Cumulative Risk Of Prostate Cancer Research Articles

Frequent mismatch-repair defects link prostate cancer to Lynch syndrome.

BackgroundA possible role for prostate cancer in Lynch syndrome has been debated based on observations of mismatch-repair defective tumors and reports of an increased risk of prostate cancer in mutation carriers. Potential inclusion of prostate cancer in the Lynch syndrome tumor spectrum is relevant for family classification, risk estimates and surveillance recommendations in mutation carriers.MethodsWe used the population-based Danish HNPCC-register to identify all prostate cancers that developed in mutation carriers and in their first-degree relatives from 288 Lynch syndrome families. The tumors were evaluated for clinicopathologic features and mismatch-repair status, and the cumulative risk of prostate cancer was determined.ResultsIn total, 28 prostate cancers developed in 16 mutation carriers and in 12 first-degree relatives at a median age of 63 years. The majority of the tumors were high-grade tumors with Gleason scores 8–10. Prostate cancer was associated with mutations in MSH2, MLH1 and MSH6 with loss of the respective mismatch repair protein in 69 % of the tumors, though a MSI-high phenotype was restricted to 13 % of the tumors. The cumulative risk of prostate cancer at age 70 was 3.7 % (95 % CI: 2.3–4.9).ConclusionWe provide evidence to link prostate cancer to Lynch syndrome through demonstration of MMR defective tumors and an increased risk of the disease, which suggests that prostate cancer should be considered in the diagnostic work-up of Lynch syndrome.

The heritability of prostate cancer in the Nordic Twin Study of Cancer.

Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age. To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability. The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability [heritability = 58% (95% confidence interval, 52%-63%)] of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary. Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age. Findings affect the search for genetic and epigenetic markers and frame prevention efforts.

Abstract 262: The PROFILE feasibility study: Genetic prostate cancer risk stratification for targeted screening

Abstract Introduction & Objectives: Prostate cancer (PC) screening is controversial and a better assessment of individualized PC risk is needed. Several single nucleotide polymorphisms (SNPs) conferring a cumulative risk of PC have been identified. We have explored the potential role of genetic markers for targeted screening in a population with increased risk of PC due to family history (FH). Material & Methods: PROFILE was developed as a pilot study to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. We also evaluated the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools. 116 men aged 40-69 with FH of PC were enrolled between October 2009 and December 2012. Cumulative SNP risk scores were calculated by summing 59 risk alleles for each locus using the weighted effect (log-additive model). DW-MRI was performed in 50 patients. Participants were asked to undergo a 10 core PB regardless of baseline PSA. Results: Median age 53 yrs (40-69) and median PSA was 1.15. One hundred and two men accepted to undergo a PB as primary PC screening. Twenty-three tumours were found (22.5% of biopsies) as well as seven men diagnosed with atypical small acinar proliferation (ASAP) (6.8%) and 8 men with high-grade prostatic intraepithelial neoplasia (HG-PIN) (7.8%). In total 37.1% received an abnormal result. Of those diagnosed with PC, 41% were intermediate or high risk and required treatment (compared to 24% in general population screening). The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed best in men with a ‘normal’ PSA (<3 ng/ml - AUC 0.63). Analyses of a 78 SNP profile incorporating the new 23 recently identified SNPs is underway. Conclusions: Our results indicate that PB used for PC screening in men with FH of PC identified a higher proportion of clinically significant PCs. The high AUC for DW-MRI would warrant a larger study. The incidence of ASAP is higher in this group than the general population.The SNP risk score was more predictive in men with PSA<3 where PB would not normally be undertaken, therefore an expanded study to investigate the role of genetic profiling in directing PB in PC screening is indicated. Citation Format: Rosalind Eeles, Zsofia Kote-Jarai, Antonis Antoniou, Pardeep Kumar, Christos Mikropoulos, Tokhir Dadaev, Natalie Taylor, Elizabeth Bancroft. The PROFILE feasibility study: Genetic prostate cancer risk stratification for targeted screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 262. doi:10.1158/1538-7445.AM2014-262

The PROFILE feasibility study: Genetic prostate cancer risk stratification for targeted screening.

