Risk Of Prostate Cancer Mortality Research Articles

Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men

BackgroundProstate-specific antigen (PSA) screening reduces prostate cancer deaths but leads to harm from overdiagnosis and overtreatment. ObjectiveTo determine the long-term risk of prostate cancer mortality using kallikrein blood markers measured at baseline in a large population of healthy men to identify men with low risk for prostate cancer death. Design, setting, participantsStudy based on the Malmö Diet and Cancer cohort enrolling 11 506 unscreened men aged 45–73 yr during 1991–1996, providing cryopreserved blood at enrollment and followed without PSA screening to December 31, 2014. We measured four kallikrein markers in the blood of 1223 prostate cancer cases and 3028 controls. Outcome measurements and statistical analysisProstate cancer death (n=317) by PSA and a prespecified statistical model based on the levels of four kallikrein markers. Results and limitationsBaseline PSA predicted prostate cancer death with a concordance index of 0.86. In men with elevated PSA (≥2.0ng/ml), predictive accuracy was enhanced by the four-kallikrein panel compared with PSA (0.80 vs 0.73; improvement 0.07; 95% confidence interval 0.04, 0.10). Nearly half of men aged 60+ yr with elevated PSA had a four-kallikrein panel score of <7.5%, translating into 1.7% risk of prostate cancer death at 15 yr—a similar estimate to that of a man with a PSA of 1.6ng/ml. Men with a four-kallikrein panel score of ≥7.5% had a 13% risk of prostate cancer death at 15 yr. ConclusionsA prespecified statistical model based on four kallikrein markers (commercially available as the 4Kscore) reclassified many men with modestly elevated PSA, to have a low long-term risk of prostate cancer death. Men with elevated PSA but low scores from the four-kallikrein panel can be monitored rather than being subject to biopsy. Patient summaryMen with elevated prostate-specific antigen (PSA) are often referred for prostate biopsy. However, men with elevated PSA but low scores from the four-kallikrein panel can be monitored rather than being subject to biopsy.

The Cambridge Prognostic Groups for improved prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer: a validation study

BackgroundThe purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer.MethodsWe applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality.ResultsThe PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n = 20,586), C-index 0.77 vs. 074; radiotherapy (n = 11,872), C-index 0.73 vs. 0.69; and conservative management (n = 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001).ConclusionsThis validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells.

Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown. To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per-cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer. Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit <10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend = 0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend = 0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells. Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes.

Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2

Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion. Fusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin-like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs), and β-actin were analyzed by Western immunoblotting. Our data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events. These novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression.

Effects of Obesity on the Regulation of Macrophage Population in the Prostate Tumor Microenvironment

ABSTRACTObesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions. Matrigel invasion chambers were used to assess macrophage recruitment in vitro, and immunohistochemical analysis evaluated recruitment in a PTEN knockout mouse model. qPCR was used to measure mRNA levels of CCL2, COX-2, IL-10, TGF-beta, VEGF-A, arginase-1, and MMP-9. PGE2 production was measured by ELISA. Obesity increased macrophage and TAM recruitment, and increased mRNA levels of TAM markers in macrophages. Similarly, obese conditions increased CCL2 and COX-2 expression, as well as PGE2 levels in prostate cancer cells. COX-2 inhibition resulted in lower expression of obesity-induced TAM markers. Our data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway.

Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10-4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society.

Abstract LB-285: Glycemia is positively associated with prostate cancer mortality in white and black men without diabetes when better classifying hyper- and normoglycemia using 3 biomarkers&amp;lt;!–EndFragment–&amp;gt;

