890 new diagnoses of prostate cancer and 26,120 deaths attributable to prostate cancer. The rate for new cases of prostate cancer is 0.1294%, and the mortality rate is 0.0207%. Age is the greatest risk factor for prostate cancer; race is second. In African-American men, however, the incidence of prostate cancer is almost 60% higher, and the mortality rate is two- to three-times greater than that of Caucasian men.2 Comorbidity also plays a role in treatment and prevention of the disease. The Veteran’s Health Administration is an unbiased, race and color blind, equal and open access, single-payer, government-run healthcare system. The VA healthcare system is labeled as a veteran-specific, national healthcare system because the Federal government owns a majority of its healthcare delivery sites, employs the healthcare providers, and directly provides the majority of healthcare services to veterans.3 Any veteran eligible for VA healthcare must meet the statutory definition of a “veteran,” meet the statutory definition of “active duty,” and serve a minimum period of “active duty.” Based on the National Center for Veterans Analysis and Statistics, the projected total veterans in 2016 is 21,368,156, of which Black
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Veterans
White Veterans
Black Veterans
Total
21,368,156
17,458,264
2,683,046
Incidence of Prostate Cancer
26,688
22,590
3471.9
Death by Prostate Cancer
6196
3614
556
% Deceased with Prostate Cancer
23%
16%
16%
veterans represent 2,683,046, the equivalent of about 8%. The number of White veterans is estimated to be around 17,458,264.4 The incidence and mortality rate of prostate cancer, respectively, are 0.129% and 0.020%.5 Quantification based on the incidence and mortality rates leads to an estimated total number of veterans with prostate cancer as 26,688 and the total number of veteran deaths as 6196. In the African-American population, the yearly total number of veterans with prostate cancer based on quantification is 3471.9, and the total number of annual prostate cancer deaths is 556. In 2012, the US Preventive Task Force (USPTF) recommended against the prostate specific antigen (PSA)based screening for prostate cancer. The VA Health System has integrated electronic records, so it is possible to review these records at the national level. Over 80% of prostate cancers diagnosed in Veterans Health Administration (VHA) are localized to the prostate gland and only 5% are metastatic.6 This means that the majority of the patients diagnosed are eligible for definitive treatment. Medical and professional organizations, such as the American Urological Association (AUA), USPSTF, and VHA, have published guidelines for prostate cancer screening. The VHA does not recommend prostate cancer screening with PSA for men ages 45e70 but recommends that any decision to initiate or continue prostate cancer screening with PSA for any veteran should be based on a decision between the patient and his provider.4 Previously, we reviewed data on African Americans in the general population and concluded that new guidelines needed to be implemented for screening African-Americans.7 Here we review issues related to African-American veterans.
METHODS We performed a PubMed and Google Scholar search using the keywords:
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African-American veteran Prostate Cancer Mortality PSA Density Molecular Markers
Agent Orange We used combinations of these words to find peerreviewed publications with information regarding African-American veterans and prostate cancer. The articles that were relevant to the clinical, molecular, social, and health policy aspects of the diagnosis, and treatment of prostate cancer in African-American veterans were analyzed. The data was then summarized.
RESULTS/DISCUSSION Incidence of prostate cancer among African-American veterans In the general population, African-Americans have a much higher incidence of prostate cancer. Within the veteran population, a striking difference in the incidence of prostate cancer is apparent once again. Prostate cancer accounts only for 28.9% of all cancers in White veterans but 42.7% of all cancers in Black veterans.4 African-American veterans also present with a more aggressive form of the disease. Indeed, one study based on data from the VHA found that while 26% of White veterans presented in Stage D, the number of Black men presenting with equivalent disease was doubled at 52%.8
Clinical course of prostate cancer in African-American veterans Along with the higher incidence noted in the AfricanAmerican male population, the clinical course of prostate cancer in African-American men differs from that of the Caucasian population. Early in the disease course, the clinical characteristics of prostate cancer in AfricanAmerican men and white men are similar, but on autopsy of men who had prostate cancer but died of unrelated causes, it was found that African-American men carried a higher prostatic tumor volume and were 4-times more likely than white men to develop aggressive, metastatic disease.9 These findings support the hypothesis that prostate cancer in African-American men has a higher growth rate or transforms to more aggressive forms earlier than in White men. Since the 5-year survival rate among men with distant metastases is only 29.3%, it is important that aggressive disease is detected early in its course.10 These findings also explain, in part, why African-American men are more likely to present at a later stage than Caucasian
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men of similar age. A study from the Shared Equal Access Regional Cancer Hospital Registry, which covers multiple VHA centers with relatively large proportions of AfricanAmerican patients, showed that African-American men were more likely to experience biochemical recurrence than men from other ethnic groups. There also seem to be multiple genetic components contributing to the differences seen in the clinical courses of African-American men compared to Caucasian men. In individuals with prostate-cancer-negative biopsies for example, the PSA levels of the African-American men were 1.8-fold higher than those found in Caucasian men, even after controlling for prostatic volume.11 Also, it has been suggested that African-American men are more susceptible to prostate cancer because of shorter repeat lengths in comparison to Caucasians and Asians.12 Lastly, several risk-associated single nucleotide polymorphisms (SNPs) are overexpressed in African-American men, which we will discuss more in depth later.13
higher serum PSA levels signify an abnormality within the prostate gland although many factors are known to affect PSA levels including age. The PSA levels of 752 men of a bi-racial veteran population were taken. In this specific population, the mean PSA level in men without prostate cancer was 7.97 ng/ml compared to the 4.94 ng/ml mean in a comparable White veteran population without prostate cancer.19 Generally, PSA levels higher than 4 ng/ml are associated with increased prostate cancer risk although prostate cancer is 1.4-times more likely to develop in men with a PSA level greater than 2.5 ng/ml. A PSA level of 2.5 ng/ml is a reasonable predictor of prostate cancer diagnosis within four years; a lower threshold of 1.9 ng/ml can be used as a predictor for African-Americans.20 While African-American men tend to have higher PSA levels than other races, they are as likely as their White veterans counterparts to get their PSA levels tested.