22 Background: Prostate cancer (PC) screening is controversial and a better assessment of individualized PC risk is needed. Several single nucleotide polymorphisms (SNPs) conferring a cumulative risk of PC have been identified. We have explored the potential role of genetic markers for targeted screening in a population with increased risk of PC due to family history (FH). Methods: PROFILE was developed as a pilot study to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. We also evaluated the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools. One hundred sixteen men age 40 to 69 with FH of PC were enrolled between October 2009 and December 2012. Cumulative SNP risk scores were calculated by summing 59 risk alleles for each locus using the weighted effect (log-additive model). DW-MRI was performed in 50 patients. Participants were asked to undergo a 10 core PB regardless of baseline PSA. Results: Median age 53 (40 to 69) and median PSA was 1.15. One hundred and two men accepted to undergo a PB as primary PC screening. Twenty-three tumours were found (22.5% of biopsies) as well as seven men diagnosed with atypical small acinar proliferation (ASAP) (6.8%) and eight men with high-grade prostatic intraepithelial neoplasia (HG-PIN) (7.8%). In total 37.1% received an abnormal result. Out of the diagnosed PC 41% were intermediate or high risk and requiring treatment, which compares with 24% in general population screening. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed best in men with a normal PSA of <3(AUC 0.63). Analyses of a 78 SNP profile from the recent COGS results are underway. Conclusions: Ourresults indicate that PB is acceptable for PC screening in men with FH of PC. The significant AUC for DW-MRI would warrant a larger study. The incidence of ASAP is higher in this group than the general population.The SNP risk score was more predictive in men with PSA less than three where PB would not normally be undertaken, therefore an expanded study to investigate the role of genetic profiling in directing PB in PC screening is indicated.

Profile study: Genetic prostate cancer risk stratification for targeted screening.

5054 Background: Prostate cancer (PC) screening is controversial and better approaches are needed, including a better assessment of individualized PC risk. Several studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer a cumulative risk of PC. We have explored the potential role of genetic markers in identifying men who should be selectively targeted for screening in a population with increased risk of PC due to family history (FH) of the disease. Methods: PROFILE has been developed as a pilot study. The primary aim is to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. Secondary aims are to evaluate the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools in this population. From December 2010 men aged 40-69 with FH of PC were invited into the study until 100 men were enrolled. Blood samples were provided for PSA and DNA extraction. The cumulative SNP risk scores for each patient were calculated by summing 59 risk alleles for each locus using the weighted effect as estimated in previous studies (log-additive model). DW-MRI was performed in 50 patients. All participants were asked to undergo a 10 core PB regardless of baseline PSA. Those who declined PB have been excluded from this analysis. Data on side effects and cancer worry were also collected. Results: 35% of invited men entered the study. Median age was 53 yrs (40-69) and median PSA was 1.15. Ninety men accepted to undergo a PB as primary PC screening. Twenty-two tumours were found and 45% of them were clinically significant [Median age 64yrs (47-69), median PSA 5.4 (0.91-9.3)]. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed better in men with PSA<3(AUC 0.63). No severe side effect or adverse psychosocial variables were noted. Conclusions: Our results indicate that PB is acceptable as a means of PC screening in men with FH of PC. Overall, DW-MRI and PSA were more predictive of PC than the genetic risk score. As more SNPs are found, a larger study is warranted to evaluate their role in the PC screening algorithm.

Elevated Risk of Prostate Cancer Among Men With Lynch Syndrome

Prostate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous studies quantifying prostate cancer risk in LS have provided conflicting results. We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population. Ninety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03). The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.