Abstract Background: Diabetes is associated with a decreased prostate cancer risk, and may increase prostate cancer mortality among men with the diagnosis. The association of diabetes or earlier hyperglycemic states (i.e. prediabetes) on the most clinically relevant outcome, prostate cancer mortality in men without the diagnosis at baseline, has not been well studied and whether associations are similar across race is unknown. Thus, we aimed to rigorously characterize the association of diabetes and hyperglycemia with prostate cancer mortality. We classified hyperglycemia with a combination of 3 blood biomarkers - fasting glucose, hemoglobin A1c (HbA1c), and glycated albumin (%GA), which capture complementary aspects of glycemia. Methods: We conducted a prospective study of 5,276 cancer-free white and black men attending visit 2 (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) Study. Death from prostate cancer was ascertained from the underlying cause on death certificates. Follow-up began at visit 2 and ended at date of death or 12/31/2012, whichever came first. There were 69 prostate cancer deaths in 96,617 person-years. Men were categorized as having diagnosed diabetes or jointly categorized using clinical or research-based cut points of the 3 biomarkers: low (HbA1c &amp;lt;5.0% or %GA &amp;lt;11.0% or fasting glucose &amp;lt;3.1 mmol/L); normal on all 3 biomarkers (reference: 5.0 to &amp;lt;5.7%; 11.0 to &amp;lt;16.0%; and &amp;lt;5.6 mmol/L, respectively); and high on any 1; on any 2; or on all 3 biomarkers. We used Cox proportional hazards regression to estimate the relative hazards (HR) of prostate cancer death and 95% confidence intervals for the joint terms for glycemia and the term for diagnosed diabetes adjusting for age, education, BMI, waist circumference, smoking, and race*field center, overall and by race. Results: Mean age was 57 years and mean BMI was 27.7 kg/m2; 81% were white. Compared to men who were normal on all 3 biomarkers of glycemia, greater than 2-fold increased risk of prostate cancer mortality was observed among men high on any 1 biomarker (HR: 3.66; 95% CI: 1.42 to 9.48), any 2 biomarkers (HR: 2.58; 95% CI: 0.92 to 7.22), all 3 biomarkers (HR: 4.8; 95% CI: 1.10 to 20.95), and among men with diagnosed diabetes (HR: 3.18; 95% CI 0.94 to 10.73). Men with low glycemia also had an elevated risk of prostate cancer mortality (HR: 2.98; 95% CI: 0.98 to 8.90). Associations were similar in white and black men. Conclusions: Using 3 biomarkers that capture complementary aspects of glycemia and have different sensitivities to non-glycemic factors, men without diagnosed diabetes who have hyperglycemia have an increased risk of death from prostate cancer compared to men who have normal glycemia levels, independent of BMI and other factors. Our findings did not appear to be influenced by racial differences in hyperglycemia. Support: NHLBI contracts, NCI grants, NPCR Citation Format: Michael Marrone, Elizabeth Selvin, John Barber, Elizabeth Platz, Corinne Joshu. Glycemia is positively associated with prostate cancer mortality in white and black men without diabetes when better classifying hyper- and normoglycemia using 3 biomarkers&amp;lt;!–EndFragment–&amp;gt; [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-285. doi:10.1158/1538-7445.AM2017-LB-285

PD03-09 RISING INCIDENCE OF METASTATIC PROSTATE CANCER IN CALIFORNIA, 1988-2014

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I1 Apr 2017PD03-09 RISING INCIDENCE OF METASTATIC PROSTATE CANCER IN CALIFORNIA, 1988-2014 Marc Dall'Era, Ralph Devere White, Danielle Rodriguez, and Rosemary Cress Marc Dall'EraMarc Dall'Era More articles by this author , Ralph Devere WhiteRalph Devere White More articles by this author , Danielle RodriguezDanielle Rodriguez More articles by this author , and Rosemary CressRosemary Cress More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.215AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Early detection of prostate cancer with PSA based screening can reduce the risk of prostate cancer mortality by 21%. Screening for prostate cancer has dramatically declined in the United States since the United States Preventive Services Task Force (USPSTF) recommended against routine PSA based prostate cancer screening for all men in 2012. This led to dramatic reductions in the diagnosis of localized disease across all clinical risk groups. We sought to study trends in newly diagnosed metastatic prostate cancer incidence, specifically the impact of patient age and race. METHODS We analyzed new prostate cancer incidence by stage at diagnosis between 1988-2014 using data from the California Cancer Registry. We further stratified cases by age and four major race/ethnicity groups (non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic and non-Hispanic Asian/PI (API)). Incidence rates per 100,000 were age-adjusted to the 2000 US Standard Population. Joinpoint regression was used to detect changes in incidence and to calculate the average percent change (APC) over time. Joinpoint finds the best fit model with the smallest number of joinpoints and will not add an additional joinpoint if it does not make significant improvement on the model. RESULTS Adjusted rates of remote prostate cancer incidence for men of all races aged 65-74 and NHW men of all ages significantly increased over the most recent time period by 2.4% and 1%, respectively, p<0.05 (Figure 1 and 2). In contrast, incidence of remote prostate cancer continued to decline for NHB (-2.42%), Hispanic (-1.94%), and API (-1.66%) men. Localized disease incidence continues to decline significantly for all age and racial groups. CONCLUSIONS Incidence rates of newly metastatic prostate cancer have significantly increased for the first time in California for men aged 65-74 and white men. Although not possible to determine the etiology of these findings, decreased PSA screening and early detection of aggressive as well as indolent tumors is likely to contribute. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e60 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Marc Dall'Era More articles by this author Ralph Devere White More articles by this author Danielle Rodriguez More articles by this author Rosemary Cress More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Patient NCCN risk classification based on combined clinical cell cycle risk (CCR) score.

