e. low-grade prostate cancer.

Answers

1.e. Is fluctuating. According to Surveillance, Epidemiology, and End Results (SEER) estimates, the incidence of prostate cancer peaked in 1992, approximately 5 years after the introduction of PSA as a screening test, fell precipitously until 1995, increased slowly at a slope similar to that observed before the PSA era until 2001, and has fluctuated year-to-year since 2001, likely related to changing screening practices in the general population.

2.b. African Americans. African-American men have the highest reported incidence of prostate cancer in the world, with an incidence of 255.5 per 100,000 person-years and a relative incidence of 1.6 compared with white men in the United States (American Cancer Society). Although African Americans have experienced a greater decline in mortality than white men since the early 1990s, their death rates remain 2.4 times higher than whites. Many biologic, environmental, and social hypotheses have been advanced to explain these differences, ranging from postulated differences in genetic predisposition; differences in mechanisms of tumor initiation, promotion and/or progression; higher fat diets, higher serum testosterone levels, or higher body mass index; structural, financial, educational and cultural barriers to screening, early detection and aggressive therapy; and physician bias. There are currently no data that clearly indicate any of these hypotheses are the determinants of the observed differences in incidence or mortality, and it seems likely that the source of the disparity is multifactorial.

3.c. Incidence is highest in countries with the highest rates of screening. The age-standardized incidence rates per 100,000 men are highest in the highest income regions of the world where PSA screening is more commonly practiced, including North America (85.6), Australia–New Zealand (104.2), Western Europe (93.1), and Scandinavia (73.1), and lowest in Asia (7.2) and Northern Africa (8.1).

4.d. Contamination of the control arm with PSA screening is a limitation of the PLCO cancer screening trial. The trial has been criticized for high rates of prescreening (44% reported undergoing PSA testing before enrollment), poor compliance with prostate biopsy, and 52% contamination by ad hoc screening in the control arm. A follow-up study in which PLCO participants were questioned about PSA testing reported a 15% non-PSA testing rate in

the control arm of PLCO, which is identical to the noncompliance with screening in the screening arm.

5.c. 2 to 3 times higher. In someone with a positive family history of prostate cancer, the relative risk increases according to the number of affected family members, their degree of relatedness, and the age at which they were affected (see Table 107-1).

Table 107-1

Family History and Risk of Prostate Cancer

Data from meta-analysis assessing risk of prostate cancer for relatives of patients with prostate carcinoma (Zeegers MP, Jellema A, Ostrer H. Empiric risk of prostate carcinoma for relatives of patients with prostate carcinoma: a meta-analysis. Cancer 2003;97:1894–903).

6.e. All of the above. All of these biologic functions are represented in genes shown to predispose men with variant gene structure to prostate cancer.

7.e. All of the above. Gene fusions, once thought to be the exclusive domain of hematologic malignancies, are common in prostate cancer and are fundamental drivers of prostate cancer growth and progression. The most commonly observed fusion results from the fusion of the 5′ untranslated end of TMPRSS2 serine protease to members of the ETS family of oncogenic transcription factors, bringing the latter growth-promoting genes under androgen control. The most common fusion identified in localized prostate cancer involves TMPRSS2 fused to ERG (ETS-related gene, 21q22.3) in approximately 50% of patients (Kumar-Sinha et al, 2008).* The

TMPRSS2 gene is prostate specific and is expressed in both benign and malignant prostatic epithelium. TRMPSS-related gene fusions are highly specific for the presence of prostate cancer.

8.c. Aromatase-knockout mice all develop prostate cancer in their lifetime.

Aromatase-knockout mice cannot produce 17β-estradiol locally in the

prostate, and despite elevated testosterone and dihydrotestosterone they do not develop prostate cancer (McPherson et al, 2001). All of the other statements are correct.

9.d. Higher risk of developing prostate cancer. A recent combined analysis found a positive correlation between serum concentration of IGF-1 and subsequent prostate cancer risk. The odds ratio (OR) in the highest versus

lowest quintile was 1.38 (95% confidence interval (CI) 1.19-1.60) (Roddam et al, 2008).

.e. Polymorphisms conferring lower vitamin D receptor activity are associated with increased risk for prostate cancer. Interest in vitamin D as a determinant of prostate cancer risk comes from several epidemiologic observations: (1) men living in northern latitudes with less exposure to

sunlight-derived ultraviolet (UV) have a higher mortality rate from prostate cancer; (2) prostate cancer occurs more frequently in older men, in whom vitamin D deficiency is more common both because of less UV exposure and age-related declines in the hydroxylases responsible for synthesis of active vitamin D; (3) African Americans, whose skin melanin blocks UV radiation and inhibits activation of vitamin D, have the highest worldwide incidence and mortality rates for prostate cancer; (4) dietary intake of dairy products rich in calcium, which depresses serum levels of vitamin D, are associated with a higher risk of prostate cancer; and (5) native Japanese, whose diet is rich in vitamin D derived from fish, have a low incidence of prostate cancer. Finally, polymorphisms resulting in vitamin D receptors with lower activity have been associated with increased risk for prostate cancer.

