Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort

Background:

The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score.

Methods:

Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort.

Results:

In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10⁻¹³) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10⁻⁶). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ²=89.0, P<10⁻²⁰) and captured virtually all available prognostic information.

Conclusions:

The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.     

Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10⁻⁸. Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.     

Rare germline genetic variants and risk of aggressive prostate cancer

Few genetic risk factors have been demonstrated to be specifically associated with aggressive prostate cancer (PrCa). Here, we report a case-case study of PrCa comparing the prevalence of germline pathogenic/likely pathogenic (P/LP) genetic variants in 787 men with aggressive disease and 769 with nonaggressive disease. Overall, we observed P/LP variants in 11.4% of men with aggressive PrCa and 9.8% of men with nonaggressive PrCa (two-tailed Fisher's exact tests, P = .28). The proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive PrCa exceeded that observed in men with nonaggressive PrCa; 18/787 carriers (2.3%) and 4/769 carriers (0.5%), P = .004, and 14/787 carriers (0.02%) and 5/769 carriers (0.01%), P = .06, respectively. Our findings contribute to the extensive international effort to interpret the genetic variation identified in genes included on gene-panel tests, for which there is currently an insufficient evidence-base for clinical translation in the context of PrCa risk.     

Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort

Background:

The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy.

Methods:

Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer.

Results:

In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10⁻⁹) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10⁻⁵), with Gleason score (P=5 × 10⁻⁴) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions.

Conclusion:

For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.     

Performance of individual and joint risk stratification by an environmental risk score and a genetic risk score in a colorectal cancer screening setting

Early detection of colorectal neoplasms can reduce the disease burden of colorectal cancer by timely intervention of individuals at high risk. Our aim was to evaluate a joint environmental-genetic risk score as a risk stratification tool for early detection of advanced colorectal neoplasm (ACRN). Known environmental risk factors and high-risk genetic loci were summarized into risk scores for ACRN in 1014 eligible participants of a screening study. The performances of single and joint environmental-genetic scores were evaluated with estimates and 95% confidence intervals (CI) of the absolute risk, relative risk and predictive ability using the area under the curve (AUC). Individuals with higher environmental risk scores showed increasing ACRN risk, with 3.1-fold for intermediate risk and 4.8-fold for very high risk, compared to the very low environmental risk group. Similarly, individuals with higher genetic risk scores showed increasing ACRN risk, with 2.2-fold for intermediate risk and 3.5-fold for very high risk, compared to the lowest genetic risk group. Moreover, the joint environmental–genetic score improved the ACRN risk stratification and showed higher predictive values (AUC = 0.64; 95%CI = 0.60–0.67) with substantial difference (p = 0.0002) compared to the single environmental score (0.58; 0.55–0.62). The integration of environmental and genetic factors looks promising for improving targeting individuals at high-risk of colorectal neoplasm. Applications in practical screening programs require optimization with additional genetic and other biomarkers involved in colorectal carcinogenesis.     

Prostate-specific antigen velocity and the detection of gleason score 7 to 10 prostate cancer

BACKGROUND: An increasing prostate-specific antigen (PSA) velocity is associated with a shorter survival after local therapy for prostate cancer. In this study, the authors evaluated whether PSA velocity was associated with prostate cancer detection and grade at diagnosis after adjusting for established predictors. METHODS: Between January 1989 and December 2003, 914 men who had PSA levels >/=4 ng/mL were identified by using the Center for Prostate Disease Research (CPDR) multicenter national database, including 541 men who were diagnosed with prostate cancer. Multivariable logistic regression analyses were performed that included continuous variables (PSA velocity and level, number of prior negative biopsies, and age) along with categorical variables (ethnicity and family history) were used to identify the factors associated with prostate cancer detection and grade. RESULTS: An increasing PSA velocity was associated with Gleason scores from 7 to 10 versus Gleason scores form 2 to 6 or no cancer (adjusted odds ratio [OR], 1.04 ng/mL per year; 95% confidence interval [95% CI], 1.003-1.085 ng/mL per year; P = .035). This finding was not evident in patients who had prostate cancers with Gleason scores between 2 and 6 or for any prostate cancer. PSA level was associated with the detection of any prostate cancer (OR, 1.06 ng/mL; 95% CI, 1.03-1.10 ng/mL; P = .004) and Gleason score 4 ng/mL. These findings, in conjunction with life expectancy, may be used when deciding which men should not be recommended for prostate biopsy despite a PSA level >4 ng/mL.     