249 Background: Improved prognostic tools for newly diagnosed prostate cancer are needed to more appropriately match treatment to a patient’s risk of progression. The cell cycle progression (CCP) score is a highly validated prognostic RNA expression signature which has been combined with CAPRA (CCR, combined clinical cell cycle risk score) to generate an estimate of prostate cancer mortality (PCM) within 10-years of diagnosis. Here, we evaluate how the prognostic information from CCR can reclassify patients compared to their initial assignment to an NCCN risk category based on clinicopathologic features alone. Methods: The CCR score was previously validated and is calculated as a linear combination of CAPRA and CCP score (0.39 x CAPRA + 0.57 x CCP). A risk reclassification scheme was applied to patients tested by the Myriad Genetics commercial laboratory (N = 16,442). First, PCM risk was assigned based on the patient’s CCR score. Next, patients whose PCM risks were outside the interquartile range (IQR) of their NCCN risk category were reclassified according to whether their PCM risks fell within the IQR of another NCCN risk category. Finally, patients whose PCM risks were below (or above) the IQR of the NCCN low (or high) category were reclassified as low (or high). Results: Based on clinicopathologic features alone the commercial cohort was classified according to NCCN Guidelines as low (N = 8,695), favorable intermediate (N = 3,347), intermediate (N = 3,086), or high risk (N = 1,224). After calculating patient risk of PCM based on CCR, 25% of the NCCN low risk men were reclassified to favorable intermediate or intermediate risk; 47% of the NCCN favorable intermediate risk men were reclassified (24% lower and 23% higher); 49% of the NCCN intermediate risk men were reclassified (24% lower and 25% higher); and 25% of the NCCN high risk were reclassified to favorable intermediate or intermediate risk. There is no outcome data associated with commercial samples. Conclusions: The prognostic information in the CCR score results in significant amounts of risk reclassification for all patients with localized disease when compared to stratification based only on NCCN risk categories.

Risk of prostate cancer diagnosis and mortality in men with a benign initial transrectal ultrasound-guided biopsy set: a population-based study

