Incidence Of PCa Research Articles

Abstract PR11: Exome sequencing identifies germline mutations in African American families with hereditary prostate cancer

Abstract Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer death among men in the United States. Although it has been demonstrated that genetics plays a strong role in PCa, the genetic risk factors responsible for PCa remain poorly understood. Family history is a significant risk factor for PCa and African American (AA) men have the highest PCa incidence among ethnic/racial groups. Genetic analysis of AA families with PCa could facilitate the identification of genetic components contributing to PCa susceptibility. However, this area of research has not been sufficiently explored. We performed Exome sequencing on one affected and one unaffected man from one AA hereditary PCa family, which consists of 9 affected and 18 unaffected men in three generations. We identified 226 novel nonsynonymous variants in the affected man. We examined these mutations in remaining family members and narrowed down to 12 novel mutations which cosegregate with the disease in this family. Further analysis of the 12 mutations in affected and unaffected men from an additional 19 AA hereditary PCa families, 95 AA men with sporadic PCa and 95 unaffected AA control subjects identified three candidate gene mutations. One of the mutations was detected in three and the other two in two AA PCa families but they were either absent or were present in a very low frequency in unaffected control subjects. The three candidate mutations are now under further investigation in additional AA PCa families. The detailed bioinformatics analysis and the significance of these mutations in PCa susceptibility will be discussed. This abstract is also presented as Poster C67. Citation Format: Zemin Wang, Chiping Qian, Elisa M. Eledet, George Washington, Jovanny Zabaleta, Jennifer J. Hu, Diptasri Mandal, Wanguo Liu. Exome sequencing identifies germline mutations in African American families with hereditary prostate cancer. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr PR11. doi:10.1158/1538-7755.DISP13-PR11

Influence of metformin use on PSA values, free-to-total PSA, prostate cancer incidence and grade and overall survival in a prospective screening trial (ERSPC Aarau).

To analyze the effect of the oral antidiabetic drug metformin on PSA level, free-to-total PSA ratio (f/t-ratio), PCa incidence and grade as well as mortality in men participating in a population-based screening trial. Data from 4,314 men aged 55-70 years from a population-based PSA-screening trial (ERSPC Aarau) were analyzed. Information on metformin exposure was obtained by a self-administered questionnaire. Serum PSA threshold at ≥3 ng/ml triggered prostate biopsy. Data on PCa incidence and mortality were obtained through registry linkages. Median follow-up time was 7.6 years. Mean age at baseline was 65.5 years (±SD 4.4). In all, n = 150 (3.5 %) men used metformin [metf+]. Mean baseline PSA levels were comparable between both groups ([metf+] 1.6 ng/ml ± 2.4 vs. [metf-] 1.8ug/l ± 2.2, p = 0.4) while f/t-ratio was slightly higher in metformin users ([metf+] 30.7 % ± 10.9 vs. [metf-] 27.3 % ± 10.9, p = 0.01). Overall, n = 372 (8.6 %) PCa cases were detected. Neither cumulative PCa incidence (n = 11; 7.3 % [metf+] vs. n = 361 8.7 % [metf-]; p = 0.5) nor d`Amico risk groups were significantly different between both groups. One man in each group (metf+ 0.7 % and metf- 0.02 %) died from PCa (p < 0.0001), respectively. All-cause mortality was significantly higher among met + compared to met- (adjusted OR 2.50, 95 %CI 1.59-3.82; p = 0.0001). No significant differences in PSA levels or PCa incidence and grade were observed. The slightly higher f/t-ratio did not result in lower PCa detection rate. Metformin users were at significantly higher risk of all-cause mortality. The relatively small number of men on metformin is a main limitation of the study.

Abstract 2502: Immunoseroproteomic profiling of autoantibodies to tumor associated autoantigens in African American and Caucasian men with prostate cancer