Social differences in the African-American population
African-Americans, in general, are three times more likely to die from prostate cancer than other races. However, the mortality rates for African-American and Caucasian veterans were similar in a study conducted in 2013 at the Connecticut VHA System. Similarly, a team with the VA and UCLA studied more than 1200 California veterans and found “no significant differences in tumor burden, treatment choice or survival for African-Americans or survival outcomes between African-Americans and Caucasians cared for in the equal-access VA health care setting.21 There was, however, a difference found in the private sector. Five reports have documented the quantitative results of the association of race and mortality among men with prostate cancer in equal-access systems, in which outcomes were similar for Black and White men.22
There are several social differences within the AfricanAmerican population that can contribute to poorer outcomes relative to Caucasians and Asians. First, there is a discrepancy between Caucasian and African-American males in insurance coverage. About 90% of Caucasian men over 50 years of age have health insurance, but only 81% of similarlage group African-American men carry health insurance.14 Second, poor health seeking behaviors in African-American men can contribute to delayed diagnosis and more advanced disease at diagnosis.15 Additionally, when compared to Caucasian men with similar stages of disease, African-American men are less likely to be treated.16 Delayed diagnosis coupled with lack of treatment thus significantly affects the outcome of AfricanAmerican men with prostate cancer. Third, many barriers traditionally associated with lower socioeconomic status are major contributors of poorer health outcomes.13,17 Fourth, there appears to be a contribution from the patient’s diet; diets high in saturated fat are associated with an increased risk of prostate cancer. In general, AfricanAmerican men tend to consume more saturated fat and calories per day than Caucasians and Asians.12 Whittemore suggests that differences in saturated fat intake could account for approximately 10% of the Black-White difference in prostate cancer incidence.18
PSA levels are higher among AfricanAmerican men PSA is a protein antigen produced only by prostate gland cells and released into the blood. Generally speaking,
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Mortality rate
USPSTF recommendation The purpose of screening for prostate cancer is to reduce the death rate linked to prostate cancer, but it was estimated that screening only benefited 0e1 men out of every 1000 screened.23 In addition to having a low influence on outcomes, there is a high rate of false-positives, which led to an over diagnosis of prostate cancer in 17e50% of cases.23 Despite the potential over-treatment in the general population, African-American males, however, are undertreated as a group, which contributes to increased prostate cancer mortality in this population. In 2008, the USPSTF took a two-tiered approach to prostate cancer screening. The guidelines noted that screening men under the age of 75 had Grade I support which meant that there was insufficient knowledge of risks to support screening. In men over 75, however, screening was not recommended based on Grade D evidence -
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meaning there was a moderate or high risk of certainty that the service had no net benefit or had an unfavorable risk/ benefit ratio.23 The current USPSTF guidelines recommend against prostate cancer screening for men of all ages, regardless of race, and the recommendation is considered to be supported by Grade D evidence. The argument that while the lifetime risk of prostate cancer is 15.9% but the risk of dying is only 2.8%, suggests that many cases of prostate cancer have favorable outcomes, regardless of early detection or treatment.24 The current guidelines, however, were based on the findings of two studies - the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). The PLCO trial noted that men in their screened group had a 12% higher incidence of prostate cancer but an equal death rate.25 Finding that screened men had similar outcomes but had been exposed to additional pain and bleeding associated with screening and follow-up led the authors to conclude that there was no net benefit to screening for prostate cancer in their population. However, the PLCO trial cohort only included w4% AfricanAmerican men, which raises questions on the ability of these results to be generalized to the African-American population as a whole.25 The ERSPC investigated whether PSA screening would lead to increased survival. After eleven years of follow-up, they reported that in order for 1 death from prostate cancer to be prevented, an additional 37 cases of prostate cancer had to be first diagnosed and 1055 individuals needed to be screened.26 Although specific demographic information was not released, this study was conducted in eight European countries which traditionally did not house large populations of African descent, which again introduces uncertainty of their findings’ applicability to the general African-American population. The Prostate Cancer Intervention Versus Observational Trial (PIVOT) is another study related to these outcome measures. This study compared expectant management of prostate cancer with radical prostatectomy and found no difference in outcomes between White and AfricanAmerican males.27 The comparable outcomes in this study are concerning for despite these findings, AfricanAmerican men generally have an increased prostate cancer mortality. Thus, although w one-third of PIVOT trial participants were African-American males, the two arms of this study may not represent the treatment choices seen in general practice or that the study may have been inadequately powered to detect racial differences.
