Cohort profile: the Turin prostate cancer prognostication (TPCP) cohort.

Introduction: Prostate cancer (PCa) is the most frequent tumor among men in Europe and has both indolent and aggressive forms. There are several treatment options, the choice of which depends on multiple factors. To further improve current prognostication models, we established the Turin Prostate Cancer Prognostication (TPCP) cohort, an Italian retrospective biopsy cohort of patients with PCa and long-term follow-up. This work presents this new cohort with its main characteristics and the distributions of some of its core variables, along with its potential contributions to PCa research. Methods: The TPCP cohort includes consecutive non-metastatic patients with first positive biopsy for PCa performed between 2008 and 2013 at the main hospital in Turin, Italy. The follow-up ended on December 31st 2021. The primary outcome is the occurrence of metastasis; death from PCa and overall mortality are the secondary outcomes. In addition to numerous clinical variables, the study's prognostic variables include histopathologic information assigned by a centralized uropathology review using a digital pathology software system specialized for the study of PCa, tumor DNA methylation in candidate genes, and features extracted from digitized slide images via Deep Neural Networks. Results: The cohort includes 891 patients followed-up for a median time of 10 years. During this period, 97 patients had progression to metastatic disease and 301 died; of these, 56 died from PCa. In total, 65.3% of the cohort has a Gleason score less than or equal to 3 + 4, and 44.5% has a clinical stage cT1. Consistent with previous studies, age and clinical stage at diagnosis are important prognostic factors: the crude cumulative incidence of metastatic disease during the 14-years of follow-up increases from 9.1% among patients younger than 64 to 16.2% for patients in the age group of 75-84, and from 6.1% for cT1 stage to 27.9% in cT3 stage. Discussion: This study stands to be an important resource for updating existing prognostic models for PCa on an Italian cohort. In addition, the integrated collection of multi-modal data will allow development and/or validation of new models including new histopathological, digital, and molecular markers, with the goal of better directing clinical decisions to manage patients with PCa.

Germline Genetic Variants Associated with Somatic TMPRSS2:ERG Fusion Status in Prostate Cancer: A Genome-Wide Association Study.

BACKGROUND: The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status. METHODS: We performed a genome-wide association study with 396 TMPRSS2:ERG(+) cases, 390 TMPRSS2:ERG(-) cases, and 2,386 cancer-free controls from the Physicians' Health Study (PHS), the Health Professionals Follow-up Study (HPFS), and a Seattle-based Fred Hutchinson (FH) Cancer Center Prostate Cancer Study. We applied logistic regression models to test the associations between ∼5 million SNPs with TMPRSS2:ERG fusion status accounting for population stratification. RESULTS: We did not identify genome-wide significant variants comparing the TMPRSS2:ERG(+) to the TMPRSS2:ERG(-) prostate cancer cases in the meta-analysis. When comparing TMPRSS2:ERG(+) prostate cancer cases with controls without prostate cancer, 10 genome-wide significant SNPs on chromosome 17q24.3 were observed in the meta-analysis. When comparing TMPRSS2:ERG(-) prostate cancer cases with controls without prostate cancer, two SNPs on chromosome 8q24.21 in the meta-analysis reached genome-wide significance. CONCLUSIONS: We observed SNPs at several known prostate cancer risk loci (17q24.3, 1q32.1, and 8q24.21) that were differentially and exclusively associated with the risk of developing prostate tumors either with or without the gene fusion. IMPACT: Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared with fusion negative cases.

Risk and mortality of testicular cancer in patients with neurodevelopmental or other psychiatric disorders.