Abstract Cancer-associated serum autoantibodies are generally considered as “sensors” of molecular events associated with tumorigenesis, and thus constitute promising biomarkers for cancer detection and management, as well as tools for the identification of novel oncoproteins. Immunoseroproteomics is a standard approach for the identification of serum autoantibodies reacting with tumor-associated antigens (TAA) in human cancer populations. This approach entails using one- and two-dimensional gel electrophoresis of proteins from aggressive PCa cell lines, coupled with immunoblotting and mass spectrometry, to characterize the anti-TAA antibody repertoire in a given patient. Immunoseroproteomics has been applied mostly to cancer patients of European and Asian ancestry, and has not been used in African American (AA) patients with PCa. AA men show a disproportionately high incidence and mortality of PCa, compared to other ethnic groups, and display more aggressive tumors developing at a younger age. Recent epidemiological studies suggest that after adjusting for socioeconomic and health care-related factors, these disparities still persist, pointing to biological factors as contributors to these disparities. Growing evidence indicates that genes associated with immune function and autoimmunity are dysregulated in prostate tumors from AA compared to Caucasian (CC) men. This prompted us to initiate an immunoproteomic analysis of the anti-TAA autoantibody response in AA and CC men with PCa. We hypothesize the anti-TAA autoantibody response might be greater in AA patients with PCa, and that it could be used to identify novel blood biomarkers for early screening and management of the disease. In initial studies, we screened aggressive PCa cell lysates with serum samples from AA (n=39) and CC (n=50) men. Early results showed the autoantibody response in the AA cohort had a greater autoantibody frequency and reactivity than the response in CC patients. Immunoproteomic analysis of select AA sera revealed alpha-enolase, fumarate hydratase, and annexin A11 as candidate TAAs in PCa. These proteins have been implicated in previous PCa studies. Additional validation will come from determining the frequency of the autoantibody response and the expression of candidate TAAs in PCa tissue microarrays. We are currently expanding our immunoseroproteomics analysis to sera from a larger cohort (n&amp;gt;200) of AA men and CC men (n&amp;gt;100) with and without PCa, stratified by age and cancer stage. Comparing the anti-TAA repertoire between AA and CC men with and without PCa will aid in the customization of TAA arrays for autoantibody profiling and lead to the identification of promising biomarkers for early PCa detection and monitoring of tumor progression in AA populations. Our approach may also help identify unique immunoserological signatures in AA and CC men to reveal biological determinants of PCa health disparities. Citation Format: Tino Wilson Sanchez, Saied Mirshahidi, Nathan Wall, Susanne Montgomery, Colwick Wilson, Carlos A. Casiano. Immunoseroproteomic profiling of autoantibodies to tumor associated autoantigens in African American and Caucasian men with prostate cancer. [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 2502. doi:10.1158/1538-7445.AM2014-2502

MP69-05 PSA VALUES AND KINETICS OF BRCA1 AND BRCA2 MUTATION CARRIERS AT HIGH RISK FOR PROSTATE CANCER

METHODS: Overall, 10,311 men aged 55-70 years were randomized 1:1 between 1998 2003 to the screening or control group, respectively. Men with PSA between 1.0 2.99ng/ml and a F/T PSA of 20% underwent prostate biopsy at baseline (initial study during the first screening round) and were analyzed separately. Men were invited every 4 years for PSA-test. A PSA of 3.0ng/ml was used as a trigger for prostate biopsy. Through registry linkages, information on PCa incidence was obtained. Primary outcome measure was PCa diagnosis. PCa risk stratification was defined according to d`Amico criteria, high risk PCa included men with N1 and/or M1. F/T PSA at study entrance was divided into quartiles and Cox regression analysis was used to assess the influence of age, family history, baseline PSA and F/T PSA at study entrance. RESULTS: The median follow-up time was 12.2 years. At baseline, 1371 (31.6%) men had a PSA of 1.0 1.99 and 563 (12.9%) men had 2.0 2.99ng/ml. Mean age was 61.6 and 62.7 years, respectively. The cumulative hazard rate for intermediate or high risk PCa diagnosis among men with baseline PSA values of 1.00 1.99 and 2.00 2.99ng/ml was 6.0 and 7.5 times higher (95%CI 3.9-9.2, p < 0.0001; 95%CI 4.6-12.2, p < 0.0001) as compared tomenwith PSA values of 0 0.99 at study entrance, respectively. Men diagnosed with intermediate/high risk PCa during follow-up had statistically significant lower F/T PSA levels at baseline than those without cancer. After adjusting for age, PSA at baseline and family history on multivariate analysis, baseline F/T PSA was the most important predictor for intermediate or high risk PCa during follow-up. Compared to the highest F/T PSA quartile, the risk was more than doubled in the lowest F/T PSA quartile (HR 2.3, 95%CI 0.4-1.9; p 1⁄4 0.006). CONCLUSIONS: Lower F/T PSA at study entrance was significant predictor for intermediate or high risk PCa throughout the follow-up of 12.2 years. These results support the idea of incorporating F/T PSA as an essential element of the risk based model for the smarter PCa screening.

MP45-15 A PROSPECTIVE ANALYSIS OF THE EFFECTS OF FOCAL THERAPY FOR PROSTATE CANCER ON ERECTILE FUNCTION FROM A COMBINED ANALYSIS OF 3 PROSPECTIVE TRIALS