Molecular markers Certain molecular markers have also been linked to the clinical course and disease outcomes in men with prostate
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cancer.28,29 For instance, several studies have identified multiple single nucleotide polymorphisms (SNPs) that are preferentially expressed in African-Americans. Approximately 100 genes containing SNPs have been linked to an increased susceptibility to prostate cancer. Single nucleotide polymorphisms are especially valuable in disease detection, monitoring, and screening because they are stable throughout the lifetime of the individual and are not affected by external factors, such as lifestyle.29 Several studies have shown that African-American males are at increased risk of prostate cancer, in part, because they possess many of these SNPs. Xu et al. showed that 17 of 20 SNPs are more common in African-American males, and of the 17 SNPs, 2 were associated with a higher risk of prostate cancer.30 Freedman et al. showed that a 3.8MB interval on chromosome 8q24 was associated with prostate cancer and was found mainly in African-Americans.31 Families with a history of particular allelic variants within this interval were 9.46 times more likely to develop prostate cancer than those without these variants.31 In addition, several biomarkers have shown differential expression between aggressive and non-aggressive forms of prostate cancer.32 Unfortunately, these molecular findings have not yet been incorporated into screening protocols. In addition to increasing the accuracy and validity of screening, incorporating biomarkers would also decrease unnecessary invasive procedures which in turn would positively impact the net benefit of screening.33 It has also been suggested that such a screening program with molecular markers could identify aggressive tumors would decrease prostate cancer morbidity and mortality.In short, effective screening for prostate cancer in AfricanAmerican males will need to incorporate these molecular findings into protocols that successfully identify individuals at increased risk for aggressive prostate cancer. Such updated guidelines would allow for more precise identification of aggressive and metastatic disease, improve survival outcomes, and lower overall treatment costs.
Other considerations (Agent Orange) About three million Americans served in the armed forces in Vietnam during the 1960s and 70s. During this time, the military used large amounts of a defoliant called Agent Orange to eliminate forest cover. In a study conducted at Portland Medical Center and Oregon Health Sciences University, it was found that veterans exposed to Agent Orange were not only more likely to develop prostate cancer, but also more likely to develop a more aggressive form of the disease.34 Agent Orange exposure is associated with a 52% increase in the detection of prostate cancer and a 75% increased risk of high-grade prostate cancer.35
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Figure 1. Proposed schema for screening.
40-year-old AA veteran Informed consent DRE Serum PSA
Abnormal DRE or PSA or PSA parameters
Normal DRE and PSA
Repeat once annually for 3 yearsDetermine: PSA density PSA velocity
Biopsy SNP testing Abnormal
Treat as clinically appropriate.
If normal, repeat at age 50.
would be able to identify patients at risk of the more aggressive forms of prostate cancer and potentially decrease prostate cancer mortality, while minimizing the rates of false positive tests that may previously have led to unnecessary treatment of benign disease. Figure 1 below represents a potential screening flowchart. In future reports, we will investigate how comorbidities may affect prostate cancer incidence and mortality rate. The most prevalent comorbid disease with prostate cancer is cardiovascular disease. This also happens to be the number one cause of death in the African-American population. Investigating these links an exploiting any identifiable links may positively impact the morbidity and mortality associated with both these diseases.
REFERENCES 1. Prostate Cancer. (n.d.). Retrieved September 14, 2016, from http://www.cancer.org/cancer/prostatecancer/. 2. Odedina, F. T., Akinremi, T. O., Chinewundoh, F., et al. (2009). Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa. Infect Cancer Agent, 4(1), S2.
There was, however, no increase in the risk of low-grade prostate cancer. Men exposed to Agent Orange were also diagnosed at a younger age compared to men who were not exposed to the carcinogen. In conclusion, exposure to Agent Orange appears to potentiate the detection of prostate cancer and incidence of high-grade prostate cancer.35
CONCLUSION There is an immense need to implement new, more targeted prostate cancer screening guidelines for AfricanAmerican males within the nation-wide VHA system. African-American male veterans have a higher incidence of prostate cancer and present at a higher stage than their peers. Prostate cancer in these men tends to be more aggressive at presentation and/or transforms to more aggressive forms earlier. Social factors, such as delayed diagnosis, lower rates of treatment, and dietary factors, can all contribute to worse disease outcomes. In addition, the exposure of many veterans to Agent Orange has been shown to increase the incidence of high-grade prostate cancer. The current USPSTF guidelines recommending against prostate cancer screening were based on trials that were not fully generalizable to the African-American population because such individuals were underrepresented in the investigational cohorts. In including techniques that detect molecular markers, future guidelines
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https://doi.org/10.1186/1750-9378-4-S1-S2. 3. Administration, V. H. (2016, September 13). Veterans Health Administration. Retrieved September 15, 2016, from http:// www.va.gov/health/. 4. Planning, O. O. (2016, April 15). National Center for Veterans Analysis and Statistics. Retrieved September 15, 2016, from http://www.va.gov/vetdata/Veteran_Population.asp. 5. Surveillance, Epidemiology, and End Results Program. (n.d.). Retrieved September 15, 2016, from http://seer.cancer.gov/ statfacts/html/prost.html. 6. GPRA Report on Prostate Cancer.(2009). 7. Shenoy, D., Packianathan, S., Chen, A. M., & Vijayakumar, S. (2016). Do African-American men need separate prostate cancer screening guidelines? BMC Urol, 16, 19. 8. Brawn, P. N., Johnson, E. H., Kuhl, D. L., Riggs, M. W., & Speights, V. O. (1993). Johnson CF Stage at presentation and survival of white and black patients with prostate carcinoma. Cancer, 71, 2569e2573. 9. Powell, I. J., Bock, C. H., Ruterbush, J. J., & Sakr, W. (2010). Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men, and influences racial progression and mortality disparity. J Urol, 183(5), 1792e1796. 10. Ries, L. A. G., Melbert, D., Krapcho, M., et al. (Eds.). (2007). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute, Bethesda, MD. Available at http://seer.cancer.gov/csr/1975_2 004/. Accessed October 16, 2009.
