Cindy Ke Zhou

Prostate cancer incidence in 43 populations worldwide: An analysis of time trends overall and by age group.

Prostate cancer is a significant public health burden and a major cause of morbidity and mortality among men worldwide. Analyzing geographic patterns and temporal trends may help identify high‐risk populations, suggest the degree of PSA testing, and provide clues to etiology. We used incidence data available from the International Agency for Research on Cancer (IARC) and certain cancer registries for 43 populations across five continents during a median period of 24 years. Trends in overall prostate cancer rates showed five distinct patterns ranging from generally monotonic increases to peaking of rates followed by declines, which coincide somewhat with changes in the prevalence of PSA testing. Trends in age‐specific rates generally mirrored those in the overall rates, with several notable exceptions. For populations where overall rates increased rapidly and then peaked, exemplified in North America and Oceania, the highest incidence tended to be most pronounced and occurred during earlier calendar years among older men compared with younger ones. For populations with almost continual increases in overall rates, exemplified in Eastern Europe and Asia, peaks were evident among men aged ≥75 years in many instances. Rates for ages 45–54 years did not clearly stabilize or decline in the majority of studied populations. Global geographic variation remained substantial for both overall and age‐specific incidence rates regardless of levels of PSA testing, with the lowest rates consistently in Asia. Explanations for the persistent geographic differences and the continuing increases of especially early‐onset prostate cancer remain unclear.

Relationship Between Male Pattern Baldness and the Risk of Aggressive Prostate Cancer: An Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

PURPOSEnMale pattern baldness and prostate cancer appear to share common pathophysiologic mechanisms. However, results from previous studies that assess their relationship have been inconsistent. Therefore, we investigated the association of male pattern baldness at age 45 years with risks of overall and subtypes of prostate cancer in a large, prospective cohort—the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.nnnMETHODSnWe included 39,070 men from the usual care and screening arms of the trial cohort who had no cancer diagnosis (excluding nonmelanoma skin cancer) at the start of follow-up and recalled their hair-loss patterns at age 45 years. Hazard ratios (HRs) and 95% CIs were estimated by using Cox proportional hazards regression models with age as the time metric.nnnRESULTSnDuring follow-up (median, 2.78 years), 1,138 incident prostate cancer cases were diagnosed, 571 of which were aggressive (biopsy Gleason score ≥ 7, and/or clinical stage III or greater, and/or fatal). Compared with no baldness, frontal plus moderate vertex baldness at age 45 years was not significantly associated with overall (HR, 1.19; 95% CI, 0.98 to 1.45) or nonaggressive (HR, 0.97; 95% CI, 0.72 to 1.30) prostate cancer risk but was significantly associated with increased risk of aggressive prostate cancer (HR, 1.39; 95% CI, 1.07 to 1.80). Adjustment for covariates did not substantially alter these estimates. Other classes of baldness were not significantly associated with overall or subtypes of prostate cancer.nnnCONCLUSIONnOur analysis indicates that frontal plus moderate vertex baldness at age 45 years is associated with an increased risk of aggressive prostate cancer and supports the possibility of common pathophysiologic mechanisms.

Male Pattern Baldness in Relation to Prostate Cancer–Specific Mortality: A Prospective Analysis in the NHANES I Epidemiologic Follow-up Study

We used male pattern baldness as a proxy for long-term androgen exposure and investigated the association of dermatologist-assessed hair loss with prostate cancer-specific mortality in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. From the baseline survey (1971-1974), we included 4,316 men who were 25-74 years of age and had no prior cancer diagnosis. We estimated hazard ratios and used Cox proportional hazards regressions with age as the time metric and baseline hazard stratified by baseline age. A hybrid framework was used to account for stratification and clustering of the sample design, with adjustment for the variables used to calculate sample weights. During follow-up (median, 21 years), 3,284 deaths occurred; prostate cancer was the underlying cause of 107. In multivariable models, compared with no balding, any baldness was associated with a 56% higher risk of fatal prostate cancer (hazard ratio = 1.56; 95% confidence interval: 1.02, 2.37), and moderate balding specifically was associated with an 83% higher risk (hazard ratio = 1.83; 95% confidence interval: 1.15, 2.92). Conversely, patterned hair loss was not statistically significantly associated with all-cause mortality. Our analysis suggests that patterned hair loss is associated with a higher risk of fatal prostate cancer and supports the hypothesis of overlapping pathophysiological mechanisms.

Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts

Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer–specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75–0.90) and 15% (HR = 0.85; 95% CI = 0.77–0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72–0.95) and 25% (HR = 0.75; 95% CI = 0.66–0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410–20. ©2017 AACR.

Is birthweight associated with total and aggressive/lethal prostate cancer risks? A systematic review and meta-analysis

Background:It has been hypothesised that intrauterine exposures are important for subsequent prostate cancer risk. Prior epidemiological studies have used birthweight as a proxy of cumulative intrauterine exposures to test this hypothesis, but results have been inconsistent partly because of limited statistical power.Methods:We investigated birthweight in relation to prostate cancer in the Medical Research Council (MRC) National Survey of Health and Development (NSHD) using Cox proportional hazards models. We then conducted a meta-analysis of birthweight in relation to total and aggressive/lethal prostate cancer risks, combining results from the NSHD analysis with 13 additional studies on this relationship identified from a systematic search in four major scientific literature databases through January 2015.Results:Random-effects models found that per kg increase in birthweight was positively associated with total (OR=1.02, 95% confidence interval (95% CI)=1.00, 1.05; I2=13%) and aggressive/lethal prostate cancer (OR=1.08, 95% CI=0.99, 1.19; I2=40%). Sensitivity analyses restricted to studies with birthweight extracted from medical records demonstrated stronger positive associations with total (OR=1.11, 95% CI=1.03, 1.19; I2=0%) and aggressive/lethal (OR=1.37, 95% CI=1.09, 1.74; I2=0%) prostate cancer. These studies heavily overlapped with those based in Nordic countries.Conclusions:This study provides evidence that heavier birthweight may be associated with modest increased risks of total and aggressive/lethal prostate cancer, which supports the hypothesis that intrauterine exposures may be related to subsequent prostate cancer risks.

Relationships between circulating and intraprostatic sex steroid hormone concentrations

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.

TMPRSS2:ERG Gene Fusions in Prostate Cancer of West African Men and a Meta-Analysis of Racial Differences

The prevalence of fusions of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2:ERG, in prostate cancer varies by race. However, such somatic aberration and its association with prognostic factors have neither been studied in a West African population nor been systematically reviewed in the context of racial differences. We used immunohistochemistry to assess oncoprotein encoded by the ERG gene as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study (2004-2006). Poisson regression with robust variance estimation provided prevalence ratios and 95% confidence intervals of ERG expression in relation to patient characteristics. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Meta-analysis showed the prevalence of TMPRSS2:ERG fusions in prostate cancer to be highest in men of European descent (49%), followed by men of Asian (27%) and then African (25%) descent. The lower prevalence of TMPRSS2:ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations.

Circulating and intraprostatic sex steroid hormonal profiles in relation to male pattern baldness and chest hair density among men diagnosed with localized prostate cancers

Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early‐life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer.

Abstract B26: Pre- and post-diagnostic use of nonsteroidal anti-inflammatory drugs and prostate cancer mortality among men diagnosed with prostate cancer in the NIH-AARP and PLCO cohorts