BACKGROUND: Both testicular germ cell tumours (TGCT) and neurodevelopmental disorders are associated with urogenital malformations. Few studies have investigated the association between psychiatric disorders and TGCT. We investigated whether history of any psychiatric or neurodevelopmental disorder is associated with increased risk or mortality of TGCT. METHOD: This is a nested case-control study including 6166 TGCT patients diagnosed during 1992-2014, individually matched for age and calendar period to 61,660 controls. We calculated odds ratios (ORs) for the association between type of psychiatric diagnoses and TGCT risk. Among the cases, we used a cohort design and calculated hazard ratios (HRs) of the association between psychiatric diagnose and all-cause and TGCT-specific death. RESULTS: History of a neurodevelopmental disorder (attention deficit hyperactivity disorder, autism spectrum disorder and intellectual disabilities) was associated with an increased risk of seminoma (OR: 1.54; 1.09-2.19). Seminoma patients with neurodevelopmental disorders were younger (34 versus 38 years, p = 0.004) and had more stage IV disease (5.4% versus 1.2%) than those without. Psychiatric history overall was not associated with TGCT. Patient history of any psychiatric disorder was associated with an increased all-cause and TGCT-specific death. CONCLUSIONS: We report an association between neurodevelopmental disorders and testicular seminoma, and an increased TGCT-specific mortality for TGCT patients with psychiatric disorders.

Transcriptomes of Prostate Cancer with TMPRSS2:ERG and Other ETS Fusions.

The most common somatic event in primary prostate cancer is a fusion between the androgen-related TMPRSS2 gene and the ERG oncogene. Tumors with these fusions, which occur early in carcinogenesis, have a distinctive etiology. A smaller subset of other tumors harbor fusions between TMPRSS2 and members of the ETS transcription factor family other than ERG. To assess the genomic similarity of tumors with non-ERG ETS fusions and those with fusions involving ERG, this study derived a transcriptomic signature of non-ERG ETS fusions and assessed this signature and ERG-related gene expression in 1,050 men with primary prostate cancer from three independent population-based and hospital-based studies. Although non-ERG ETS fusions involving ETV1, ETV4, ETV5, or FLI1 were individually rare, they jointly accounted for one in seven prostate tumors. Genes differentially regulated between non-ERG ETS tumors and tumors without ETS fusions showed similar differential expression when ERG tumors and tumors without ETS fusions were compared (differences explained: R2 = 69-77%), including ETS-related androgen receptor (AR) target genes. Differences appeared to result from similarities among ETS tumors rather than similarities among non-ETS tumors. Gene sets associated with ERG fusions were consistent with gene sets associated with non-ERG ETS fusions, including fatty acid and amino acid metabolism, an observation that was robust across cohorts. IMPLICATIONS: Considering ETS fusions jointly may be useful for etiologic studies on prostate cancer, given that the transcriptome is profoundly impacted by ERG and non-ERG ETS fusions in a largely similar fashion, most notably genes regulating metabolic pathways.

Differences in Prostate Cancer Transcriptomes by Age at Diagnosis: Are Primary Tumors from Older Men Inherently Different?

Older age at diagnosis is consistently associated with worse clinical outcomes in prostate cancer. We sought to characterize gene expression profiles of prostate tumor tissue by age at diagnosis. We conducted a discovery analysis in The Cancer Genome Atlas prostate cancer dataset (n = 320; 29% of men >65 years at diagnosis), using linear regressions of age at diagnosis and mRNA expression and adjusting for TMPRSS2:ERG fusion status and race. This analysis identified 13 age-related candidate genes at FDR < 0.1, six of which were also found in an analysis additionally adjusted for Gleason score. We then validated the 13 age-related genes in a transcriptome study nested in the Health Professionals Follow-up Study and Physicians' Health Study (n = 374; 53% of men >65 years). Gene expression differences by age in the 13 candidate genes were directionally consistent, and age at diagnosis was weakly associated with the 13-gene score. However, the age-related genes were not consistently associated with risk of metastases and prostate cancer-specific death. Collectively, these findings argue against tumor genomic differences as a main explanation for age-related differences in prostate cancer prognosis. PREVENTION RELEVANCE: Older age at diagnosis is consistently associated with worse clinical outcomes in prostate cancer. This study with independent discovery and validation sets and long-term follow-up suggests that prevention of lethal prostate cancer should focus on implementing appropriate screening, staging, and treatment among older men without expecting fundamentally different tumor biology.