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24. SEER Cancer Statistics Review, 1975e2006. National Cancer
Prostate specific antigen (PSA) and PSA density: racial differ-
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25. Andriole, G. L., Crawford, E. D., Grubb, R. L., 3rd, et al. (2012).
12. McIntosh, H. (1997). Why do african-american men suffer more prostate cancer? J Natl Cancer Inst, 89(3), 188e189. 13. Du, X. L., Fang, S., Coker, A. L., et al. (2006). Racial disparity and
Prostate cancer screening in the randomized prostate, Lung, colorectal, and ovarian cancer screening trial: mortality results after 13 years of follow-up. J Natl Cancer Inst, 104(2), 125e132.
socioeconomic status in association with survival in older men
26. Schröder, F. H., Hugosson, J., Roobol, M. J., et al. (2012). Pros-
with local/regional stage prostate carcinoma: findings from a
tate-cancer mortality at 11 years of follow-up. N Engl J Med,
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14. Behavioral Risk Factor Surveillance System Survey Data. Center
27. Wilt, T. J., Brawer, M. K., Barry, M. J., et al. (2009). The Prostate
for Disease Control and Prevention.(2009). http://www.cdc.
cancer Intervention versus Observation Trial:VA/NCI/AHRQ
gov/brfss/. Accessed June 3, 2015.
Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing
15. Powell, I. J., Heilbrun, L., Littrup, P. L., et al. (1997). Outcome of african-american men screened for prostate cancer: the detroit education and early detection study. J Urol, 158(1), 146e149.
radical prostatectomy to watchful waiting for men with clinically localized prostate cancer. Contemp Clin Trials, 30(1), 81e87.
16. Underwood, W., De Monner, S., Ubel, P., Fagerlin, A., Sanda,
28. Hicks, C., Koganti, T., Giri, S., et al. (2014). Integrative genomic
M. G., & Wei, J. T. (2004). Racial/ethnic disparities in in the
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29. Helfand, B. T., Catalona, W. J., & Xu, J. (2015). A genetic-based
17. Ward, E., Jemal, A., Cokkinides, V., et al. (2004). Cancer disparities by race/ethnic and socioeconomic status. CA Cancer J Clin, 54(2), 78e93. 18. Whittemore, A. S., Kolonel, L. N., Wu, A. H., et al. (1995). Prostate cancer in relation to diet, physical activity, and body size in blacks, whites, and Asians in the United States and Canada. J Natl Cancer Inst, 87(9), 652e661. 19. R. Jonathan Henderson, James A. Eastham, Culkin Daniel J., Terence Whatley, John Mata, Dennis Venable, Michael W. Kattan, and Oliver Sartor, Prostate-Specific Antigen (PSA) and PSA Density: Racial Differences in Men without Prostate Cancer. 20. Sutton, S. S., Crawford, E. D., Moul, J. W., Hardin, J. W., & Kruep, E. (2016). Determining optimal prostate-specific antigen thresholds to identify an increased 4-year risk of prostate cancer development: an analysis within the Veterans Affairs Health Care System. World J Urol. https://doi.org/10.1007/s00345-015-1754-6. 21. Office of Research & Development. (n.d.). Retrieved October 02, 2016, from http://www.research.va.gov/currents/0915-1.cfm. 22. Graham-Steed, Tisheeka, et al. (2013). ‘Race’ and Prostate Cancer Mortality in Equal-access Healthcare Systems. Am J Med, 126(12), 1084e1088. 23. Final recommendation statement: Prostate cancer: screening.
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approach to personalized prostate cancer screening and treatment. Curr Opin Urol, 25(1), 53e58. 30. Xu, J., Kibel, A. S., Hu, J. J., et al. (2009). Prostate cancer risk associated loci in African-Americans. Cancer Epidemiol Biomark Prev, 18(7), 2145e2149. 31. Freedman, M. L., Haiman, C. A., Patterson, N., et al. (2006). Admixture mapping identified 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A, 103(38), 14068e14073. 32. David, S., & Chan, D. W. (2014). Biomarkers in prostate cancer: what’s new? Curr Opin Oncol, 26(3), 259e264. 33. Kader, K., Sun, J., Reck, B., et al. (2012). Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial. Eur Urol, 62(6), 953e961. 34. Ansbaugh, N. (n.d.). ResultAgent Orange as a risk factor for high-grade prostate cancer Filters. Retrieved October 02, 2016; https://www.ncbi.nlm.nih.gov/pubmed/23670242. 35. Ansbaugh, N., Shannon, J., Mori, M., Farris, P. E., & Garzotto, M. (2013). Agent orange as a risk factor for high-grade prostate cancer. Cancer, 119(13), 2399e2404. https://doi.
U.S. Preventive services Task forcewebsite.(2014). Accessed
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0.1007/s00345-015-1754-6.