The risk of missing prostate cancer in the transrectal ultrasound-guided systematic biopsies of the prostate in men with suspected prostate cancer is a key problem in urological oncology. Repeat biopsy or MRI-guided biopsies have been suggested to increase sensitivity for diagnosis of prostate cancer, but the risk of disease-specific mortality in men who present with raised prostate-specific antigen (PSA) concentration and a benign initial biopsy result remains unknown. We investigated the risk of overall and prostate cancer-specific mortality in men with a benign initial biopsy set. Data were extracted from the Danish Prostate Cancer Registry-a population-based registry including all men undergoing histopathological assessment of prostate tissue. All men who were referred for transrectal ultrasound-guided biopsy for assessment of suspected prostate cancer between Jan 1, 1995, and Dec 31, 2011, in Denmark were eligible for inclusion. Follow-up data were obtained on April 28, 2015. The primary endpoint was the cumulative incidence of prostate cancer-specific mortality, analysed in a competing risk setting, with death from other causes as the competing event. Between Jan 1, 1995, and Dec 31, 2011, 64 430 men were referred for transrectal ultrasound-guided biopsy, of whom 63 454 were eligible for inclusion. Median follow-up was 5·9 years (IQR 3·8-8·5) and the total follow-up time, from the enrolment of the first patient on Jan 1, 1995, until the extraction of causes of death on April 28, 2015, was 20 years. 10 407 (30%) of 35 159 men with malignant initial biopsy sets died from prostate cancer, compared with 541 (2%) of 27 181 men with benign initial biopsy sets. Estimated overall 20-year mortality was 76·1% (95% CI 73·0-79·2). In all men referred for transrectal ultrasound-guided biopsy, the cumulative incidence of prostate cancer-specific mortality after 20 years was 25·6% (24·7-26·5) versus 50·5% (47·5-53·5) for mortality from other causes. In men with benign initial biopsy sets, the cumulative incidence of prostate cancer-specific mortality was 5·2% (3·9-6·5) versus 59·9% (55·2-64·6) for mortality from other causes. In men with PSA concentrations 10 μg/L or lower and benign initial biopsy sets (2779 men), the cumulative incidence of prostate cancer-specific mortality was 0·7% (0·2-1·3). Cumulative incidence of prostate cancer specific mortality in men with benign initial biopsy sets was 3·6% (95% CI 0·1-7·2) for men with a PSA higher than 10 ng/mL but 20 ng/mL or less (855 men) and 17·6% (12·7-22·4) and for men with a PSA higher than 20 ng/mL (454 men). The first systematic transrectal ultrasound-guided biopsy set holds important prognostic information. The 20-year risk of prostate cancer-specific mortality in men with benign initial results is low. Our findings question whether men with low PSA concentration and a benign initial biopsy set should undergo further diagnostic assessment in view of the high risk of mortality from other causes. Capital Region of Denmark's Fund for Health Research, Danish Cancer Society, Danish Association for Cancer Research, and Krista and Viggo Petersen's Foundation.

Physiological Effort in Submaximal Fitness Tests Predicts Weight Loss in Overweight and Obese Men with Prostate Cancer in a Weight Loss Trial.

BackgroundObesity and weight gain after the diagnosis of prostate cancer are associated with an increased risk of prostate cancer recurrence and mortality; individualized plans to help prostate cancer survivors maintain or lose weight may be beneficial for recurrence risk reduction. Herein, we explore whether gains in cardiovascular fitness predict successful weight loss in men participating in a weight loss trial (NCT01886677).MethodsForty men were randomized to receive twice-weekly in-person and telephone-based guidance on calorie-restricted diets and aerobic exercise to promote ~0.91 kg/week weight loss, or wait-list control. Thirty-two men completed submaximal VO2 Treadmill Tests (TT), anthropometric measures and two 24-hour dietary recalls at baseline and follow-up. For this secondary analysis, study arms were combined and associations between baseline and longitudinal changes in physiological effort (PE, measured by heart rate during TT), predicted VO2max, caloric intake and weight loss were analyzed.ResultsMen lost 3.4 kg in 50 ± 23 days on the study. Multivariate linear regression indicated weight change was associated with change in PE at stage 2TT (Partial R = 0.635, p < 0.001), days on study (Partial R = −0.589, p = 0.002) and change in caloric intake (Partial R = 0.457, p = 0.019).ConclusionsUntrained men experiencing elevated heart rates during stage 2TT at baseline were able to achieve greater weight loss over the study period; this association was strengthened by a decrease in PE at the same level from baseline to follow-up concomitant with reduced caloric intake. Therefore, for these middle-aged and older men with lower aerobic fitness, exercise appears to be a key factor in achieving higher degrees of weight loss.