rates to QOL surveys, as well as factors associated with response, in these two patient populations. METHODS: Patients who underwent surgery for RCC or PCa at our institution between 2006 and 2012 were offered enrollment in a prospective registry that included baseline and annual QoL assessment. We identified 201 patients in the RCC registry and 616 patients in the PCa registry who completed a baseline QoL survey and were mailed a follow-up QoL at one and two years post surgery [RCC: SF-36, FACTeG (73 questions), PCa: EPIC, IIEF, Max-PC (80 questions)]. We compared patient characteristics between responders (i.e. those that returned at least a one or two-year follow-up) and non-responders using a Wilcoxon rank-sum test for continuous variables and a Fisher’s Exact test for categorical variables. To compare cancer-specific survival (CSS) between responders and non-responders we employed Cox Proportional Hazards models. All statistical tests were two-sided, with significance set at p1⁄4 0.05. RESULTS: The overall response rate for the PCa and RCC groups were 63% and 48% (p<0.001), respectively. Interestingly, this difference in response rate remained when we limited analysis to only those with early stage disease (pT2a for PCa and pT1 RCC, 62% vs. 52%; p1⁄40.03). Among the PCa group, characteristics associated with response included older age (64.1 vs 62.6 years, p1⁄40.032) and robotic versus open surgery (56% vs 44%; p1⁄40.009). We observed no significant difference in CSS between PCa responders and non-responders. By comparison, we identified no characteristics that were associated with response in RCC group; however, non-responders had poorer CSS compared to responders. CONCLUSIONS: Surgically treated PCa patients have significantly higher QOL survey response rates than those patients with RCC. Societal awareness and education regarding RCC remains behind that of PCa, possibly due to the increased incidence of PCa, as well as an increase in men’s health awareness programs. The results may also indicate that patient’s expectations regarding surgery for RCC rely more heavily on survival, as opposed to PCa, where long-term quality of life continues to be a focus following surgery.

OP1-02 THE ASSOCIATION BETWEEN MIF-173 G>C POLYMORPHISM AND PROSTATE CANCER IN SOUTHERN CHINESE.

You have accessJournal of UrologyOutstanding Posters: Research1 Apr 2014OP1-02 THE ASSOCIATION BETWEEN MIF-173 G>C POLYMORPHISM AND PROSTATE CANCER IN SOUTHERN CHINESE. Ninghong Song and Huang Su Ninghong SongNinghong Song More articles by this author and Huang SuHuang Su More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.610AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Accumulating epidemiological and molecular evidence suggests that inflammation is an important component in the etiology of PCa. Macrophage migration inhibitory factor (MIF) plays an important role in the pro- and anti-inflammatory response to infection. This study is aimed at investigating the potential association between MIF-173 G>C polymorphism, Gleason score, clinical stage, and prostate-specific antigen (PSA) value with respect to PCa incidence among the Han nationality in Southern China. METHODS Genotyping was performed by using tetraprimer polymerase chain reaction (PCR) on 259 PCa patients and 301 cancer-free controls. RESULTS We found that the MIF-173*C variant allele was significantly associated with an increased risk of PCa [adjusted odd ratio (OR) = 2.99, 95% confident interval (CI): 1.94-4.60] and higher Gleason scores from the PCa subjects (adjusted OR = 10.72, 95% CI: 5.35-21.49). In addition, we noted that the MIF -173*C variant allele was related to higher clinical stages and PSA values in PCa patients (adjusted OR = 15.68, 95% CI: 7.40-33.23; adjusted OR = 4.37, 95% CI: 2.41-7.92, respectively). CONCLUSIONS Our data suggest that MIF-173 polymorphisms may be associated with a higher incidence of prostate cancer compared to controls, and appears to be associated with higher Gleason scores, higher clinical stages, and PSA values in those with prostate cancer. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e162 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Ninghong Song More articles by this author Huang Su More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Familial clustering of prostate cancer (Pca) cases in a nonselected south European population (sEp).

233 Background: Universal Pca screening programs (SP) are controversial. The selection of high-risk subjects might improve the efficiency of early SP. A positive family history (FH) of Pca increases its relative risk and also increases with multiple affected relatives. Pca FH is associated with earlier onset and aggressive behavior. Therefore, in this subpopulation SP would have clear advantages. This is the first study to investigate the incidence of familial Pca conducted in a sEp. Methods: Overall, 365 cancer patients (pts) of Spanish (n=342) or Portuguese (n=23) origin diagnosed at a single institution were included in the analysis. A non-selected cohort of 182 (173 with known FH) consecutive males (cases) diagnosed with Pca was studied for FH of any type of cancer including Pca. Another cohort of 183 (174 with known FH) males (controls) with similar demographic characteristics and diagnosed with other cancer types different from Pca was also studied for FH of cancer. We investigated whether Pca pts in a sEp show a higher incidence of familial Pca aggregation than subjects affected by other solid tumors. Results: Among Pca pts with a positive FH for Pca, 30.2% showed their father as the only Pca relative, 22.6% one or more brothers, 15% one or more uncles, 13.3% their father and one or more brothers, 9.4% their grandfather and 9.5% showed other combinations. Regarding the number of relatives affected, in our Pca cohort 1 relative was the most frequent finding with 41/53 pts (77.1%), 2 in 4 cases (7.6%), 3 in 3 subjects (5.8%) and 4 or more relatives in 5 cases (9.5%). We studied the overall incidence of any type of family cancer among cases and controls. No differences were found between groups (64.7% vs 67.8%; p=0.664). However, in our cohort of Pca cases, 53/173 pts (30.6%) had a FH of Pca in first or second degree whereas, among cancer control pts only 18/174 pts (10.34%) showed a Pca FH (p=0.001). Conclusions: We present the first estimation of Pca FH in a non-selected sEp with Pca. 30% of Pca cases showed a positive FH for Pca, being that incidence significantly higher (threefold) compared to cancer pts from a different origin. Therefore, the usefulness of directed SP for subjects with positive FH of Pca should be prospectively evaluated.