Background: Prostate cancer is the second leading cause of cancer death in American men, but few modifiable risk factors have been established for prostate cancer progression and survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through anti-thrombotic and anti-inflammation mechanisms. However, previous observational studies have shown mixed results. No study has examined over-the-counter non-aspirin NSAIDs in relation to prostate cancer survival. Few studies have assessed aspirin use before prostate cancer diagnosis in relation to prostate cancer survival, and whether any etiologically relevant time window of exposure exists remains unclear. Methods: We assessed two cohorts of prostate cancer cases from two large prospective studies in the United States NIH-AARP Diet and Health Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to investigate associations of aspirin and other nonselective non-aspirin NSAID use before and after prostate cancer diagnosis with prostate cancer-specific and all-cause mortality. Cox proportional hazards models with age as the time metric were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results across the two studies were meta-analyzed in a fixed effects model if consistent associations were observed. Results: We did not find statistically significant associations of pre- or post-diagnostic NSAID use with prostate cancer-specific mortality. However, aspirin users versus nonusers five years or more before prostate cancer diagnosis had a 14% (95%CI=0.74 to 1.00) and a 16% (95%CI=0.78 to 0.89) reduced prostate cancer-specific and all-cause mortality when combining the two studies. Post-diagnostic occasional (less than once per day) and daily aspirin use were associated with 17% (95%CI=0.72 to 0.95) and 25% (95%CI=0.66 to 0.86) reductions in all-cause mortality independent of pre-diagnostic use, comparing with no use. Conclusions: This analysis suggests a modest delayed survival benefit of aspirin use before prostate cancer diagnosis and highlights the importance of comorbidity prevention among prostate cancer survivors. Citation Format: Cindy Ke Zhou, Sarah E. Daugherty, Amanda Black, Linda M. Liao, Neal D. Freedman, Christian C. Abnet, Ruth Pfeiffer, Michael B. Cook. Pre- and post-diagnostic use of nonsteroidal anti-inflammatory drugs and prostate cancer mortality among men diagnosed with prostate cancer in the NIH-AARP and PLCO cohorts. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B26.

Abstract LB-371: ERG protein expression in diagnostic prostate cancer tissues among West African men

Background: Fusion of androgen regulated TMPRSS2 gene and the ERG oncogene is a common recurrent chromosomal aberration in prostate cancer, which leads to elevated expression of ERG oncoprotein. ERG expression detected by immunohistochemistry (IHC) has been validated as a proxy of TMPRSS2-ERG gene fusion. The prevalence of TMPRSS2-ERG gene fusion has been shown to vary by race being highest in Caucasian prostate cancer patients, followed by African American and then Asian. However, the prevalence of TMPRSS2-ERG gene fusion in African prostate cancer populations remains to be determined. Methods and Materials: There were 428 prostate cancer patients diagnosed during 2004-2012 in the Ghana Prostate Study who had formalin-fixed paraffin-embedded needle biopsy tissues available for analysis. Pathologists centrally scored 262 tissue samples for ERG expression and Gleason patterns, after excluding 166 without sufficient tissues. ERG-positive nuclear immunostaining of normal endothelial cells was used as an internal control and only nuclear immunostaining of prostate cancer cells was deemed ERG-positive. We evaluated ERG expression status in relation to clinicopathological characteristics using logistic regression models. To assess potential selection bias, we performed sensitivity analyses comparing clinicopathological characteristics extracted from medical records by inclusion/exclusion status. Results: We found 47 (18%) tissue samples were ERG-positive. Since recently preserved tissues appeared more likely to be ERG-negative (P = 0.044), all logistic regression models were adjusted for calendar year of diagnosis. Negative ERG staining was significantly associated with higher Gleason score (P = 0.035), in particular with higher primary Gleason grade (P = 0.028). Age at diagnosis, PSA concentration at diagnosis, and tribal group were not significantly associated with ERG expression status. Sensitivity analyses revealed that excluded tissues were more likely to be preserved in earlier years (P = 0.033) and to have lower Gleason scores (P = 0.003). Conclusions: This first study of ERG expression in an African prostate cancer population indicates that the prevalence of TMPRSS2-ERG gene fusion is similar to that of African American patients but lower than those with European ancestry. Whether this lower proportion of TMPRSS2-ERG gene fusion leads to a greater proportion of aggressive prostate cancer in African men or is the result of diagnostic selection of a higher proportion of symptomatic, high Gleason score prostate cancers in such populations remains unknown. Citation Format: Cindy Ke Zhou, Denise Young, Edward D. Yeboah, Richard B. Biritwum, Andrew A. Adjei, Yao Tettey, Evelyn Tay, Shelley Niwa, Ann L. Truelove, Isabell A. Sesterhenn, Shiv Srivastava, Robert N. Hoover, Ann W. Hsing, Michael B. Cook. ERG protein expression in diagnostic prostate cancer tissues among West African men. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-371.