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Declarations of interest: There are no interests to declare. Disclosure statement for authors: 1. Ownership: No authors own or have an equity position in a health-care-related company who product or category of products is mentioned in the article. 2. Patents: No authors hold any patents for a health-care-related product or category of products named in the article. 3. Participation.a. No authors are paid consultants to health-care-related companies whose product or category of products is mentioned in the article.b. No authors have ongoing relationships (advisory board membership, research grant, speaker’s program, etc.) with a health-care-related company whose product or category of products is mentioned in the article. Abstract: Background: Prostate cancer is the most common form of cancer, other than skin cancers, in American men and the second leading cause of cancer deaths. In 2012, the US Preventative Task Force recommended against the prostate specific antigen-based screening for prostate cancer, regardless of race or age, due to overtreatment of low-risk disease and lack of impact on disease outcomes. In African-American men, however, the incidence of prostate cancer is almost 60% higher and the mortality rate is two- to three-times greater than that of Caucasian men. In the subpopulation of African-American veterans, many have been exposed to chemicals that increase incidence of high-risk prostate cancer. The yearly total number of veterans with prostate cancer based on quantification is 3471.9, and the total number of annual prostate cancer deaths is 556. Considering these facts, we examine whether or not it is appropriate to screen African-American veteran males for prostate cancer. Previously, we reviewed data on African-Americans in the general population. We concluded that new guidelines needed to be implemented for screening AfricanAmericans. Here we review the pertinent issues related to African-American veterans. Methods: We performed a PubMed and Google Scholar search using the keywords: African-American veteran, prostate cancer, mortality, PSA density, molecular markers, and Agent Orange. The articles that were relevant to the clinical, molecular, social, and health policy aspects of the diagnosis and treatment of prostate cancer in African-American veterans were analyzed. The data was then summarized. Results: After surveying the literature, we found several areas where the AfricanAmerican veteran population differed from their Caucasian counterparts. These areas were incidence, clinical course, social differences, PSA levels, mortality rate, and molecular markers. A subset of the veteran population was also exposed to Agent Orange, which has been shown to increase the incidence of aggressive forms of prostate cancer. Lastly, the current USPTF guidelines recommending against prostate cancer screening were based on patient cohorts containing disproportionately low numbers of African-Americans, limiting their extension to the African-American veteran population. Conclusion: After reviewing and summarizing the literature, we contend that a need exists to develop and implement more targeted prostate cancer screening guidelines for African-American veterans. Abbreviations: AUA, American Urological Association; ERSPC, European Randomized Study of Screening for Prostate Cancer; PIVOT, Prostate cancer Intervention Versus Observation Trial; PLCO, Prostate, Lung, Colorectal, and Ovarian cancer screening trial; PSA, Prostate Specific Antigen; SNP, Single Nucleotide Polymorphism; UCLA, University of California, Los Angeles; USPSTF, US Preventative Services Task Force; VA, Veterans Affairs; VHA, Veterans Health Administration Keywords: Prostate cancer screening-PSA-African american-Veteran
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Author affiliations: Arthi Reddy, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Russell Roberts, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Divya Shenoy, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Satyaseelan Packianathan, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA; Shankar Giri, G.V. (Sonny) Montgomery VA Medical Center Radiation Oncology, 1500 E Woodrow Wilson Ave, Jackson, MS 39216; Srinivasan Vijayakumar, UMMC Radiation Oncology, 2500 N State St, Jackson, MS 39216, USA Correspondence: Srinivasan Vijayakumar, email: [email protected] ª 2018 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jnma.2018.10.010
BACKGROUND
P
rostate cancer is the most common form of cancer, other than skin cancers, in American men and the second leading cause of cancer deaths.1 AfricanAmerican men have the highest incidence of prostate cancer and are more likely than Caucasian men to be diagnosed with an advanced form of prostate cancer.2 In 2016, there are estimated to be 180,890 new diagnoses of prostate cancer and 26,120 deaths attributable to prostate cancer. The rate for new cases of prostate cancer is 0.1294%, and the mortality rate is 0.0207%. Age is the greatest risk factor for prostate cancer; race is second. In African-American men, however, the incidence of prostate cancer is almost 60% higher, and the mortality rate is two- to three-times greater than that of Caucasian men.2 Comorbidity also plays a role in treatment and prevention of the disease. The Veteran’s Health Administration is an unbiased, race and color blind, equal and open access, single-payer, government-run healthcare system. The VA healthcare system is labeled as a veteran-specific, national healthcare system because the Federal government owns a majority of its healthcare delivery sites, employs the healthcare providers, and directly provides the majority of healthcare services to veterans.3 Any veteran eligible for VA healthcare must meet the statutory definition of a “veteran,” meet the statutory definition of “active duty,” and serve a minimum period of “active duty.” Based on the National Center for Veterans Analysis and Statistics, the projected total veterans in 2016 is 21,368,156, of which Black
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Veterans
White Veterans
Black Veterans
Total
21,368,156
17,458,264
2,683,046
Incidence of Prostate Cancer
26,688
22,590
3471.9
Death by Prostate Cancer
6196
3614
556
% Deceased with Prostate Cancer
23%
16%
16%
veterans represent 2,683,046, the equivalent of about 8%. The number of White veterans is estimated to be around 17,458,264.4 The incidence and mortality rate of prostate cancer, respectively, are 0.129% and 0.020%.5 Quantification based on the incidence and mortality rates leads to an estimated total number of veterans with prostate cancer as 26,688 and the total number of veteran deaths as 6196. In the African-American population, the yearly total number of veterans with prostate cancer based on quantification is 3471.9, and the total number of annual prostate cancer deaths is 556. In 2012, the US Preventive Task Force (USPTF) recommended against the prostate specific antigen (PSA)based screening for prostate cancer. The VA Health System has integrated electronic records, so it is possible to review these records at the national level. Over 80% of prostate cancers diagnosed in Veterans Health Administration (VHA) are localized to the prostate gland and only 5% are metastatic.6 This means that the majority of the patients diagnosed are eligible for definitive treatment. Medical and professional organizations, such as the American Urological Association (AUA), USPSTF, and VHA, have published guidelines for prostate cancer screening. The VHA does not recommend prostate cancer screening with PSA for men ages 45e70 but recommends that any decision to initiate or continue prostate cancer screening with PSA for any veteran should be based on a decision between the patient and his provider.4 Previously, we reviewed data on African Americans in the general population and concluded that new guidelines needed to be implemented for screening African-Americans.7 Here we review issues related to African-American veterans.