Population-Based Estimate of Prostate Cancer Risk for Carriers of the HOXB13 Missense Mutation G84E

The HOXB13 missense mutation G84E (rs138213197) is associated with increased risk of prostate cancer, but the current estimate of increased risk has a wide confidence interval (width of 95% confidence interval (CI) >200-fold) so the point estimate of 20-fold increased risk could be misleading. Population-based family studies can be more informative for estimating risks for rare variants, therefore, we screened for mutations in an Australian population-based series of early-onset prostate cancer cases (probands). We found that 19 of 1,384 (1.4%) probands carried the missense mutation, and of these, six (32%) had a family history of prostate cancer. We tested the 22 relatives of carriers diagnosed from 1998 to 2008 for whom we had a DNA sample, and found seven more carriers and one obligate carrier. The age-specific incidence for carriers was estimated to be, on average, 16.4 (95% CI 2.5–107.2) times that for the population over the time frame when the relatives were at risk prior to baseline. We then estimated the age and birth year- specific cumulative risk of prostate cancer (penetrance) for carriers. For example, the penetrance for an unaffected male carrier born in 1950 was 19% (95% CI 5–46%) at age 60 years, 44% (95% CI 18–74%) at age 70 years and 60% (95% CI 30–85%) at age 80 years. Our study has provided a population-based estimate of the average risk of prostate cancer for HOXB13 missense mutation G84E carriers that can be used to guide clinical practice and research. This study has also shown that the majority of hereditary prostate cancers due to the HOXB13 missense mutation are ‘sporadic’ in the sense that unselected cases with the missense mutation do not typically report having a family history of prostate cancer.

1917 DIAGNOSTIC VALUE OF FREE PROSTATE-SPECIFIC ANTIGEN AMONG MEN WITH PROSTATE-SPECIFIC ANTIGEN 2.0 TO 4.0NG/ML AT SCREENING COHORT IN JAPAN

You have accessJournal of UrologyProstate Cancer: Detection and Screening III1 Apr 20121917 DIAGNOSTIC VALUE OF FREE PROSTATE-SPECIFIC ANTIGEN AMONG MEN WITH PROSTATE-SPECIFIC ANTIGEN 2.0 TO 4.0NG/ML AT SCREENING COHORT IN JAPAN Mitsuharu Sasaki, Shigeto Ishidoya, Akihiro Ito, Hideo Saito, Daisuke Shibuya, and Yoichi Arai Mitsuharu SasakiMitsuharu Sasaki Sendai, Japan More articles by this author , Shigeto IshidoyaShigeto Ishidoya Sendai, Japan More articles by this author , Akihiro ItoAkihiro Ito Sendai, Japan More articles by this author , Hideo SaitoHideo Saito Sendai, Japan More articles by this author , Daisuke ShibuyaDaisuke Shibuya Sendai, Japan More articles by this author , and Yoichi AraiYoichi Arai Sendai, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2074AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To investigate the usefulness of measuring the percentage of free prostate-specific antigen (%fPSA), we performed comprehensive measurement of total PSA (tPSA) and free PSA(fPSA) for all screening cohort and evaluated as a predictor of the future risk of developing prostate cancer in men with initial PSA levels of 2.0 to 4.0 ng/ml. METHODS We annually examined tPSA and fPSA for Japanese screening population between July 2001 and March 2010 (Architect®, Abbott, USA). Among 8,319 men participated in this screening (age:40 to 79), 5,377 men underwent twice or more examinations and were enrolled in this study. We deicided that men with tPSA over 4 ng/ml or tPSA ranging from 2 to 4 ng/ml with %fPSA of <12% were screening positive and performed 12 core biopsy. Screening negative and biopsy negative men were longitudinally followed up. They were planned to undergo subsequent annual tPSA/fPSA screening until March 2010. We calculated cumulative risk of prostate cancer retrospectively. RESULTS During the median follow-up of 34 months (range, 10–95 months), 92 men were initial screening negative and were thereafter diagnosed as prostate cancer. Among them, 42.4% (n=39) had a Gleason score of 4+3=7 or higher. Cumulative risk of prostate cancer was 1.71% (95%CI, 1.40–2.09%). Men with a initial %fPSA in the lowest quartile (<13.3%) showed a 23.6-fold risk compared with those with a level in the highest quartile (>21.4%). And the intermediate quartiles (17.0-21.4 % and 13.3-16.9%) showed a 6.0 and 10.2-fold risk respectively. CONCLUSIONS This study is the largest series of evaluating the serum tPSA and %fPSA values in a population-based cohort in Japan. In men with a tPSA 2.0 to 4.0ng/ml, a low %fPSA is a strong predictor of subsequent diagnosis of prostate cancer. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e773-e774 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mitsuharu Sasaki Sendai, Japan More articles by this author Shigeto Ishidoya Sendai, Japan More articles by this author Akihiro Ito Sendai, Japan More articles by this author Hideo Saito Sendai, Japan More articles by this author Daisuke Shibuya Sendai, Japan More articles by this author Yoichi Arai Sendai, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Prostate Disease Risk Factors among a New Zealand Cohort