Confirmation of genetic variants associated with lethal prostate cancer in a cohort of men from hereditary prostate cancer families

Germline genetic variants have been suggested as prognostic biomarkers for identifying patients at high risk for lethal prostate cancer (PCa). Validation studies have confirmed the association of several single nucleotide polymorphisms (SNPs) with fatal PCa, but whether these variants affect PCa‐specific mortality (PCSM) in patients with an inherited predisposition to PCa, based on familial history, is unknown. For this study, a cohort of 957 PCa patients from 270 hereditary prostate cancer families of European ancestry was genotyped for a panel of 22 PCSM‐associated SNPs. Death certificates were reviewed to confirm cause of death. Mixed‐effect Cox proportional hazards models were used to assess survival according to genotypes, accounting for relatedness and clinicopathological factors. Within this cohort, 98 PCa deaths were confirmed over an average follow‐up period of 12.7 years after diagnosis. Variant allele carriers for three SNPs had significantly altered risk for PCSM [rs635261 at RNASEL, hazard ratio (HR), 0.35, 95% CI, 0.18–0.66; p = 0.002; rs915927 in XRCC1, HR, 1.91, 95% CI, 1.21–3.02; p = 0.009; and rs2494750 at AKT1, HR, 0.45, 95% CI, 0.23–0.90; p = 0.016). These results confirm the association of genetic variation in three genes with PCa lethality in a cohort of men with an inherited susceptibility to the disease and provide validation evidence that germline SNPs provide prognostic information for PCa patients. Development of a panel of germline biomarkers with clinical utility for distinguishing patients at detection who have an increased risk for fatal PCa is warranted.     

Active surveillance for the management of prostate cancer in a contemporary cohort

BACKGROUND: Active surveillance followed by selective treatment for men who have evidence of disease progression may be an option for select patients with early-stage prostate cancer. In this article, the authors report their experience in a contemporary cohort of men with prostate cancer who were managed with active surveillance. METHODS: All men who were managed initially with active surveillance were identified through the authors' institutional database. Selection criteria for active surveillance included: prostate-specific antigen (PSA)<10 ng/mL, biopsy Gleason sum 0.75 ng/mL per year), was a secondary outcome. Chi-square and log-rank tests were used to compare groups. The association between clinical characteristics and receipt of active treatment was analyzed by using Cox proportional hazards regression. RESULTS: Three hundred twenty-one men (mean age [+/-standard deviation]: 63.4+/-8.5 years) selected active surveillance as their initial management. The overall median follow-up was 3.6 years (range, 1-17 years). The initial mean PSA level was 6.5+/-3.9 ng/mL. One hundred twenty men (37%) met at least 1 criterion for progression. Overall, 38% of men had higher grade on repeat biopsy, and 26% of men had a PSA velocity>0.75 ng/mL per year. Seventy-eight men (24%) received secondary treatment at a median 3 years (range, 1-17 years) after diagnosis. Approximately 13% of patients with no disease progression elected to obtain treatment. PSA density at diagnosis and rise in Gleason score on repeat biopsy were associated significantly with receipt of secondary treatment. The disease-specific survival rate was 100%. CONCLUSIONS: Selected individuals with early-stage prostate cancer may be candidates for active surveillance. Specific criteria can be and need to be developed to select the most appropriate individuals for this form of management and to monitor disease progression. A small attrition rate can be expected because of men who are unable or unwilling to tolerate surveillance.     