METHODS We performed a PubMed and Google Scholar search using the keywords:
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African-American veteran Prostate Cancer Mortality PSA Density Molecular Markers
Agent Orange We used combinations of these words to find peerreviewed publications with information regarding African-American veterans and prostate cancer. The articles that were relevant to the clinical, molecular, social, and health policy aspects of the diagnosis, and treatment of prostate cancer in African-American veterans were analyzed. The data was then summarized.
RESULTS/DISCUSSION Incidence of prostate cancer among African-American veterans In the general population, African-Americans have a much higher incidence of prostate cancer. Within the veteran population, a striking difference in the incidence of prostate cancer is apparent once again. Prostate cancer accounts only for 28.9% of all cancers in White veterans but 42.7% of all cancers in Black veterans.4 African-American veterans also present with a more aggressive form of the disease. Indeed, one study based on data from the VHA found that while 26% of White veterans presented in Stage D, the number of Black men presenting with equivalent disease was doubled at 52%.8
Clinical course of prostate cancer in African-American veterans Along with the higher incidence noted in the AfricanAmerican male population, the clinical course of prostate cancer in African-American men differs from that of the Caucasian population. Early in the disease course, the clinical characteristics of prostate cancer in AfricanAmerican men and white men are similar, but on autopsy of men who had prostate cancer but died of unrelated causes, it was found that African-American men carried a higher prostatic tumor volume and were 4-times more likely than white men to develop aggressive, metastatic disease.9 These findings support the hypothesis that prostate cancer in African-American men has a higher growth rate or transforms to more aggressive forms earlier than in White men. Since the 5-year survival rate among men with distant metastases is only 29.3%, it is important that aggressive disease is detected early in its course.10 These findings also explain, in part, why African-American men are more likely to present at a later stage than Caucasian
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men of similar age. A study from the Shared Equal Access Regional Cancer Hospital Registry, which covers multiple VHA centers with relatively large proportions of AfricanAmerican patients, showed that African-American men were more likely to experience biochemical recurrence than men from other ethnic groups. There also seem to be multiple genetic components contributing to the differences seen in the clinical courses of African-American men compared to Caucasian men. In individuals with prostate-cancer-negative biopsies for example, the PSA levels of the African-American men were 1.8-fold higher than those found in Caucasian men, even after controlling for prostatic volume.11 Also, it has been suggested that African-American men are more susceptible to prostate cancer because of shorter repeat lengths in comparison to Caucasians and Asians.12 Lastly, several risk-associated single nucleotide polymorphisms (SNPs) are overexpressed in African-American men, which we will discuss more in depth later.13
higher serum PSA levels signify an abnormality within the prostate gland although many factors are known to affect PSA levels including age. The PSA levels of 752 men of a bi-racial veteran population were taken. In this specific population, the mean PSA level in men without prostate cancer was 7.97 ng/ml compared to the 4.94 ng/ml mean in a comparable White veteran population without prostate cancer.19 Generally, PSA levels higher than 4 ng/ml are associated with increased prostate cancer risk although prostate cancer is 1.4-times more likely to develop in men with a PSA level greater than 2.5 ng/ml. A PSA level of 2.5 ng/ml is a reasonable predictor of prostate cancer diagnosis within four years; a lower threshold of 1.9 ng/ml can be used as a predictor for African-Americans.20 While African-American men tend to have higher PSA levels than other races, they are as likely as their White veterans counterparts to get their PSA levels tested.