Prognostic Utility of the Gleason Grading System Revisions and Histopathological Factors Beyond Gleason Grade.

BACKGROUND: The International Society of Urological Pathology (ISUP) revised the Gleason system in 2005 and 2014. The impact of these changes on prostate cancer (PCa) prognostication remains unclear. OBJECTIVE: To evaluate if the ISUP 2014 Gleason score (GS) predicts PCa death better than the pre-2005 GS, and if additional histopathological information can further improve PCa death prediction. PATIENTS AND METHODS: We conducted a case-control study nested among men in the National Prostate Cancer Register of Sweden diagnosed with non-metastatic PCa 1998-2015. We included 369 men who died from PCa (cases) and 369 men who did not (controls). Two uro-pathologists centrally re-reviewed biopsy ISUP 2014 Gleason grading, poorly formed glands, cribriform pattern, comedonecrosis, perineural invasion, intraductal, ductal and mucinous carcinoma, percentage Gleason 4, inflammation, high-grade prostatic intraepithelial neoplasia (HGPIN) and post-atrophic hyperplasia. Pre-2005 GS was back-transformed using i) information on cribriform pattern and/or poorly formed glands and ii) the diagnostic GS from the registry. Models were developed using Firth logistic regression and compared in terms of discrimination (AUC). RESULTS: The ISUP 2014 GS (AUC = 0.808) performed better than the pre-2005 GS when back-transformed using only cribriform pattern (AUC = 0.785) or both cribriform and poorly formed glands (AUC = 0.792), but not when back-transformed using only poorly formed glands (AUC = 0.800). Similarly, the ISUP 2014 GS performed better than the diagnostic GS (AUC = 0.808 vs 0.781). Comedonecrosis (AUC = 0.811), HGPIN (AUC = 0.810) and number of cores with ≥50% cancer (AUC = 0.810) predicted PCa death independently of the ISUP 2014 GS. CONCLUSION: The Gleason Grading revisions have improved PCa death prediction, likely due to classifying cribriform patterns, rather than poorly formed glands, as Gleason 4. Comedonecrosis, HGPIN and number of cores with ≥50% cancer further improve PCa death discrimination slightly.

Replication of Oncology Randomized Trial Results using Swedish Registry Real World-Data: A Feasibility Study.

Nationwide healthcare registries are potential important real-world data (RWD) sources for assessing drug effectiveness in oncology. However, it is unclear whether registry-derived RWD are suitable for clinical development. In this study, we replicate results from the comparator arm of two previously published oncology randomized controlled trials (RCTs) using RWD from Swedish nationwide healthcare registries. For replication 1, the RCT included 553 patients and the RWD included 283 patients treated with sorafenib for advanced hepatocellular cancer. The median overall survival (OS) was 11.2 (95% confidence interval (CI): 10.1-13.2) months in the RCT and 8.2 (95% CI: 7.0-9.9) months in the RWD, unadjusted hazard ratio (HR) 0.75 (95% CI: 0.63-0.88). For time-to-treatment discontinuation (TTD), the HR was 1.00 (95% CI: 0.87-1.16). For replication 2, the RCT included 154 patients and the RWD included 704 patients treated with melphalan, prednisone, and thalidomide for untreated multiple myeloma. The median OS was 52.6 (95% CI: 40-not applicable) months in the RCT and 36.9 (95% CI: 33.8-40.5) months in the RWD, unadjusted HR 0.67 (95% CI: 0.51-0.87). For TTD, the HR was 0.89 (95% CI: 0.74-1.06). The results were similar when applying various propensity-based confounding adjustments. In conclusion, OS was shorter in the RWD, whereas TTD was similar. Importantly, the data necessary (ex: eligibility criteria and baseline confounders) for replicating RCTs was mostly not available and these results further underscore the importance of developing frameworks for capturing relevant patient-level RWD for clinical and regulatory decision making in oncology.