Vasectomy and the risk of prostate cancer in a cohort of multiphasic health-checkup examinees: second report

The relationship of vasectomy to prostate cancer was studied in 5,119 men with a self-reported history of vasectomy, identified at multiphasic health checkups undergone during 1977–82 while members of the Northern California Kaiser Permanente Medical Care Program. Three unvasectomized comparison subjects were identified for each vasectomized man, matched for age, race, marital status, and date and location of the examination. Follow-up for incident prostate cancer was conducted for a mean length of 6.8 years. The relative risk of prostate cancer associated with vasectomy was 1.0 (95% confidence interval = 0.7–1.6); the relative risk was approximately one, regardless of length of interval (less than 10 years, 10–20 years, more than 20 years) between vasectomy and multiphasic health checkup or the age at vasectomy (less than 40 years vs more than 40 years). These data support earlier findings reported in this study group of the lack of an association of vasectomy with subsequent risk of prostate cancer.Supported by a grant from Merck Sharp and Dobme Research Laboratories.     

Obesity does not predispose to more aggressive prostate cancer either at biopsy or radical prostatectomy in European men

Many investigators suggested that obesity predisposes to adverse prostate cancer characteristics and outcomes. We tested the effect of obesity on the rate of aggressive prostate cancer at either prostate biopsy or radical prostatectomy (RP). Clinical and pathological data were available for 1,814 men. Univariable and multivariable logistic regression models addressed the rate of high grade prostate cancer (HGPCa) at either biopsy or final pathology. Clinical stage, prostate-specific antigen (PSA), percentage of free PSA and prostate volume were the base predictors. All models were fitted with and without body mass index (BMI), which quantified obesity. BMI and its reciprocal (InvBMI) were coded as cubic splines to allow nonlinear effects. Predictive accuracy (PA) was quantified with area under curve estimates, which were subjected to 200 bootstrap re-samples to reduce overfit bias. Gains in PA related to the inclusion of BMI were compared using the Mantel-Haenszel test. HGPCa at biopsy was detected in 562 (31%) and HGPCa at RP pathology was present in 931 (51.3%) men. In either univariable or multivariable models predicting HGPCa at biopsy, BMI or InvBMI failed to respectively reach statistical significance or add to multivariable PA (BMI gain = 0%, p = 1.0; InvBMI gain = -0.2%, p = 0.9). Conversely, in models predicting HGPCa at RP, BMI and InvBMI represented independent predictors but failed to increase PA (BMI gain = 0.7%, p = 0.6; InvBMI gain = 0.5, p = 0.7%). Obesity does not predispose to more aggressive prostate cancer at biopsy. Similarly, obesity does not change the ability to identify those who may harbor HGPCa at RP.     

African‐specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross‐validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10‐fold cross‐validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross‐validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47‐4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65‐0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.     

A prospective cohort study of red wine consumption and risk of prostate cancer

In light of recent, strong inverse findings between lifetime red wine consumption and prostate cancer among younger men, we revisited our previous cohort analysis to more thoroughly investigate red wine consumption and prostate cancer in the Health Professionals Follow-up Study (HPFS). In 1986, HPFS participants reported their average consumption of red wine, white wine, beer and liquor during the past year, and their change in alcohol consumption over the prior 10 years. Prostate cancer diagnoses were ascertained on each biennial questionnaire and confirmed by medical record review. Between 1986 and 2002, 3,348 cases of prostate cancer were diagnosed among 45,433 eligible participants. Using men who did not consume red wine as the reference, no linear trend was observed between red wine consumption and prostate cancer in the full analytic cohort (p-trend = 0.57). Among men with unchanged alcohol consumption in the prior 10 years, and those additionally <65 years of age, slightly lower risks were observed for men who consumed 4 glasses/week, resulting in a lack of linear trend. These findings suggest that red wine does not contribute appreciably to the etiology of prostate cancer.