Population‐based analysis of prostate‐specific antigen (PSA) screening in younger men (&lt;55 years) in Australia

To analyse the trends in opportunistic PSA screening in Australia, focusing on younger men (<55 years of age), to examine the effects of this screening on transrectal ultrasonography (TRUS)-guided biopsy rates and to determine the nature of prostate cancers (PCas) being detected. All men who received an opportunistic screening PSA test and TRUS-guided biopsy between 2001 and 2008 in Australia were analysed using data from the Australian Cancer registry (Australian Institute of Health and Welfare) and Medicare databases. The Victorian cancer registry was used to obtain Gleason scores. Age-standardized and age-specific rates were calculated, along with the incidence of PCa, and correlated with Gleason scores. A total 5 174 031 PSA tests detected 128 167 PCas in the period 2001-2008. During this period, PSA testing increased by 146% (a mean of 4629 tests per 100 000 men annually), with 80 and 59% increases in the rates of TRUS-guided biopsy and incidence of PCa, respectively. The highest increases in PSA screening occurred in men <55 years old and up to 1101 men had to be screened to detect one incident case of PCa (0.01%). Screening resulted in two thirds of men aged <55 years receiving a negative TRUS biopsy. There was no correlation with Gleason >7 tumours in patients aged <55 years. Despite the ongoing controversy about the merits of PCa screening, there was an increase in PSA testing, especially in men <55 years old, leading to a modestly higher incidence of PCa in Australia. Overall, PSA screening was associated with high rates of negative TRUS-biopsy and the detection of low/intermediate grade PCa among younger patients.

Mediterranean Diet and Prostate Cancer Risk and Mortality in the Health Professionals Follow-up Study

BackgroundProstate cancer (PCa) mortality rates are lower in the Mediterranean countries compared with northern Europe. Although specific components of the Mediterranean diet (Med-Diet) may influence PCa risk, few studies have assessed the traditional Med-Diet pattern with the risk of incident advanced or lethal PCa or with disease progression among men diagnosed with nonmetastatic PCa. ObjectiveTo determine whether the traditional Med-Diet pattern is associated with risk of incident advanced or lethal PCa and with PCa-specific and overall mortality among men with PCa. Design, setting, and participantsWe prospectively followed 47 867 men in the Health Professionals Follow-up Study followed from 1986 to 2010. The case-only analysis included 4538 men diagnosed with nonmetastatic PCa, followed from diagnosis to lethal outcome or to January 2010. Outcome measurements and statistical analysisWe used Cox proportional hazards models to examine traditional and alternative Med-Diet scores in relation to PCa incidence outcomes (advanced and lethal disease). In a case-only survival analysis, we examined postdiagnostic Med-Diet and risk of lethal (metastases or PCa death) and fatal PCa as well as overall mortality among men diagnosed with nonmetastatic disease. Results and limitationsBetween 1986 and 2010, 6220 PCa cases were confirmed. The Med-Diet was not associated with risk of advanced or lethal PCa. In the case-only analysis, there was no association between the Med-Diet after diagnosis and risk of lethal or fatal PCa. However, there was a 22% lower risk of overall mortality (hazard ratio: 0.78; 95% confidence interval, 0.67–0.90; ptrend=0.0007) among men with greater adherence to the Med-Diet after PCa diagnosis. We found similar associations for the alternative score. ConclusionsA higher Med-Diet score was not associated with risk of advanced PCa or disease progression. Greater adherence to the Med-Diet after diagnosis of nonmetastatic PCa was associated with lower overall mortality.

The Interactions of Dietary Tomato Powder and Soy Germ on Prostate Carcinogenesis in the TRAMP Model

The interactions between bioactive-rich food components within a complex human diet for the inhibition of prostate carcinogenesis are largely unknown and difficult to quantify in humans. Tomato and soy products have each shown anti-prostate cancer (PCa) activity in laboratory studies. The objective of this study was to determine the efficacy of dietary tomato and soy germ, alone and in combination, for the inhibition of PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. At 4 weeks of age, male C57BL/6 × FVB TRAMP mice (n = 119) were randomized to consume: AIN-93G control, 10% whole tomato powder (TP), 2% soy germ powder (SG), or 10% tomato powder with 2% soy germ powder (TP+SG) for 14 weeks. One hundred percent of mice fed the control diet had PCa, whereas PCa incidence was significantly lower in mice consuming TP (61%, P < 0.001), SG (66%, P < 0.001), and TP+SG (45%, P < 0.001). Although the protection offered by the combination of TP and SG was not synergistic, it was the most effective intervention. TP, SG, and TP+SG increased apoptotic index (AI) and modestly reduced the proliferative index (PI) in the prostate epithelium of TRAMP mice exhibiting primarily prostatic intraepithelial neoplasia. The dramatic reduction in the PI/AI ratio by the dietary interventions suggests that the control mice experience a stronger stimulus for malignant progression in the prostate microenvironment. Maximally effective and safe strategies for PCa prevention may result from optimizing combinations of nutrients and bioactives through an orchestration of dietary patterns.