Background: Prostate cancer is a leading public health burden worldwide, and in New Zealand it is the most commonly registered cancer and the third leading cause of cancer deaths among males. Genetic variability and its associations with diet, demographic and lifestyle factors could influence the risk of this disease. Methods: The single nucleotide polymorphisms (SNPs) within a group of antioxidant genes and related markers were tested between patient and control cohorts, adjusted for significant differences between basic lifestyle and demographic characteristics. Results: Increasing age, smoking and low serum selenium levels were significantly associated with an increased risk for prostate disease. Alcohol consumption increased the glutathione peroxidase (GPx) activity. A significant reduction in alcohol consumption was recorded with prostate disease. Three SNPs, namely GPx1 rs1050450, SEL15 rs5845 and CAT rs1001179, were significantly associated with prostate disease risk. A cumulative risk of prostate cancer was noted with 6 risk alleles. A lower GPx activity was recorded with prostate disease compared to the controls. However, the GPx1 rs1050450 allele T in association with prostate cancer recorded a significantly higher GPx activity compared to the controls. Conclusions: These data point to a possibility of identifying individuals at risk of prostate cancer for better management purposes.

Lead-time in the European Randomised Study of Screening for Prostate Cancer

Background Lead-time is defined as the time by which screening advances the diagnosis compared with absence of screening. A sufficiently long lead-time needs to be achieved so that cancer can be detected while still curable. A very short lead-time may indicate poor sensitivity of the screening test, while a very long lead-time suggests overdiagnosis. Material and methods In the first screening round, a total of 56,294 men aged 55–74 years were screened with serum prostate specific antigen (PSA) in five countries of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with an overall detection rate (prevalence) of 2.8% (1972 prostate cancers). Prostate cancer incidence among 92,142 men randomly allocated to the control arm of the trial was also assessed. Lead-time was estimated as the time required to accumulate a similar cumulative risk of prostate cancer in the control arm to the detection rate in the intervention arm, i.e. from the ratio of detection rate (prevalence of screen-detected cases) and expected incidence (cumulative risk). Results Using a serum PSA cut-off of 4 ng/ml, the mean lead-time in the whole study population was estimated as 6.8 years (95% confidence interval (95% CI) 7.9–8.4). It was 8 years in The Netherlands, 6 in Sweden and Finland, 5 in Italy and 4 in Belgium. The mean lead-time was similar, 6–7 years, at ages 50–64 years, but close to 8 years among men aged 65–74 years. A lower PSA cut-off level of 3 ng/ml used in Sweden and The Netherlands prolonged the mean lead-time by approximately 1 year. Lead-time based on advanced prostate cancer only was slightly shorter, mean 5.3 years (95% CI 4.6–6.0). The lead-time for the second screening round was slightly shorter than that for the first (5.9, 95% CI 5.4–6.4), reflecting a similar relation between detection rate and control group incidence. Conclusion The lead-time for prostate cancer found in ERSPC substantially exceeded that found for breast, cervical and colorectal cancer screening. One round of prostate cancer screening can advance clinical diagnosis by 4–8 years. Overdiagnosis or detection of non-progressive tumours may contribute substantially to the lead-time.