Social differences in the African-American population
African-Americans, in general, are three times more likely to die from prostate cancer than other races. However, the mortality rates for African-American and Caucasian veterans were similar in a study conducted in 2013 at the Connecticut VHA System. Similarly, a team with the VA and UCLA studied more than 1200 California veterans and found “no significant differences in tumor burden, treatment choice or survival for African-Americans or survival outcomes between African-Americans and Caucasians cared for in the equal-access VA health care setting.21 There was, however, a difference found in the private sector. Five reports have documented the quantitative results of the association of race and mortality among men with prostate cancer in equal-access systems, in which outcomes were similar for Black and White men.22
There are several social differences within the AfricanAmerican population that can contribute to poorer outcomes relative to Caucasians and Asians. First, there is a discrepancy between Caucasian and African-American males in insurance coverage. About 90% of Caucasian men over 50 years of age have health insurance, but only 81% of similarlage group African-American men carry health insurance.14 Second, poor health seeking behaviors in African-American men can contribute to delayed diagnosis and more advanced disease at diagnosis.15 Additionally, when compared to Caucasian men with similar stages of disease, African-American men are less likely to be treated.16 Delayed diagnosis coupled with lack of treatment thus significantly affects the outcome of AfricanAmerican men with prostate cancer. Third, many barriers traditionally associated with lower socioeconomic status are major contributors of poorer health outcomes.13,17 Fourth, there appears to be a contribution from the patient’s diet; diets high in saturated fat are associated with an increased risk of prostate cancer. In general, AfricanAmerican men tend to consume more saturated fat and calories per day than Caucasians and Asians.12 Whittemore suggests that differences in saturated fat intake could account for approximately 10% of the Black-White difference in prostate cancer incidence.18
PSA levels are higher among AfricanAmerican men PSA is a protein antigen produced only by prostate gland cells and released into the blood. Generally speaking,
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Mortality rate
USPSTF recommendation The purpose of screening for prostate cancer is to reduce the death rate linked to prostate cancer, but it was estimated that screening only benefited 0e1 men out of every 1000 screened.23 In addition to having a low influence on outcomes, there is a high rate of false-positives, which led to an over diagnosis of prostate cancer in 17e50% of cases.23 Despite the potential over-treatment in the general population, African-American males, however, are undertreated as a group, which contributes to increased prostate cancer mortality in this population. In 2008, the USPSTF took a two-tiered approach to prostate cancer screening. The guidelines noted that screening men under the age of 75 had Grade I support which meant that there was insufficient knowledge of risks to support screening. In men over 75, however, screening was not recommended based on Grade D evidence -
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meaning there was a moderate or high risk of certainty that the service had no net benefit or had an unfavorable risk/ benefit ratio.23 The current USPSTF guidelines recommend against prostate cancer screening for men of all ages, regardless of race, and the recommendation is considered to be supported by Grade D evidence. The argument that while the lifetime risk of prostate cancer is 15.9% but the risk of dying is only 2.8%, suggests that many cases of prostate cancer have favorable outcomes, regardless of early detection or treatment.24 The current guidelines, however, were based on the findings of two studies - the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). The PLCO trial noted that men in their screened group had a 12% higher incidence of prostate cancer but an equal death rate.25 Finding that screened men had similar outcomes but had been exposed to additional pain and bleeding associated with screening and follow-up led the authors to conclude that there was no net benefit to screening for prostate cancer in their population. However, the PLCO trial cohort only included w4% AfricanAmerican men, which raises questions on the ability of these results to be generalized to the African-American population as a whole.25 The ERSPC investigated whether PSA screening would lead to increased survival. After eleven years of follow-up, they reported that in order for 1 death from prostate cancer to be prevented, an additional 37 cases of prostate cancer had to be first diagnosed and 1055 individuals needed to be screened.26 Although specific demographic information was not released, this study was conducted in eight European countries which traditionally did not house large populations of African descent, which again introduces uncertainty of their findings’ applicability to the general African-American population. The Prostate Cancer Intervention Versus Observational Trial (PIVOT) is another study related to these outcome measures. This study compared expectant management of prostate cancer with radical prostatectomy and found no difference in outcomes between White and AfricanAmerican males.27 The comparable outcomes in this study are concerning for despite these findings, AfricanAmerican men generally have an increased prostate cancer mortality. Thus, although w one-third of PIVOT trial participants were African-American males, the two arms of this study may not represent the treatment choices seen in general practice or that the study may have been inadequately powered to detect racial differences.
Molecular markers Certain molecular markers have also been linked to the clinical course and disease outcomes in men with prostate
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cancer.28,29 For instance, several studies have identified multiple single nucleotide polymorphisms (SNPs) that are preferentially expressed in African-Americans. Approximately 100 genes containing SNPs have been linked to an increased susceptibility to prostate cancer. Single nucleotide polymorphisms are especially valuable in disease detection, monitoring, and screening because they are stable throughout the lifetime of the individual and are not affected by external factors, such as lifestyle.29 Several studies have shown that African-American males are at increased risk of prostate cancer, in part, because they possess many of these SNPs. Xu et al. showed that 17 of 20 SNPs are more common in African-American males, and of the 17 SNPs, 2 were associated with a higher risk of prostate cancer.30 Freedman et al. showed that a 3.8MB interval on chromosome 8q24 was associated with prostate cancer and was found mainly in African-Americans.31 Families with a history of particular allelic variants within this interval were 9.46 times more likely to develop prostate cancer than those without these variants.31 In addition, several biomarkers have shown differential expression between aggressive and non-aggressive forms of prostate cancer.32 Unfortunately, these molecular findings have not yet been incorporated into screening protocols. In addition to increasing the accuracy and validity of screening, incorporating biomarkers would also decrease unnecessary invasive procedures which in turn would positively impact the net benefit of screening.33 It has also been suggested that such a screening program with molecular markers could identify aggressive tumors would decrease prostate cancer morbidity and mortality.In short, effective screening for prostate cancer in AfricanAmerican males will need to incorporate these molecular findings into protocols that successfully identify individuals at increased risk for aggressive prostate cancer. Such updated guidelines would allow for more precise identification of aggressive and metastatic disease, improve survival outcomes, and lower overall treatment costs.