133 PSA-pyramid in men with low range PSA: PCa incidence and mortality – a plea for risk-based prostate cancer screening strategy in the European Randomized study of Screening for Prostate Cancer (ERSPC), Aarau

133 PSA-pyramid in men with low range PSA: PCa incidence and mortality – a plea for risk-based prostate cancer screening strategy in the European Randomized study of Screening for Prostate Cancer (ERSPC), Aarau

National Prostate Cancer Registry 2010 in Spain

ObjectivesTo estimate the 2010 incidence of PCa in Spain and describe the clinical profile of newly diagnosed cases using a nationwide hospital-based registry. Material and methodsNational epidemiological study in 25 public hospitals with a specific reference population according to the National Health System. Sociodemographic and clinical variables of all newly diagnosed, histopathological confirmed PCa cases were collected in 2010, in the area of influence of each center. The age-standardized PCa incidence was determined based on the age distribution of the Spanish population in Spain and in 3 regions: Andalusia, Catalonia and Region of Madrid. Results4087 new cases of PCa were diagnosed for a reference population of 4,933,940 men (21.8% of the Spanish male population). The estimated age-standardized PCa incidence was 82.27 cases per 100,000 men in Spain, 70.38 in Andalusia, 85.70 in Catalonia and 92.29 in the Region of Madrid. Mean age at diagnosis was 69 years. Median PSA was 8ng/ml. Gleason score was ≤6 in 56.5%, 7 in 26.7% and >7 in 16.8% of patients. At diagnosis, 90% had localized disease. ConclusionsIn the 3 Regions analyzed, around 80–90% of the cases are diagnosed in a clinical localized stage. The incidence rates in Andalusía, Catalonia and Region of Madrid show a great difference between them due to several factors.

Registro nacional de cáncer de próstata 2010 en España

ObjectivesTo estimate the 2010 incidence of PCa in Spain and describe the clinical profile of newly-diagnosed cases using a nationwide hospital-based registry. Material and methodsNational epidemiological study in 25 public hospitals with a specific reference population according to the National Health System. Sociodemographic and clinical variables of all newly diagnosed, histopathological confirmed PCa cases were collected in 2010, in the area of influence of each centre. The age–standardised PCa incidence was determined based on the age distribution of the Spanish population in Spain and in 3 regions: Andalusia, Catalonia and Region of Madrid. Results4,087 new cases of PCa were diagnosed for a reference population of 4,933,940 men (21.8% of the Spanish male population). The estimated age-standardised PCa incidence was 82.27 cases per 100,000 men in Spain, 70,38 in Andalusia, 85,70 in Catalonia and 92,29 in the Region of Madrid. Mean age at diagnosis was 69 years. Median PSA was 8 ng/ml. Gleason score was ≤6 in 56.5%, 7 in 26.7% and >7 in 16.8% of patients. At diagnosis, 90% had localised disease. ConclusionsIn the 3 Regions analyzed, around 80-90% of the cases are diagnosed in a clinical localised stage. The incidence rates in Andalusía, Catalonia and Region of Madrid show a great difference between them due to several factors.

Abstract A66: βarrestin2 contributes to aggressive tumor growth in African American prostate cancer cells

Abstract Prostate cancer (PCa) is the second leading cause of death in African American males (AA). Studies have found the incidence of PCa to be 60% higher in AA men than their Caucasian American counterparts (CA). Poorer prognosis in AA men is exacerbated by lack of adequate access to healthcare and non financial factors such as distrust of the healthcare system. However, these social and socioeconomic factors fail to fully account for this disparity. AA men are diagnosed at younger ages and often present with more advanced tumor stages and higher Gleason scores. Thus, elucidating possible biological causes of prostate cancer disparity is of utmost importance. βarrestin2 (βarr2) is a scaffold protein that associates with G protein coupled receptors (GPCRs) and leads to the desensitization and internalization of these receptors. In addition, more recent studies have implicated βarr2 in a variety of cellular processes including androgen metabolism. We have shown increased βarrestin2 expression in prostate cell lines from AA men (MDA PCa 2B) when compared to those from CA men (LNCap). Furthermore, overexpression of βarr2 in LNCap cells or knockdown of βarr2 in MDA PCa 2B cells was sufficient to alter the growth properties of these cells. These results were seen both in vitro and in vivo. Thus preliminary data indicates that βarr2 may contribute to differences between tumor growth in our model system. Further studies are needed to ascertain the cause and mechanism of βarr2 overexpression in AA men, as well as the clinical significance of these findings. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A66.

