Dataset Information

Reclassification of prostate cancer risk using sequentially identified SNPs: Results from the REDUCE trial.

ABSTRACT: BACKGROUND:Although the clinical validity of risk-associated single nucleotide polymorphisms (SNPs) for assessment of disease susceptibility has been consistently established, risk reclassification from increasing numbers of implicated risk-associated SNPs raises concern that it is premature for clinical use. Our objective is to assess the degree and impact of risk reclassification with the increasing number of SNPs. METHODS:A total of 3239 patients from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial were included. Four genetic risk scores (GRSs) were calculated based on sets of sequentially discovered prostate cancer (PCa) risk-associated SNPs (17, 34, 51, and 68 SNPs). RESULTS:Pair-wise correlation coefficients between sets of GRSs increased as more SNPs were included in the GRS: 0.80, 0.86, and 0.95 for 17 versus 34 SNPs, 34 versus 51 SNPs, and 51 versus 68 SNPs, respectively. Using a GRS of 1.5 as a cutoff for higher versus lower risk, reclassification rates of PCa risk decreased: 14.11%, 12.04%, and 8.15% for 17 versus 34 SNPs, 34 versus 51 SNPs, and 51 versus 68 SNPs, respectively. Evolving GRSs, nevertheless, provide a tool for further refining risk assessment. When all four sequential GRSs were considered, the detection rates of PCa for men whose GRSs were consistently <1.5, reclassified, and consistently ?1.5 were 20.8%, 29.67%, and 39.26%, respectively (Ptrend ?=?1.12?×?10-8 ). In comparison, the detection rates of PCa in men with negative or positive family history were 23.75% and 31.78%, respectively. CONCLUSIONS:Risk assessment using currently available SNPs is justified. Multiple GRS values from evolving sets of SNPs provide a valuable tool for better refining risk.

SUBMITTER: Chen H

PROVIDER: S-EPMC6949015 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Reclassification of prostate cancer risk using sequentially identified SNPs: Results from the REDUCE trial.

Chen Haitao H Na Rong R Packiam Vignesh T VT Conran Carly A CA Jiang Deke D Tao Sha S Yu Hongjie H Lin Xiaoling X Meng Wei W Zheng S Lilly SL Brendler Charles B CB Helfand Brian T BT Xu Jianfeng J

The Prostate 20170702 11

<h4>Background</h4>Although the clinical validity of risk-associated single nucleotide polymorphisms (SNPs) for assessment of disease susceptibility has been consistently established, risk reclassification from increasing numbers of implicated risk-associated SNPs raises concern that it is premature for clinical use. Our objective is to assess the degree and impact of risk reclassification with the increasing number of SNPs.<h4>Methods</h4>A total of 3239 patients from the Reduction by Dutasteri ...[more]

PMID: 28670847

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Project description:Background: Prostate cancer incidence rates vary 25-fold worldwide. Differences in PSA screening are largely, but not entirely, responsible. We examined geographic differences in prevalence of histologic prostate inflammation and subsequent prostate cancer risk.Methods: Seven thousand nonHispanic white men were enrolled in the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial from Europe (n = 4,644), North America (n = 1,746), South America (n = 466), and Australia/New Zealand (n = 144). Histologic inflammation in baseline negative prostate biopsies was classified as chronic (lymphocytes/macrophages) or acute (neutrophils). Multivariable logistic regression was used to examine associations between region and prostate inflammation, and between region and prostate cancer risk at 2-year biopsy.Results: Prevalence of prostate inflammation varied across region, with broadly similar patterns for acute and chronic inflammation. Relative to Europe, prevalence of acute inflammation was higher in North America [odds ratio (OR), 1.77; 95% confidence interval (CI), 1.51-2.08] and Australia/New Zealand (OR, 2.07; 95% CI, 1.40-3.06). Men from these regions had lower prostate cancer risk than Europeans at biopsy. Among North Americans, prevalence of acute inflammation was higher in Canada versus the United States (OR, 1.40; 95% CI, 1.07-1.83), but prostate cancer risk did not differ between these regions. Among Europeans, prevalence of acute inflammation was lower in Northern and Eastern (OR, 0.79; 95% CI, 0.65-0.97 and OR 0.62; 95% CI, 0.45-0.87, respectively), relative to Western Europe, and these men had higher prostate cancer risk at biopsy.Conclusions: Prevalence of histologic prostate inflammation varied by region. Geographic differences in prostate inflammation tracked inversely with geographic differences in prostate cancer risk.Impact: Characterization of premalignant prostate biology and the relationship with subsequent prostate cancer risk could inform prostate cancer prevention efforts. Cancer Epidemiol Biomarkers Prev; 27(7); 783-9. ©2018 AACR.