Real world treatment utilization patterns in patients with castration-resistant prostate cancer.

BACKGROUND: Studies describing treatment utilization for castration-resistant prostate cancer (CRPC) are limited. We aimed to describe the treatment utilization of a contemporary population-based CRPC cohort between 2006 and 2016. METHODS: We identified 1699 men with a PC diagnosis between 2005 and 2015, who developed CRPC between 2006 and 2015 in the Stockholm region of Sweden. Demographic information, stage and grade at PC diagnosis, stage at CRPC, prostate-specific antigen (PSA) nadir, PSA doubling time, treatment utilization rate within 1 year of CRPC diagnosis, reason for stopping therapy, treatment sequence trajectory, overall and PC specific survival was described. RESULTS: Treatment for men with de novo metastatic disease (n = 463) was 32%, treatment for men with progressive metastatic disease after PC diagnosis (n = 66) was 44%, treatment for men with nonmetastatic CRPC (n = 113) was 34% and treatment for those with an unknown stage at time of CRPC diagnosis (n = 857) was 12%. Docetaxel was used in 39%, abiraterone acetate plus prednisone in 15%, enzalutamide in 13%, cabazitaxel in 11% and radium-223 in 5% of treatments. Treatment increased from 22% in 2006-2009 for metastatic cancer to 50% in 2013-2015 (p < .001). Factors associated with treatment were an unknown stage at diagnosis (OR: 0.3, 95% CI: 0.2-0.4), age ≥75 years (OR: 0.2, 95% CI: 0.1 - 0.3), PSA doubling time >3 months (OR: 0.4, 95% CI: 0.3 - 0.6) and a diagnosis between 2013 and 2015 (OR: 3.4, 95% CI: 2.0 - 5.8). CONCLUSIONS: Despite treatment availability, in this large real-world cohort we found treatment utilization to remain low.

Interchangeability of light and virtual microscopy for histopathological evaluation of prostate cancer.

Virtual microscopy (VM) holds promise to reduce subjectivity as well as intra- and inter-observer variability for the histopathological evaluation of prostate cancer. We evaluated (i) the repeatability (intra-observer agreement) and reproducibility (inter-observer agreement) of the 2014 Gleason grading system and other selected features using standard light microscopy (LM) and an internally developed VM system, and (ii) the interchangeability of LM and VM. Two uro-pathologists reviewed 413 cores from 60 Swedish men diagnosed with non-metastatic prostate cancer 1998-2014. Reviewer 1 performed two reviews using both LM and VM. Reviewer 2 performed one review using both methods. The intra- and inter-observer agreement within and between LM and VM were assessed using Cohen's kappa and Bland and Altman's limits of agreement. We found good repeatability and reproducibility for both LM and VM, as well as interchangeability between LM and VM, for primary and secondary Gleason pattern, Gleason Grade Groups, poorly formed glands, cribriform pattern and comedonecrosis but not for the percentage of Gleason pattern 4. Our findings confirm the non-inferiority of VM compared to LM. The repeatability and reproducibility of percentage of Gleason pattern 4 was poor regardless of method used warranting further investigation and improvement before it is used in clinical practice.

Tumor protein expression of the DNA repair gene BRCA1 and lethal prostate cancer.

DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7-59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18-3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82-3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54-2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease.

Comparative Effectiveness of Different Radical Radiotherapy Treatment Regimens for Prostate Cancer: A Population-Based Cohort Study.