Mortality Among Men with Locally Advanced Prostate Cancer Managed with Noncurative Intent: A Nationwide Study in PCBaSe Sweden

BackgroundThere are limited prognostic data for locally advanced prostate cancer PCa to guide in the choice of treatment. ObjectiveTo assess mortality in different prognostic categories among men with locally advanced PCa managed with noncurative intent. Design, setting, and participantsWe conducted a register-based nationwide cohort study within the Prostate Cancer DataBase Sweden. The entire cohort of locally advanced PCa included 14 908 men. After the exclusion of 2724 (18%) men treated with curative intent, 12 184 men with locally advanced PCa either with local clinical stage T3 or T4 or with T2 with serum levels of prostate-specific antigen (PSA) between 50 and 99 ng/ml and without signs of metastases remained for analysis. MeasurementsWe followed up the patient cohort in the Cause of Death Register for ≤11 yr and assessed cumulative incidence of PCa -specific death stratified by age and clinical characteristics. Results and limitationsThe PCa -specific mortality at 8 yr of follow-up was 28% (95% confidence interval [CI], 25–32%) for Gleason score (GS) 2–6, 41% (95% CI, 38–44%) for GS 7, 52% (95% CI, 47–57%) for GS 8, and 64% (95% CI, 59–69%) for GS 9–10. Even for men aged >85 yr at diagnosis with GS 8–10, PCa was a major cause of death: 42% (95% CI, 37–47%). Men with locally advanced disease and a PSA<4 ng/ml at diagnosis were at particularly increased risk of dying from PCa. One important limitation is the lack of bone scans in 42% of the patient cohort, but results remained after exclusion of patients with unknown metastasis status. ConclusionsThe PCa-specific mortality within 8 yr of diagnosis is high in locally advanced PCa, suggesting undertreatment, particularly among men in older age groups. Our results underscore the need for more studies of treatment with curative intent for locally advanced tumors.

Abstract 2493: Capsaicin, a novel radiosensitizer, acts via a TRPV6 mediated mechanism

Abstract Radiosensitizing agents sensitize cells to the lethal effects of ionizing radiation (IR). This permits use of lower doses of radiation to achieve equivalent cancer control thereby minimizing adverse effects to normal tissues. Given their lack of toxicity compounds occurring naturally in the diet make ideal potential radiosensitizing agents. Capsaicin, a compound found in the Capsicum sp. of plants, is a widely consumed food additive in areas with low PCa incidence. Traditionally capsaicin is used to treat chronic pain syndromes; however, recently evidence using in vitro PCa models describes its anti-carcinogenic potential. The transient receptor potential vanilloid-receptor (TRPV)-1 and TRPV6 cation selective channels are thought to be partly responsible for mediating these effects. TRPV-1 and TRPV-6 expression is up-regulated in PCa tissue correlating directly with increasing tumor grade. This suggests TRPV1 and/or TRPV6 may be potential therapeutic targets for capsaicin mediated interventions in PCa patients. As IR and capsaicin both promote apoptosis and inhibit cell cycle progression in vitro we hypothesize an at least additive effect of combining these two therapies. Using clonogenic assays we assessed the effect of ionizing radiation (1-8 Gy) and/or capsaicin (1-10μM) on colony formation rates in 4 human PCa cell lines (LNCaP, PC3, PC3AR2, DU145). Proliferative, apoptotic, TRPV-6 protein markers were assessed using Western blot analyses. Exposure of cells to capsaicin (1-10μM) or IR (1-8Gy) caused significant dose-dependent inhibition of colony formation (p&amp;lt;0.001). Combining capsaicin with IR resulted in further significant inhibition of colony formation rates (P&amp;lt;0.001). Western blot analyses showed LNCaP cells treated with capsaicin and/or IR to have increased expression of pro-apoptotic proteins BAX and Bad, tumor-suppressor proteins p21 and p27 and reduced androgen-receptor. Additionally, capsaicin monotherapy caused a dramatic alteration in TRPV1 and TRPV6 expression. These studies confirm the radiosensitizing capacity of capsaicin in PCa cells in vitro. Ongoing studies using are further delineating the mechanism of interaction of these treatment modalities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2493. doi:10.1158/1538-7445.AM2011-2493

2136 EFFICACY OF DUTASTERIDE IN MEN WITH LOW PROSTATE VOLUME IN THE REDUCTION BY DUTASTERIDE OF PROSTATE CANCER EVENTS (REDUCE) STUDY