Diagnostic Value of Free Prostate-Specific Antigen among Men with a Prostate-Specific Antigen Level of

ObjectivesThe percentage of free prostate-specific antigen (%fPSA) improves the diagnostic accuracy for prostate cancer when the serum level of total PSA (tPSA) is elevated. Approximately 14% of men with a tPSA below 3μg/l have prostate cancer on biopsy, but the diagnostic value of %fPSA in such men is rather unknown. The purpose was to estimate the impact of %fPSA on future prostate cancer risk among men with a normal tPSA in prostate cancer screening. Subjects and methodsThe first round of the Finnish arm of the European Randomized Trial for Screening of Prostate Cancer in 1996 to 1999 comprised 20,793 men aged 55–67 yr. Screen-negative men (tPSA level below 3.0μg/l, n=17,680) were followed up until the end of 2003. Cumulative risk of prostate cancer was calculated as a function of %fPSA. ResultsDuring the median follow-up of 5.8 yr (range, 0–7.7 yr), 327 men were diagnosed with prostate cancer and 25% of them had a Gleason score of 7 or higher. Five years after the first screening, cumulative risk of prostate cancer was 1.7% (95%CI, 1.5–1.9%). Men with a %fPSA in the lowest quartile (<14.2%) showed a 6.9-fold risk compared with those with a level in the highest quartile (>23.7%). ConclusionsIn men with a low serum tPSA, a low %fPSA is a strong predictor of later diagnosis of prostate cancer.

Detection of Prostate Cancer via Biopsy in the Medicare-SEER Population During the PSA Era

Despite the considerable attention given to the prostate-specific antigen (PSA) as a screening test for prostate cancer, it is needle biopsy--and not the PSA test result--that actually establishes the diagnosis of prostate cancer. We sought national estimates on the proportion of men found to have prostate cancer after a needle biopsy of the prostate and the risk of subsequent biopsies among those not found to have prostate cancer. We linked Medicare claims data to Surveillance, Epidemiology, and End Results (SEER) data to analyze outcomes after 10,429 needle biopsies performed in 1993 through 2001 in 8273 men aged 65 years and older enrolled in Medicare Part B who resided in a SEER area. We determined the proportion of needle biopsies that were followed by a diagnosis of prostate cancer, the cumulative risk of prostate cancer following multiple biopsies, and the risk of subsequent biopsy among men not found to have prostate cancer in the previous biopsy. All statistical tests were two-sided. The overall proportion of needle biopsies found to contain prostate cancer was 32% (95% confidence interval [CI] = 31% to 33%). The yield increased with age (26% for men aged 65-69 years, 31% for men aged 70-74 years, 35% for men aged 75-79 years, and 41% for men aged 80 years and older; P(trend)<.001). The cumulative risk of prostate cancer diagnosis increased with repeated biopsy, with 50% of men receiving a prostate cancer diagnosis after two biopsies, 62% after three biopsies, and 68% after four biopsies. Among men whose first recorded biopsy did not detect prostate cancer, the risk of having a subsequent biopsy was 11.6% (95% CI = 11% to 12%) at 1 year and 38% (95% CI = 36% to 40%) at 5 years. About one-third of prostate biopsies identified prostate cancer in this population. Men not found to have prostate cancer on a first biopsy frequently undergo repeat biopsies, which raise the cumulative risk of prostate cancer diagnosis.