Prognostic Significance of a Negative Prostate Biopsy: An Analysis of Subjects Enrolled in a Prostate Cancer Screening Trial

To our knowledge the optimal treatment of patients following a negative prostate biopsy is unknown. Consequently, resources are increasingly being directed toward risk stratification in this cohort. However, the risk of prostate cancer mortality in this group before the introduction of supplemental biomarkers and imaging techniques is unclear. The PLCO (Prostate, Lung, Colorectal and Ovarian Cancer) Screening Trial provides survival data prior to the implementation of new diagnostic interventions. We divided men with an initial positive screen and a subsequent prostate biopsy into cohorts based on positive or negative results. Prostate cancer specific mortality was then compared to that in the trial control arm to estimate the prognostic significance of biopsy results relative to the general population. A total of 36,525 and 36,560 patients comprised the screening and control arms, respectively. Of 4,064 subjects with a positive first screen 1,233 underwent a linked biopsy, of which 473 were positive and 760 were negative. At a median followup of 12.9 years, 1.1% of men in the negative biopsy cohort had died of prostate cancer. The difference in mortality rates between the negative biopsy and control arms was 0.734 deaths per 1,000 person-years. The proportional subhazard ratios of prostate cancer specific mortality for negative biopsy and positive biopsy relative to the control arm were 2.93 (95% CI 1.44-5.99) and 18.77 (95% CI 12.62-27.93), respectively. After a negative prostate biopsy, men face a relatively low risk of death from prostate cancer when followed with traditional markers and biopsy techniques. This suggests limited potential for new diagnostic interventions to improve survival in this group.

Obesity and Other Cancers.

Purpose Evidence on overweight, obesity, and an increased risk of cancer continues to accumulate and was updated in the 2016 handbook on weight control from the International Agency for Research on Cancer (IARC). The underlying primary data, together with dose-response meta-analysis and, finally, pooled analysis of individual participant data, add insight into the relation between obesity and cancer risk and prognosis. We summarize the evidence for mortality from prostate cancer, hematologic malignancies, and kidney cancer. Methods We reviewed pooled analysis of rare end points across cohorts, regardless of primary results reported from the individual studies, further reducing risk of publication bias. Of these cancer sites, only kidney cancer was included in the IARC 2002 report, although mortality from prostate cancer and hematologic malignancies was noted in the American Cancer Society prospective cohort study in 2003. The 2016 update from the IARC added details for prostate and hematologic malignancies, classifying the evidence as sufficient to conclude that avoiding excess body fatness lowers the risk of multiple myeloma but found that the evidence for it lowering the risk of prostate cancer mortality or diffuse large B-cell lymphoma was limited. Results A higher body mass index is associated with an increased risk of advanced prostate cancer and prostate cancer mortality and is associated with worse survival in most subtypes of hematologic malignancies, in a dose-response fashion. Evidence for kidney cancer is built mostly on retrospective data, which supports an obesity paradox in patients with the clear cell variant; however, population-based cohort data indicate that a higher cohort-entry body mass index is associated with worse kidney cancer-specific survival. Conclusion Together, these data add support to the evidence for a growing cancer burden caused by adiposity in both early adult and later adult life, yet leave open the question of the means of weight management after diagnosis as a strategy to improve survival.

5-Alpha Reductase Inhibitors and the Risk of Prostate Cancer Mortality in Men Treated for Benign Prostatic Hyperplasia

ObjectiveTo compare the risk of prostate cancer mortality among men treated with 5- alpha reductase inhibitors (5-ARIs) with those treated with alpha-adrenergic blockers (ABs) in community practice settings. Patients and MethodsA retrospective matched cohort (N=174,895) and nested case-control study (N=18,311) were conducted in 4 regions of an integrated health care system. Men 50 years and older who initiated pharmaceutical treatment for benign prostatic hyperplasia between January 1, 1992, and December 31, 2007, and had at least 3 consecutive prescriptions were followed through December 31, 2010. Adjusted subdistribution hazard ratios, accounting for competing risks of death, and matched odds ratios were used to estimate prostate cancer mortality associated with 5-ARI use (with or without concomitant ABs) as compared with AB use. ResultsIn the cohort study, 1,053 men died of prostate cancer (mean follow-up, 3 years), 15% among 5-ARI users (N= 25,388) and 85% among AB users (N=149,507) (unadjusted mortality rate ratio, 0.80). After accounting for competing risks, it was found that 5-ARI use was not associated with prostate cancer mortality when compared with AB use (adjusted subdistribution hazard ratio, 0.85; 95% CI, 0.72-1.01). Similar results were observed in the case-control study (adjusted matched odds ratio, 0.95; 95% CI, 0.78-1.17). ConclusionAmong men being pharmaceutically treated for benign prostatic hyperplasia, 5-ARI use was not associated with an increased risk of prostate cancer–specific mortality when compared with AB use. The increased prevalence of high-grade lesions at the time of diagnosis noted in our study and the chemoprevention trials may not result in increased prostate cancer mortality.