INTRODUCTION AND OBJECTIVES: In the REDUCE study, dutasteride (DUT) compared with placebo (PBO) reduced the risk of incident prostate cancer by 23% and improved outcomes related to benign prostatic hyperplasia (BPH) in men with increased risk of PCa. Because previous DUT studies only enrolled men with enlarged prostates, and because prostate cancer has been reported to be more prevalent in men with small prostates, we now report the effect of DUT on PCa and BPH endpoints in men with low baseline prostate volume (PV) in REDUCE. METHODS: The REDUCE study was an international, randomized, double-blind, PBO-controlled study. Men received DUT (0.5 mg daily) or PBO for 4 yrs. Eligible subjects included men 50–75 yrs, with prostate specific antigen (PSA) level 2.5–10 ng/ml and a single negative prostate biopsy (6–12 cores) within 6 months of enrollment. International Prostate Symptom Score (IPSS) and serum PSA levels were measured every 6 months. PV was measured by ultrasonography at randomization and at 2 and 4 yrs. Biopsies (10 cores) were performed at 2 and 4 yrs or when clinically indicated. Two-sided P values of 0.01 indicated statistical significance in the assessment of the superiority of DUT over PBO. In the present analysis we investigate outcomes related to PCa and BPH in the subgroup of men with a baseline PV 30 cc. RESULTS: Within the REDUCE population, 774 men from the DUT group and 807 men from the PBO group had a PV 30 cc. Baseline characteristics were similar between treatment groups (Table). 225 cases of PCa were detected in the PBO group and 165 cases in the DUT group (p 0.0035), representing an incidence of 27.9% vs. 21.3%, respectively. Fewer men in the DUT group had BPH-related surgery (p 0.0014) and acute urinary retention (AUR) (p 0.00540) than in the PBO group. IPSS scores were lower than baseline at Month 48 in the DUT group, but higher than baseline in the PBO group (p 0.0001). The change in PV from baseline to Month 48 was significantly different between treatment groups (p 0.0001), however, the minimal decrease in the DUT group and large increase in the PBO group may imply a regression of the mean from baseline to follow-up PV measurements. CONCLUSIONS: In men with low PV, DUT lowered the overall incidence of PCa, led to greater improvements in IPSS scores and improved BPH-related outcomes over the 4-yr study period. Table. Baseline characteristics and PCa and BPH results in men with low prostate volume Dutasteride (n 774) Placebo (n 807) BASELINE CHARACTERISTICS Mean age (yr) 61.5 61.6 Mean total PSA (ng/ml) 5.45 5.60 Mean IPSS 7.6 7.6 Mean PV (cc) 23.6 23.5 — — — PROSTATE CANCER RESULTS Incidence (%) 165 (21.3) 225 (27.9) Relative risk reduction (95% CI) 24.1 (8.6, 36.9) — — — — BENIGN PROSTATIC HYPERPLASIA RESULTS BPH-related surgery: incidence (%) 5 (0.6) 22 (2.7) BPH-related surgery: relative risk reduction (95% CI) 76.6 (38.3, 91.2) — AUR: Incidence (%) 9 (1.2) 26 (3.2) AUR: relative risk reduction (95% CI) 64.3 (23.8, 83.3) — Change in IPSS at Month 48: adjusted mean (SE) 0.36 (0.186) 1.21 (0.181) % change in PV at Month 48: adjusted mean (SE) 0.7 (1.88) 41.4 (2.60) Use of alpha blocker (%) 74/774 (9.6) 115/807 (14.3) *Percentages based on biopsied population (placebo n 620; dutasteride n 671). CI confidence interval; SE standard error.

Capsaicin, a novel radiosensitizer, acts via a TRPV6 mediated phenomenon.

23 Background: Radiosensitizing agents sensitize cells to the lethal effects of ionizing radiation (IR). This permits use of lower doses of radiation to achieve equivalent cancer control thereby minimizing adverse effects to normal tissues. Given their lack of toxicity compounds occurring naturally in the diet make ideal potential radiosensitizing agents. Capsaicin, a compound found in the Capsicum sp. of plants, is a widely consumed food additive in areas with low PCa incidence. Traditionally capsaicin is used to treat chronic pain syndromes; however, recently evidence using in vitro PCa models describes its anti-carcinogenic potential. The transient receptor potential vanilloid-receptor (TRPV)-1 and TRPV6 cation selective channels are thought to be partly responsible for mediating these effects. TRPV-1 and TRPV-6 expression is up-regulated in PCa tissue correlating directly with increasing tumor grade. This suggests TRPV1 and/or TRPV6 may be potential therapeutic targets for capsaicin mediated interventions in PCa patients. As IR and capsaicin both promote apoptosis and inhibit cell cycle progression in vitro we hypothesize an at least additive effect of combining these two therapies. Methods: Using clonogenic assays we assessed the effect of ionizing radiation (1-8 Gy) and/or capsaicin (1-10μ M) on colony formation rates in 4 human PCa cell lines (LNCaP, PC3, PC3AR2, DU145). Proliferative, apoptotic, TRPV-6 protein markers were assessed using Western blot analyses. Results: Exposure of cells to capsaicin (1-10μ M) or IR (1-8Gy) caused significant dose-dependent inhibition of colony formation (p&lt;0.001). Combining capsaicin with IR resulted in further significant inhibition of colony formation rates (P&lt;0.001). Western blot analyses showed LNCaP cells treated with capsaicin and/or IR to have increased expression of pro- apoptotic proteins BAX and Bad, tumor-suppressor proteins p21 and p27 and reduced androgen-receptor. Additionally, capsaicin monotherapy caused a dramaticalteration in TRPV1 and TRPV6 expression. Conclusions: These studies confirm the radiosensitizing capacity of capsaicin in PCa cells in vitro. Ongoing studies are further delineating the mechanism of interaction of these treatment modalities. No significant financial relationships to disclose.