Toremifene for the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia: Results of a Double-Blind, Placebo Controlled, Phase IIB Clinical Trial

A randomized, double-blind, dose finding, placebo controlled, parallel group clinical study was done to determine the incidence of prostate cancer in men with high grade prostatic intraepithelial neoplasia treated with toremifene. A total of 514 patients with high grade prostatic intraepithelial neoplasia and no evidence of prostate cancer on screening biopsy were randomized to 20, 40 or 60 mg toremifene, or placebo daily for 12 months. Patients underwent re-biopsy at 6 and 12 months. The number of evaluable patients, that is those with 1 on study biopsy who were compliant, was 447. The cumulative risk of prostate cancer was decreased in patients on 20 mg toremifene compared with placebo (24.4% vs 31.2%, p <0.05). The annualized rate of prevention was 6.8 cancers per 100 men treated. In patients with no biopsy evidence of cancer at baseline and 6 months, the 12-month incidence of prostate cancer was decreased by 48.2% with 20 mg toremifene compared with placebo (9.1% vs 17.4%, p <0.05). The 20 mg dose was most effective but cumulative and 12-month incidences of prostate cancer were lower for each toremifene dose vs placebo with a cumulative risk of 29.2% and 28.1%, and a 12-month incidence of 14.3% and 13.0% for 40 and 60 mg, respectively. Gleason scores were similar across treatments. The overall incidence of drug related and serious adverse events did not differ between any of the toremifene groups and the placebo group. Toremifene decreased the incidence of prostate cancer by 1 year and had a tolerability profile comparable to that of placebo in a high risk population.

Individualized Screening Interval for Prostate Cancer Based on Prostate-Specific Antigen Level

The aim of the present study was to evaluate the future cumulative risk of prostate cancer in relation to levels of prostate-specific antigen (PSA) in blood and to determine whether this information could be used to individualize the PSA testing interval. The study included 5855 of 9972 men (aged 50-66 years) who accepted an invitation to participate in a prospective, randomized study of early detection for prostate cancer. We used a protocol based on biennial PSA measurements starting from 1995 and 1996. Men with serum PSA levels of 3.0 ng/mL or more were offered prostate biopsies. Among the 5855 men, 539 cases of prostate cancer (9.2%) were detected after a median follow-up of 7.6 years (up to July 1, 2003). Cancer detection rates during the follow-up period in relation to PSA levels were as follows: 0 to 0.49 ng/mL, 0% (0/958); 0.50 to 0.99 ng/mL, 0.9% (17/1992); 1.00 to 1.49 ng/mL, 4.7% (54/1138); 1.50 to 1.99 ng/mL, 12.3% (70/571); 2.00 to 2.49 ng/mL, 21.4% (67/313); 2.50 to 2.99 ng/mL, 25.2% (56/222); 3.00 to 3.99 ng/mL, 33.3% (89/267); 4.00 to 6.99 ng/mL, 38.9% (103/265); 7.00 to 9.99 ng/mL, 50.0% (30/60); and for men with an initial PSA of 10.00 ng/mL or higher, 76.8% (53/69). Not a single case of prostate cancer was detected within 3 years in 2950 men (50.4% of the screened population) with an initial PSA level less than 1 ng/mL. Retesting intervals should be individualized on the basis of the PSA level, and the large group of men with PSA levels of less than 1 ng/mL can safely be scheduled for a 3-year testing interval.

Mendelian inheritance of familial prostate cancer.

Previous studies have demonstrated familial clustering of prostate cancer. To define the nature of this familial aggregation and to assess whether Mendelian inheritance can explain prostate cancer clustering, proportional hazards and segregation analyses were performed on 691 families ascertained through a single prostate cancer proband. The proportional hazards analyses revealed that two factors, early age at onset of disease in the proband and multiple affected family members, were important determinants of risk of prostate cancer in these families. Furthermore, segregation analyses revealed that this clustering can be best explained by autosomal dominant inheritance of a rare (q = 0.0030) high-risk allele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer for carriers revealed that the allele was highly penetrant: by age 85, 88% of carriers compared to only 5% of noncarriers are projected to be affected with prostate cancer. The best fitting autosomal dominant model further suggested that this inherited form of prostate cancer accounts for a significant proportion of early onset disease but overall is responsible for a small proportion of prostate cancer occurrence (9% by age 85). These data provide evidence that prostate cancer is inherited in Mendelian fashion in a subset of families and provide a foundation for gene mapping studies of heritable prostate cancer. Characterization of genes involved in inherited prostate cancer could provide important insight into the development of this disease in general.