Dairy products intake and cancer mortality risk: a meta-analysis of 11 population-based cohort studies.

BackgroundDairy products are major components of daily diet and the association between consumption of dairy products and public health issues has captured great attention. In this study, we conducted a meta-analysis to investigate the association between dairy products intake and cancer mortality risk.MethodsAfter a literature search in PubMed and EMBASE, 11 population-based cohort studies involving 778,929 individuals were considered eligible and included in the analyses. Data were extracted and the association between dairy products intake and cancer mortality risk was estimated by calculating pooled relative risks (RRs) and corresponding 95 % confidence intervals (CIs). Sensitivity analyses and subgroup analyses based on regions, genders and dairy types were performed as well. Potential dose–response relationship was further explored by adopting the generalized least squares (GLST) method.ResultsTotal dairy products intake was not associated with all cancer mortality risk, with the pooled RR of 0.99 (95 % CI 0.92–1.07, p = 0.893). Subgroup analyses showed that the pooled RRs were 0.97 (95 % CI 0.92–1.03, p = 0.314) for milk, 0.88 (95 % CI 0.71–1.10, p = 0.271) for yogurt, 1.23 (95 % CI 0.94–1.61, p = 0.127) for cheese and 1.13 (95 % CI 0.89–1.44, p = 0.317) for butter in male and female, however the pooled RR was 1.50 (95 % CI 1.03–2.17, p = 0.032) for whole milk in male, which was limited to prostate cancer. Further dose–response analyses were performed and we found that increase of whole milk (serving/day) induced elevated prostate cancer mortality risk significantly, with the RR of 1.43 (95 % CI 1.13–1.81, p = 0.003).ConclusionsTotal dairy products intake have no significant impact on increased all cancer mortality risk, while low total dairy intake even reduced relative risk based on the non-linear model. However, whole milk intake in men contributed to elevated prostate cancer mortality risk significantly. Furthermore, a linear dose–response relationship existed between increase of whole milk intake and increase of prostate cancer mortality risk.

Snus use, smoking and survival among prostate cancer patients.

Smoking is associated with prostate cancer mortality. The Scandinavian smokeless tobacco product snus is a source of nicotine but not the combustion products of smoke and has not been studied with respect to prostate cancer survival. The study is nested among 9,582 men with incident prostate cancer within a prospective cohort of 336,381 Swedish construction workers. Information on tobacco use was collected at study entry between 1971 and 1992, and categorized into (i) never users of any tobacco, (ii) exclusive snus: ever users of snus only, (iii) exclusive smokers: ever smokers (cigarette, cigar and/or pipe) only and (iv) ever users of both snus and smoking. Hazard ratios for prostate cancer-specific and total mortality for smoking and snus use based on Cox proportional hazards models adjusted for age, calendar period at diagnosis and body mass index at baseline. During 36 years of follow-up, 4,758 patients died-2,489 due to prostate cancer. Compared to never users of tobacco, exclusive smokers were at increased risk of prostate cancer mortality (HR 1.15, 95% CI: 1.05-1.27) and total mortality (HR 1.17, 95% CI: 1.09-1.26). Exclusive snus users also had increased risks for prostate cancer mortality (HR 1.24, 95% CI: 1.03-1.49) and total mortality (HR 1.19, 95% CI: 1.04-1.37). Among men diagnosed with nonmetastatic disease, the HR for prostate cancer death among exclusive snus users was 3.17 (95% CI: 1.66-6.06). The study is limited by a single assessment of tobacco use prior to diagnosis. Snus use was associated with increased risks of prostate cancer and total mortality among prostate cancer patients. This suggests that tobacco-related components such as nicotine or tobacco-specific carcinogens may promote cancer progression independent of tobacco's combustion products.