Abstract A24: Resveratrol-induced and MTA1-associated miRNAs in prostate cancer prevention

Abstract Prostate cancer (PCa) remains one of the most frequently diagnosed cancers in men in Western countries. Since noticeable geographic variations have been observed in the incidence of PCa, studies have implicated a “Western” diet in the development of PCa. Because of this and the nature of PCa, which is typically diagnosed in the elderly population wth a relatively slower rate of growth and progression, chemoprevention through dietary compounds promises to be an effective approach for PCa. Resveratrol (Res) (3,5,4’-trihydroxy-trans-stilbene), a natural compound found in grapes, peanuts and berries, is one of the most promising diet-derived chemopreventive agent with potential chemotherapeutic capacities. There is growing evidence that Res may contribute to chromatin remodeling that are important in cancer progression. Metastasis-associated protein 1 (MTA1), which is overexpressed in many cancer, is a part of nucleosome remodeling and deacetylation (NuRD) complex that mediates posttranslational modifications of histones and nonhistone proteins resulting in transcriptional gene silencing. The complex also contains histone deacetylases 1 and 2 (HDAC1 and 2). MTA1/HDAC1 subunit plays an essential role in governing deacetylation of histones and other proteins. We recently demonstrated that Res down-regulated MTA1 protein levels in PCa cells, leading to destabilization of MTA1/HDAC1/NuRD complex thus allowing acetylation and activation of tumor suppressor p53. MTA1 silencing by RNA interference further sensitized PCa cells to Res-dependent p53 acetylation, transcriptional activation of p21 and Bax and apoptosis. To further understand Res-induced MTA1-associated epigenetic alterations, we analyzed MTA1-associated and Res-induced microRNAs expression changes using LNCaP cells expressing and silenced for MTA1. We found that expression of 13 miRNA was increase, and 17 miRNAs was decreased in cells silenced for MTA1 gene. In addition, 28 miRNAs were overexpresed, and 23 miRNAs were degreased under Res treatment. Among these miRNAs were some with well-characterized cancer association, such as let-7g, miR-16-2, miR-26a, miR-20b, miR-27a, miR-22, miR-34a, miR-92 and others. The predicted targets for the overlapping miRNAs are significantly enriched for protein-coding oncogenes and tumor suppressors. Our data indicate that MTA1-associated miRNAs are involved in Res-mediated anticancer and preventive effects in prostate cancer. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A24.

Prostate cancer mortality in screen and clinically detected prostate cancer: Estimating the screening benefit

BackgroundTo estimate the benefits of prostate-specific antigen (PSA) screening on prostate cancer (Pca) metastasis and Pca-specific mortality, we compared two populations with a well-defined difference in intensity of screening. MethodsBetween 1997 and 1999, a total of 11,970 men, aged 55–74years, were included in the intervention arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) section Rotterdam. Control population consisted of 133,287 men, aged 55–74years, between 1998 and 1999 in Northern Ireland (NI). Men were followed for Pca incidence, Pca metastasis and cause of death until 31st December 2006. ResultsMedian age in both groups was 63years at study entry (p=0.184). In Rotterdam 94.2% of men and in NI 6% of men underwent PSA testing. In Rotterdam, 1153 men (9.6%) were diagnosed with Pca with median baseline PSA of 5.1ng/ml. In NI, 3962 men (3.0%, p<0.001) were diagnosed with Pca with median baseline PSA of 18.0ng/ml (p<0.001). The relative risk of Pca metastasis during observation in the intervention population compared to control population was 0.47 (95% confidence interval (CI), 0.35–0.63; p<0.001). The relative risk of Pca-specific mortality was also lower in the intervention population compared to the control population after a median follow-up of 8.5years: 0.63 (95% CI, 0.45–0.88; p=0.008); absolute mortality reduction was 1.8 deaths per 1000 men. ConclusionsA relative reduction in Pca metastasis of 53% and Pca mortality of 37% was observed in the intervention population after 8.5years of observation. The impact of overdiagnosis, quality of life benefits and cost-effectiveness need to be assessed before population-based PSA screening can be recommended.