BACKGROUND: It is unclear which radiotherapy technique and dose fractionation scheme is most effective in decreasing the risk of prostate cancer death. METHODS: We conducted a population-based cohort study among 15 164 men in the Prostate Cancer database Sweden (version 4.0) treated with primary radical radiotherapy for prostate cancer in Sweden from 1998 to 2016. We calculated hazard ratios with 95% confidence intervals (CIs) of the association between the following exposure groups and outcome: conventionally fractionated external beam radiotherapy (EBRT) to 78 Gy (39 × 2 Gy), EBRT combined with high dose-rate brachytherapy (HDR-BT) (25 × 2 Gy + 2 × 10 Gy), conventionally fractionated EBRT to 70 Gy (35 × 2 Gy), and moderately hypofractionated (M-HF) dose-escalated EBRT (29 × 2.5 Gy or 22 × 3 Gy). RESULTS: Of the men, 7296 received conventionally fractionated EBRT to 78 Gy, 4657 EBRT combined with HDR-BT, 1672 conventionally fractionated EBRT to 70 Gy, and 1539 M-HF EBRT. Using EBRT to 78 Gy as the reference, the multivariable hazard ratios (95% CIs) of prostate cancer death was 0.64 (0.53 to 0.78) for EBRT combined with HDR-BT, 1.00 (0.80 to 1.27) for EBRT to 70 Gy, and 1.51 (0.99 to 2.32) for M-HF EBRT. The multivariable hazard ratios (95% CIs) for death from any cause were 0.79 (0.71 to 0.88), 0.99 (0.87 to 1.14), and 1.12 (0.88 to 1.42), respectively. The lower risk of prostate cancer death comparing EBRT combined with HDR-BT with conventionally fractionated EBRT to 78 Gy was more pronounced for men with high-risk or poorly differentiated tumors. CONCLUSIONS: In this study, EBRT combined with HDR-BT was the most effective radiotherapy treatment regimen, especially for poorly differentiated tumors. Randomized trials comparing EBRT combined with HDR-BT with dose-escalated EBRT should be a priority.

Risk of breast cancer before and after rheumatoid arthritis, and the impact of hormonal factors.

OBJECTIVES: To examine the risk of incident breast cancer in women with rheumatoid arthritis (RA), and the risk of RA in women with a history of breast cancer, taking antihormonal treatment for breast cancer into account. METHODS: Using nationwide Swedish registers, women with new-onset RA diagnosed in 2006-2016 were identified and analysed using a cohort and a case-control design. Each patient with RA was matched on age, sex and place of residence to five randomly selected subjects from the general population. Through register linkages, we collected information on breast cancer, breast cancer risk factors (reproductive history and hormone replacement therapy) and socio-economy. The relative risk of breast cancer after RA was assessed using Cox regression, and the relative risk of RA in women with a history of breast cancer was assessed using conditional logistic regression. RESULTS: The risk of incident breast cancer in women with RA was reduced and the association was not attenuated by adjustment for breast cancer risk factors (HR=0.80, 95% CI 0.68 to 0.93). The risk of RA in women with a history of breast cancer was similarly reduced (OR=0.87, 95% CI 0.79 to 0.95). Women with breast cancer treated with tamoxifen (OR=0.86, 95% CI 0.62 to 1.20) or aromatase inhibitors (OR=0.97, 95% CI 0.69 to 1.37) did not have an increased risk of RA compared with women with breast cancer treated differently. CONCLUSIONS: The decreased occurrence of breast cancer in patients with RA is present already before RA diagnosis; these reduced risks are not readily explained by hormonal risk factors. Adjuvant antihormonal therapy for breast cancer does not seem to increase RA risk.

Treatment patterns and survival outcomes for small-cell lung cancer patients - a Swedish single center cohort study.