Project description:PurposeA recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy.Experimental designWe examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason < 7), or high-grade (Gleason ≥ 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent ≥1 on-study biopsy. Multivariable analyses were adjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, statins, hypertension, diabetes, and cardiovascular disease.ResultsOverall, 3,169 men (50%) were nonusers, 1,368 (21%) used aspirin, 1,176 (18%) used NSAIDs, and 677 (11%) used both. In unadjusted models, aspirin was associated with reduced prostate cancer risk (OR = 0.85, P = 0.036). In multivariable analyses, aspirin was associated with reduced total prostate cancer risk (OR = 0.81, P = 0.015). Use of NSAIDs or NSAIDs and aspirin was not associated with total, low-grade, or high-grade prostate cancer, though all ORs were <1 (all P ≥ 0.08). Therefore, we created a dichotomous variable of aspirin and/or NSAID users versus nonusers. On multivariable analysis, the use of aspirin and/or NSAIDs was significantly associated with decreased total (OR = 0.87, P = 0.030) and high-grade (OR = 0.80, P = 0.040), but not with low-grade, prostate cancer risk (OR = 0.90, P = 0.15). Results were similar in placebo and dutasteride arms.ConclusionsAmong men with a negative biopsy, aspirin and/or NSAID use was associated with decreased prostate cancer risk. Additional studies are warranted.

Project description:Prostate specific antigen velocity is an unreliable predictor of adverse pathology findings in patients on active surveillance for low risk prostate cancer. However, to our knowledge a new concept called prostate specific antigen velocity risk count, recently validated in a screening cohort, has not been investigated in an active surveillance cohort.We evaluated a cohort of men from 1995 to 2012 with prostate cancer on active surveillance. They had stage T1c disease, prostate specific antigen density less than 0.15 ng/ml, Gleason score 6 or less, 2 or fewer biopsy cores and 50% or less involvement of any core with cancer. The men were observed by semiannual prostate specific antigen measurements, digital rectal examinations and an annual surveillance biopsy. Treatment was recommended for biopsy reclassification. Patients with 30 months or greater of followup and 3 serial prostate specific antigen velocity measurements were used in primary analysis by logistic regression, Cox proportional hazards, Kaplan-Meier analysis and performance parameters, including the AUC of the ROC curve.Primary analysis included 275 of 668 men who met very low risk inclusion criteria, of whom 83 (30.2%) were reclassified at a median of 57.1 months. Reclassification risk increased with risk count, that is a risk count of 3 (HR 4.63, 95% CI 1.54-13.87) and 2 (HR 3.73, 95% CI 1.75-7.97) compared to zero. Results were similar for Gleason score reclassification (HR 7.45, 95% CI 1.60-34.71 and 3.96, 95% CI 1.35-11.62, respectively). On secondary analysis the negative predictive value (risk count 1 or less) was 91.5% for reclassification in the next year. Adding the prostate specific antigen velocity risk count improved the AUC in a model including baseline prostate specific antigen density (0.7423 vs 0.6818, p = 0.025) and it outperformed the addition of overall prostate specific antigen velocity (0.7423 vs 0.6960, p = 0.037).Prostate specific antigen velocity risk count may be useful for monitoring patients on active surveillance and decreasing the frequency of biopsies needed in the long term.

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Reclassification of prostate cancer risk using sequentially identified SNPs: Results from the REDUCE trial.

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Reclassification of prostate cancer risk using sequentially identified SNPs: Results from the REDUCE trial.

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