Other considerations (Agent Orange) About three million Americans served in the armed forces in Vietnam during the 1960s and 70s. During this time, the military used large amounts of a defoliant called Agent Orange to eliminate forest cover. In a study conducted at Portland Medical Center and Oregon Health Sciences University, it was found that veterans exposed to Agent Orange were not only more likely to develop prostate cancer, but also more likely to develop a more aggressive form of the disease.34 Agent Orange exposure is associated with a 52% increase in the detection of prostate cancer and a 75% increased risk of high-grade prostate cancer.35
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Figure 1. Proposed schema for screening.
40-year-old AA veteran Informed consent DRE Serum PSA
Abnormal DRE or PSA or PSA parameters
Normal DRE and PSA
Repeat once annually for 3 yearsDetermine: PSA density PSA velocity
Biopsy SNP testing Abnormal
Treat as clinically appropriate.
If normal, repeat at age 50.
would be able to identify patients at risk of the more aggressive forms of prostate cancer and potentially decrease prostate cancer mortality, while minimizing the rates of false positive tests that may previously have led to unnecessary treatment of benign disease. Figure 1 below represents a potential screening flowchart. In future reports, we will investigate how comorbidities may affect prostate cancer incidence and mortality rate. The most prevalent comorbid disease with prostate cancer is cardiovascular disease. This also happens to be the number one cause of death in the African-American population. Investigating these links an exploiting any identifiable links may positively impact the morbidity and mortality associated with both these diseases.
REFERENCES 1. Prostate Cancer. (n.d.). Retrieved September 14, 2016, from http://www.cancer.org/cancer/prostatecancer/. 2. Odedina, F. T., Akinremi, T. O., Chinewundoh, F., et al. (2009). Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa. Infect Cancer Agent, 4(1), S2.
There was, however, no increase in the risk of low-grade prostate cancer. Men exposed to Agent Orange were also diagnosed at a younger age compared to men who were not exposed to the carcinogen. In conclusion, exposure to Agent Orange appears to potentiate the detection of prostate cancer and incidence of high-grade prostate cancer.35
CONCLUSION There is an immense need to implement new, more targeted prostate cancer screening guidelines for AfricanAmerican males within the nation-wide VHA system. African-American male veterans have a higher incidence of prostate cancer and present at a higher stage than their peers. Prostate cancer in these men tends to be more aggressive at presentation and/or transforms to more aggressive forms earlier. Social factors, such as delayed diagnosis, lower rates of treatment, and dietary factors, can all contribute to worse disease outcomes. In addition, the exposure of many veterans to Agent Orange has been shown to increase the incidence of high-grade prostate cancer. The current USPSTF guidelines recommending against prostate cancer screening were based on trials that were not fully generalizable to the African-American population because such individuals were underrepresented in the investigational cohorts. In including techniques that detect molecular markers, future guidelines
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https://doi.org/10.1186/1750-9378-4-S1-S2. 3. Administration, V. H. (2016, September 13). Veterans Health Administration. Retrieved September 15, 2016, from http:// www.va.gov/health/. 4. Planning, O. O. (2016, April 15). National Center for Veterans Analysis and Statistics. Retrieved September 15, 2016, from http://www.va.gov/vetdata/Veteran_Population.asp. 5. Surveillance, Epidemiology, and End Results Program. (n.d.). Retrieved September 15, 2016, from http://seer.cancer.gov/ statfacts/html/prost.html. 6. GPRA Report on Prostate Cancer.(2009). 7. Shenoy, D., Packianathan, S., Chen, A. M., & Vijayakumar, S. (2016). Do African-American men need separate prostate cancer screening guidelines? BMC Urol, 16, 19. 8. Brawn, P. N., Johnson, E. H., Kuhl, D. L., Riggs, M. W., & Speights, V. O. (1993). Johnson CF Stage at presentation and survival of white and black patients with prostate carcinoma. Cancer, 71, 2569e2573. 9. Powell, I. J., Bock, C. H., Ruterbush, J. J., & Sakr, W. (2010). Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men, and influences racial progression and mortality disparity. J Urol, 183(5), 1792e1796. 10. Ries, L. A. G., Melbert, D., Krapcho, M., et al. (Eds.). (2007). SEER Cancer Statistics Review, 1975-2004, National Cancer Institute, Bethesda, MD. Available at http://seer.cancer.gov/csr/1975_2 004/. Accessed October 16, 2009.
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approach to personalized prostate cancer screening and treatment. Curr Opin Urol, 25(1), 53e58. 30. Xu, J., Kibel, A. S., Hu, J. J., et al. (2009). Prostate cancer risk associated loci in African-Americans. Cancer Epidemiol Biomark Prev, 18(7), 2145e2149. 31. Freedman, M. L., Haiman, C. A., Patterson, N., et al. (2006). Admixture mapping identified 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A, 103(38), 14068e14073. 32. David, S., & Chan, D. W. (2014). Biomarkers in prostate cancer: what’s new? Curr Opin Oncol, 26(3), 259e264. 33. Kader, K., Sun, J., Reck, B., et al. (2012). Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial. Eur Urol, 62(6), 953e961. 34. Ansbaugh, N. (n.d.). ResultAgent Orange as a risk factor for high-grade prostate cancer Filters. Retrieved October 02, 2016; https://www.ncbi.nlm.nih.gov/pubmed/23670242. 35. Ansbaugh, N., Shannon, J., Mori, M., Farris, P. E., & Garzotto, M. (2013). Agent orange as a risk factor for high-grade prostate cancer. Cancer, 119(13), 2399e2404. https://doi.
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