Objectives: This real-world study on small-cell lung cancer (SCLC) patients aimed to investigate treatment patterns, outcome of re-challenge with platinum doublet chemotherapy (PDCT), and associations between clinical characteristics and survival outcomes.Material and methods: This retrospective single center cohort study was based on patients diagnosed with SCLC between 2008 and 2016 at the Karolinska University Hospital, Stockholm, Sweden. Patients were divided into two subgroups; limited disease (LD), receiving concomitant chemo- and radiotherapy and extensive disease (ED), receiving palliative PDCT. The progression-free survival (PFS) was defined as the interval between the start of CT and the earliest date of documented progression. 'Refractory relapse' (Rr) and 'Sensitive relapse' (Sr) were defined as relapse occurring < or ≥180 days after start of PDCT, respectively. The results for treatment patterns were reported as numbers and percentages of patients, and descriptive analyses including medians and 95% confidence intervals (CIs). The Cox proportional hazards regression model was applied to assess the relationship between clinical characteristics and overall survival (OS).Results: The study included 544 patients; 408 with ED and 136 patients had LD. The median PFS and OS for ED patients were 5.1 and 7.0, respectively. In the ED subgroup, Sr occurred in 169 patients (41%), with a longer median OS when compared to Rr patients (10.8 vs. 3.6 months). Patients with LD had a median PFS and OS of 12 and 24 months, respectively. Some LD patients did not show a sign of relapse (22%). The majority of LD patients who relapsed had Sr (66%), with a longer median OS when compared to patients with Rr (20.9 vs. 7.8 mo).Conclusions: The survival outcomes for ED and LD SCLC patients correspond to historical data. Patients with Sr after 1st line therapy might benefit from re-challenge with PDCT in the 2nd line setting.

Family history of prostate cancer and the incidence of ERG- and phosphatase and tensin homolog-defined prostate cancer.

Family history is among the strongest known risk factors for prostate cancer (PCa). Emerging data suggest molecular subtypes of PCa, including two somatic genetic aberrations: fusions of androgen-regulated promoters with ERG and, separately, phosphatase and tensin homolog (PTEN) loss. We examined associations between family history and incidence of these subtypes in 44,126 men from the prospective Health Professionals Follow-up Study. ERG and PTEN status were assessed by immunohistochemistry. Multivariable competing risks models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self-reported family history of PCa and molecular subtypes of disease. Thirteen percent of men had a positive family history of PCa at baseline. During a median follow-up of 18.5 years, 5,511 PCa cases were diagnosed. Among them, 888 were assayed for ERG status (47% ERG-positive) and 715 were assayed for PTEN loss (14% PTEN null). Family history was more strongly associated with risk of ERG-negative (HR: 2.15; 95% CI: 1.71-2.70) than ERG-positive (HR: 1.49; 95% CI: 1.13-1.95) disease (pheterogeneity : 0.04). The strongest difference was among men with an affected father (HRERG-negative : 2.09; 95% CI: 1.64-2.66; HRERG-positive : 1.30; 95% CI: 0.96-1.76; pheterogeneity : 0.01). Family history of PCa was positively associated with both PTEN null (HR: 2.10; 95% CI: 1.26-3.49) and PTEN intact (HR: 1.72; 95% CI: 1.39-2.13) PCa (pheterogeneity : 0.47). Our results indicate that PCa family history may be positively associated with PCa in all ERG and PTEN subtypes, suggesting a role of genetic susceptibility in their development. It is possible that ERG-negative disease could be especially associated with positive family history.

Predicting Prostate Cancer Death with Different Pretreatment Risk Stratification Tools: A Head-to-head Comparison in a Nationwide Cohort Study.