.c. Lower serum PSA levels. Higher body mass index has been associated with increased biologic measures of oxidative stress, lower circulating androgen levels, lower serum PSA (perhaps as a consequence of lower

circulating androgens), higher serum free IGF-1 levels, and worse cancerspecific survival after radical prostatectomy. Obese men have lower PSA levels and larger prostates, which together may lead to fewer biopsies and more sampling error, potentially contributing to an increased risk of highgrade disease.

.e. All of the above. A variety of genes implicated in prostate cancer initiation and progression are affected by these processes, including hypermethylation of hormonal response genes (ERαA, ERβ, and RARβ), genes controlling the cell cycle (CyclinD2 and 14-3-3σ), tumor cell invasion/tumor architecture genes (CD44), DNA repair genes (GSTpi, GPX3, and GSTM1), tumor

suppressor genes (APC, RASSF1α, DKK3, p16INK4?−α, E-cadherin, and p57WAF1), signal transduction genes (EDNRB and SFRP1), and inflammatory response genes (PTGS/COX2); hypomethylation of CAGE, HPSE, and PLAU; histone hypoacetylation of CAR, CPA3, RARB, and VDR; and histone methylation of GSTP1 and PSA.

.c. Genetic heterogeneity in the cause of prostate cancer. Current evidence suggests that most prostate cancer is polygenic in origin. GWAS studies have identified more than 70 risk alleles and chromosomal loci, many of which

occur in noncoding areas of the genome.

.e. All of the above. Epigenetic events affect gene expression without altering the actual sequence of DNA, and in prostate cancer all of the listed mechanisms are important.

.e. An increased risk of prostate cancer in those taking vitamin E alone. SELECT demonstrated no beneficial effect of vitamin E or selenium on the risk of prostate cancer (alone or in combination). Hazard ratios (HR) for prostate cancer were 1.13 (99% CI: 0.95-1.13) for vitamin E, 1.04 (99% CI: 0.87-1.24) for selenium, and 1.05 (99% CI: 0.88-1.25) for selenium and vitamin E. A follow-up study that included an additional 54,464 personyears showed that dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men (HR 1.17; 95% CI: 1.004-1.36; P = 0.008).

.a. Cooked foods. Lycopene is a red-orange carotenoid found primarily in tomatoes and tomato-derived products including tomato sauce, tomato paste, and ketchup, and other red fruits and vegetables. In an in vivo model in which male rats were treated with N-methyl-N-nitrosourea and testosterone to induce prostate cancer, a protective effect was observed for both calorie restriction and tomato powder but not pure lycopene. This observation suggests that

tomato products contain compounds in addition to lycopene that modify prostate carcinogenesis and that reduced caloric consumption and a diet rich in tomato-based foods may be more beneficial than taking oral lycopene supplements in reducing the risk of prostate cancer.

.d. Sexual dysfunction. The incidence of erectile dysfunction and other sexually related side effects was more frequent in the finasteride arm, whereas the incidence of prostatitis, urinary tract infection, benign prostatic hyperplasia, urinary retention, and surgical intervention for lower urinary tract symptoms or retention was lower.

Chapter review

1.The median age for diagnosis of prostate cancer is 68 years. Men with prostate cancer younger than 50 years account for 2% of all cases. The average age of death from prostate cancer is 77 years.

2.Prostate cancer is an indolent disease with a very low cause-specific death rate and will only impact life expectancy in a minority of men.

3.The risk of developing prostate cancer increases with the number of family members with prostate cancer, their degree of relatedness, and the age at which they were affected.

4.Approximately 15% of patients with prostate cancer have the familial or hereditary form.

5.Carriers of the HOXB13, BRCA1 and BRCA2 genes have an increased risk for developing prostate cancer. BRCA2 related tumors are more aggressive.

6.Chronic inflammation and infections may play a role in the genesis of prostate cancer.

7.Estrogens may act as procarcinogens in the prostate.

8.The androgen receptor is biologically important in the development and progression of prostate cancer even after androgen deprivation therapy.

9.Finasteride improves the sensitivity of PSA and the digital rectal exam.

10.Several studies have shown that there is no increased risk for developing prostate cancer in those who have had a vasectomy.

11.The chemoprevention trials with 5 alpha reductase inhibitors showed a reduced risk of diagnosing prostate cancer by about 25%. While it is unclear in these trials whether there is an increased risk of developing high-grade tumors in those who took 5 alpha reductase inhibitors for chemoprevention, several studies have shown no difference in overall mortality between patients who took 5 alpha reductase inhibitors and those who took a placebo.

12.African-American men have the highest reported incidence of prostate cancer in the world.

13.The most common gene fusion identified in localized prostate cancer involves TMPRSS2 fused to ERG (ETS-related gene, 21q22.3) in approximately 50% of patients. The TMPRSS2 gene is prostate specific, and is expressed in both benign and malignant prostatic epithelium. TRMPSS-related gene fusions are highly specific for the presence of prostate cancer.

14.Polymorphisms resulting in vitamin D receptors with lower activity have been associated with increased risk for prostate cancer.

15.Higher body mass index has been associated with increased biologic measures of oxidative stress, lower circulating androgen levels, lower serum PSA (perhaps as a consequence of lower circulating androgens), higher serum free IGF-1 levels, and worse cancer specific survival after radical prostatectomy.

16.There is no beneficial effect of vitamin E or selenium on altering the risk of prostate cancer (alone or in combination).

* Sources referenced can be found in Campbell-Walsh Urology, 11th Edition, on the Expert Consult website.