724PD - Risk of prostate cancer mortality in men with an initial benign needle core biopsy set: a population based analysis with up to 20 years of follow-up

724PD - Risk of prostate cancer mortality in men with an initial benign needle core biopsy set: a population based analysis with up to 20 years of follow-up

Design-corrected variation by centre in mortality reduction in the ERSPC randomised prostate cancer screening trial.

Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years' follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method.

Abstract A29: Effects of obesity on regulation of macrophage population in the prostate tumor microenvironment

Abstract Background: Obesity is associated with a greater risk of prostate cancer mortality, but the mechanisms driving this progression are still unclear. A high concentration of macrophages within the tumor microenvironment, especially tumor-associated macrophages (TAMs), has been linked to progression and metastasis in numerous cancer types, including prostate. Obesity increases circulating levels of monocyte chemotactic protein-1 (MCP-1), a chemokine involved in monocyte migration. In addition, prostaglandin E2 (PGE2), a molecule closely associated with obesity, appears to be involved in macrophage polarization. Our preliminary in vitro data suggest that obese conditions promote both macrophage recruitment and TAM polarization. Hypothesis: Based upon these preliminary results, we hypothesize that obesity-induced prostate cancer progression is due, in part, to increased TAM concentrations in the prostate tumor micro-environment, promoting pro-metastatic signaling. Methods: In order to mimic the prostate tumor microenvironment, an in vitro model composed of adipose stromal cells, macrophages, prostate cancer epithelial cells and sera from obese and non-obese men was used to assess the impact of obesity on the paracrine signaling network. Matrigel invasion chambers were used to assess macrophage recruitment. qPCR was used to measure mRNA levels of proteins associated with a TAM phenotype as well as mRNA levels of MCP-1 and cyclooxygenase-2 (COX-2), an enzyme involved in PGE2 production. Results: Obese conditions resulted in increased macrophage recruitment and increased mRNA levels of TAM markers in macrophages. Furthermore, MCP-1 mRNA levels in adipose stromal cells and prostate cancer cells were higher under obese conditions compared to non-obese conditions. Similarly, obese conditions increased COX-2 mRNA levels in prostate cancer cells. Conclusions: Data from our in vitro study suggest that obesity may promote macrophage infiltration into the prostate tumor microenvironment and play a role in macrophage polarization towards a tumor-associated phenotype. This study will potentially serve to determine the value of macrophage and TAM concentration as biomarkers in this patient population, and lay the foundation for future studies investigating whether this phenomenon might be an effective therapeutic target. Citation Format: Gloria C. Galvan, Shruti Apte, Linda A. deGraffenried. Effects of obesity on regulation of macrophage population in the prostate tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A29.

Vascular morphology differentiates prostate cancer mortality risk among men with higher Gleason grade.

Higher Gleason grade is associated with prostate cancer mortality; however, there is significant heterogeneity in this association. We evaluated whether vessel morphology, a biomarker of angiogenesis, aided in distinguishing mortality risks among men with high Gleason grading. We characterized vessel morphology (area and irregularity) among 511 patients diagnosed with prostate cancer during 1986 to 2000, re-reviewed Gleason grade, and followed men through 2012. Men were grouped according to integrated vessel lumen irregularity and vessel area across Gleason grade. The more angiogenic group was identified as those with more irregular vessel lumen and smaller vessel area. Crude rates (95% confidence intervals) and survival probability were estimated across Gleason grade and vessel morphology. During a median 14-year follow-up, 62 men developed bone metastases or died of prostate cancer. Lethality rates were uniformly low within Gleason grade categories 6 and 7(3+4), regardless of vessel morphology. However, among men with Gleason grades of 7(4+3) or 8-10, the more angiogenic group was associated with fourfold higher risk of lethal outcomes compared to those with less angiogenic potential. Ten-year survival probability ranged from 95 to 74% according to the extent of vessel morphology (p<0.0001, log-rank test). Vessel morphology may aid Gleason grading in predicting prostate cancer mortality risks among men diagnosed with high-grade Gleason cancers.