BACKGROUND: Numerous pretreatment risk classification tools are available for prostate cancer. Which tool is best in predicting prostate cancer death is unclear. OBJECTIVE: To systematically compare the prognostic performance of the most commonly used pretreatment risk stratification tools for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A nationwide cohort study was conducted, including 154 811 men in Prostate Cancer data Base Sweden (PCBaSe) 4.0 diagnosed with nonmetastatic prostate cancer during 1998-2016 and followed through 2016. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared the D'Amico, National Institute for Health and Care Excellence (NICE), European Association of Urology (EAU), Genito-Urinary Radiation Oncologists of Canada (GUROC), American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), and Cambridge Prognostic Groups (CPG) risk group systems; the Cancer of the Prostate Risk Assessment (CAPRA) score; and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram in predicting prostate cancer death by estimating the concordance index (C-index) and the observed versus predicted cumulative incidences at different follow-up times. RESULTS AND LIMITATIONS: A total of 139 515 men were included in the main analysis, of whom 15 961 died from prostate cancer during follow-up. The C-index at 10 yr of follow-up ranged from 0.73 (95% confidence interval [CI]: 0.72-0.73) to 0.81 (95% CI: 0.80-0.81) across the compared tools. The MSKCC nomogram (C-index: 0.81, 95% CI: 0.80-0.81), CAPRA score (C-index: 0.80, 95% CI: 0.79-0.81), and CPG system (C-index: 0.78, 95% CI: 0.78-0.79) performed the best. The order of performance between the tools remained in analyses stratified by primary treatment and year of diagnosis. The predicted cumulative incidences were close to the observed ones, with some underestimation at 5 yr. It is a limitation that the study was conducted solely in a Swedish setting (ie, case mix). CONCLUSIONS: The MSKCC nomogram, CAPRA score, and CPG risk grouping system performed better in discriminating prostate cancer death than the D'Amico and D'Amico-derived systems (NICE, GUROC, EAU, AUA, and NCCN). Use of these tools may improve clinical decision making. PATIENT SUMMARY: There are numerous pretreatment risk classification tools that can aid treatment decision for prostate cancer. We systematically compared the prognostic performance of the most commonly used tools in a large cohort of Swedish men with prostate cancer. The Memorial Sloan Kettering Cancer Center nomogram, Cancer of the Prostate Risk Assessment score, and Cambridge Prognostic Groups performed best in predicting prostate cancer death. The use of these tools may improve treatment decisions.

DNA methylation in repeat negative prostate biopsies as a marker of missed prostate cancer.

BACKGROUND: Men often undergo repeat prostate biopsies because of suspicion of missed cancer. We assessed if (i) methylation of selected genes in prostate tissue vary with aging and (ii) methylation alterations in repeat biopsies predict missed prostate cancer. METHODS: We conducted a case-control study among men who underwent at least two negative prostate biopsies followed by a sampling either positive (cases n = 111) or negative (controls n = 129) for prostate cancer between 1995 and 2014 at the University Hospital (Turin, Italy). Two pathology wards were included for replication purposes. We analyzed methylation of GSTP1, APC, PITX2, C1orf114, GABRE, and LINE-1 in the first two negative biopsies. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of the association between genes methylation and prostate cancer. RESULTS: Age at biopsy and time interval between the two negative biopsies were not associated with methylation levels of the selected genes in neither cases nor controls. GSTP1 methylation in the first and in the second negative biopsy was associated with prostate cancer detection [OR per 1% increase: 1.14 (95% CI 1.01-1.29) for the second biopsy and 1.21 (95% CI 1.07-1.37) for the highest methylation level (first or second biopsy)]. A threshold > 10% for GSTP1 methylation corresponded to a specificity of 0.98 (positive likelihood ratio 7.87). No clear association was found for the other genes. Results were consistent between wards. CONCLUSIONS: Our results suggest that GSTP1 methylation in negative prostate biopsies is stable over time and can predict missed cancer with high specificity.

Bilateral Risk-Reducing Mastectomies with Implant-Based Reconstructions Followed Long Term: A Consecutive Series of 185 Patients.

