Jennifer R. Stark

Circulating prediagnostic interleukin-6 and C-reactive protein and prostate cancer incidence and mortality.

Interleukin‐6 (IL‐6) and C‐reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case‐control study to evaluate the relation between prediagnostic levels of IL‐6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL‐6 (−174 G/C) polymorphism in relation to circulating levels of IL‐6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL‐6 nor CRP plasma levels varied significantly by IL‐6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL‐6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL‐6 and BMI on prostate cancer incidence (pinteraction < 0.01). Increasing IL‐6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in overweight men. Further, prediagnostic IL‐6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (ptrend = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL‐6 level. Our study suggests that IL‐6 may potentially be involved in the development or progression of prostate cancer.

Screening for prostate cancer remains controversial

Two long awaited randomised trials of PSA screening have reported this year. However, as Jennifer Stark and colleagues explain, the results are unlikely to end the controversy over the benefits and harms of testing

Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma

Study Type – Aetiology (case series)

Testing a multigene signature of prostate cancer death in the Swedish Watchful Waiting Cohort

Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Örebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1682–8)

Managing localized prostate cancer by radical prostatectomy or watchful waiting: Cost analysis of a randomized trial (SPCG-4)

Abstract Objective. The cost of radical prostatectomy (RP) compared to watchful waiting (WW) has never been estimated in a randomized trial. The goal of this study was to estimate long-term total costs per patient associated with RP and WW arising from inpatient and outpatient hospital care. Material and methods. This investigation used the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial, comparing RP to WW, and included data from 212 participants living in two counties in Sweden from 1989 to 1999 (105 randomized to WW and 107 to RP). All costs were included from randomization date until death or end of follow-up in July 2007. Resource use arising from inpatient and outpatient hospital costs was measured in physical units and multiplied by a unit cost to come up with a total cost per patient. Results. During a median follow-up of 12 years, the overall cost in the RP group was 34% higher (p < 0.01) than in the WW group, corresponding to €6123 in Sweden. The difference was driven almost exclusively by the cost of the surgical procedure. The cost difference between RP and WW was two times higher among men with low (2–6) than among those with high (7–10) Gleason score. Conclusion. In this economic evaluation of RP versus WW of localized prostate cancer in a randomized study, RP was associated with 34% higher costs. This difference, attributed exclusively to the cost of the RP procedure, was not overcome during extended follow-up.

Toll-like Receptor Signaling Pathway Variants and Prostate Cancer Mortality

An understanding of factors associated with prostate cancer (PCa) mortality is increasingly important given the biological heterogeneity of disease. Previous studies have shown that genetic variation in the Toll-like receptor (TLR) signaling pathway is associated with PCa incidence, but any role in progression and mortality is unclear. Among 1,252 PCa cases from the Cancer Prostate in Sweden study, we conducted time-to-event analyses of PCa mortality for 99 individual tagging SNPs and haploytpes from 20 genes in the TLR pathway. Cox proportional hazards models were used to estimate hazard ratios (HR) and 99% confidence intervals (99% CI). Global P values were estimated from a likelihood ratio test. During a median follow-up of 5.1 years, 191 PCa deaths occurred. Controlling for age and geographic location, two polymorphisms were statistically significantly associated with PCa mortality (P < 0.01). Compared with homozygous wild-type carriers of the TLR-9 polymorphism (rs187084), the HR (99% CI) was 1.57 (1.02, 2.41) for heterozygotes and 1.02 (0.57, 1.84) for rare homozygotes (P = 0.009). For a MIC-1 SNP (rs1227732), the HR comparing carriers of at least one copy of the minor allele to wild-type homozygotes was 0.54 (99% CI: 0.34, 0.87). Only the MIC-1 SNP remained significant after additional adjustment for treatment. No significant associations were observed for common haplotypes and PCa mortality. This study highlights the importance of studies of PCa mortality because risk factors for incidence and mortality may differ. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1859–63)

Genetic variation in the toll-like receptor 4 and prostate cancer incidence and mortality.

Common genetic variants in the Toll‐like receptor 4 (TLR4), which is involved in inflammation and immune response pathways, may be important for prostate cancer.

Nine-Gene Molecular Signature Is Not Associated with Prostate Cancer Death in a Watchful Waiting Cohort

Tumor molecular markers hold promise to distinguish potentially lethal from indolent prostate cancer and to guide treatment choices. A previous study identified a nine-gene molecular signature in tumors associated with prostate-specific antigen relapse after prostatectomy. We examined this molecular model in relation to prostate cancer death among 172 men with initially localized disease. We quantified protein expression of the nine genes in tumors to classify progression risk. Accounting for clinical prognostic factors, the nine-gene model did not provide discrimination to predict lethal and indolent prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(1):249–51)

Staging mammography nonadherent women: A qualitative study

Background. Few studies have related stages of mammography screening nonadherence with the rationale used by overdue women. Methods. We used a grounded theory approach to obtain and analyze data from focus groups, telephone interviews, and surveys. Emergent specific themes were compared with emerging decision levels of nonadherence. Each decision level was then compared with the Precaution Adoption Process Model and the Transtheoretical Model. Results. A total of 6 key themes influencing mammogram nonadherence emerged as did 6 decision levels. Variability within themes was associated with specific decision levels. The decision levels were not adequately classified by either stage model. Conclusions. Stage-based educational strategies may benefit by tailoring interventions to these 6 decision levels.

NO ASSOCIATION BETWEEN A POLYMORPHIC VARIANT OF THE IRS-1 GENE AND PROSTATE CANCER RISK

Insulin receptor substrate‐1 (IRS‐1) acts as a docking protein between the insulin‐like growth factor‐1 (IGF‐1) receptor and intracellular signaling molecules in the IGF‐1 signaling pathway. Accumulating data support a role of IGF‐1 in prostate carcinogenesis. We assessed the influence of the most common IRS‐1 gene polymorphism (Gly972Arg) on prostate cancer risk, alone and in combination with IGF‐1 and other components in the IGF‐1 signaling pathway.