BACKGROUND: Bilateral risk-reducing mastectomy (BRRM) is the most effective method to prevent breast cancer in genetically predisposed women and is often performed concomitantly with breast reconstruction. The reconstruction time varies and corrective surgeries are common. METHODS: This study evaluated 185 consecutive cases of BRRM and immediate breast reconstruction with implants with regard to surgical outcome and resource consumption. With an 18-year observation period, it was possible to compare permanent expander implants (PEIs) with permanent fixed volume implants (PIs). RESULTS: A minimum follow-up of 2 years for all participants but one was achieved. Seventy-five percent (n = 138) of the women received PEI and 25% (n = 47) PI. In a multivariate analysis including age, BMI (<25, ≥25), smoking (yes, no), implant type (PEI, PI), incision technique, operation time and specimen weight <350 g, ≥350 g), only BMI ≥25 was associated with an increased risk of an early complication (OR 7.1, 95% CI 2.44-20.4). As expected, there was a significant difference in median reconstruction time between PEI and PI (12.4 vs. 1.0 months, p < 0.001). The cumulative reoperation-free 2-year survival was significantly higher in the PI than in the PEI group (81% vs. 26%, p < 0.001). CONCLUSION: Implant-based reconstruction remains a valid option after BRRM in high-risk women. Whenever possible (low BMI and small breast volume without severe ptosis), permanent fixed volume implants can be safely recommended and are resource saving in comparison with permanent expander implants.

Estimation of Relative and Absolute Risks in a Competing-Risks Setting Using a Nested Case-Control Study Design: Example From the ProMort Study.

In this paper, we describe the Prognostic Factors for Mortality in Prostate Cancer (ProMort) study and use it to demonstrate how the weighted likelihood method can be used in nested case-control studies to estimate both relative and absolute risks in the competing-risks setting. ProMort is a case-control study nested within the National Prostate Cancer Register (NPCR) of Sweden, comprising 1,710 men diagnosed with low- or intermediate-risk prostate cancer between 1998 and 2011 who died from prostate cancer (cases) and 1,710 matched controls. Cause-specific hazard ratios and cumulative incidence functions (CIFs) for prostate cancer death were estimated in ProMort using weighted flexible parametric models and compared with the corresponding estimates from the NPCR cohort. We further drew 1,500 random nested case-control subsamples of the NPCR cohort and quantified the bias in the hazard ratio and CIF estimates. Finally, we compared the ProMort estimates with those obtained by augmenting competing-risks cases and by augmenting both competing-risks cases and controls. The hazard ratios for prostate cancer death estimated in ProMort were comparable to those in the NPCR. The hazard ratios for dying from other causes were biased, which introduced bias in the CIFs estimated in the competing-risks setting. When augmenting both competing-risks cases and controls, the bias was reduced.

A Prospective Study of the Association between Physical Activity and Risk of Prostate Cancer Defined by Clinical Features and TMPRSS2:ERG.

BACKGROUND: Growing evidence shows that clinical and molecular subtypes of prostate cancer (PCa) have specific risk factors. Observational studies suggest that physical activity may lower the risk of aggressive PCa. To our knowledge, the association between physical activity and PCa defined by TMPRSS2:ERG has not been evaluated. OBJECTIVE: To prospectively examine the association between physical activity and risk of PCa defined by clinical features and TMPRSS2:ERG. DESIGN, SETTING, AND PARTICIPANTS: We studied 49160 men aged 40-75 yr in the Health Professionals Follow-up Study from 1986 to 2012. Data was collected at baseline and every 2 yr with >90% follow-up. Total and vigorous physical activity were measured in metabolic equivalent of task (MET)-h/wk. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Advanced PCa was defined as stage T3b, T4, N1, or M1 at diagnosis and lethal PCa as distant metastases or death due to disease over follow-up. Presence of TMPRSS2:ERG was estimated by immunohistochemistry of ERG protein expression. Cox proportional hazards models were used to obtain multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of subtype-specific PCa. RESULTS AND LIMITATIONS: During 26 yr of follow-up, 6411 developed PCa overall and 888 developed lethal disease. There were no significant associations between total physical activity and risk of PCa in the overall cohort. In multivariable-adjusted models, men in the highest quintile of vigorous activity had a significant 30% lower risk of advanced PCa (HR: 0.70, 95% CI: 0.53-0.92) and 25% lower risk of lethal PCa (HR: 0.75, 95% CI: 0.59-0.94) than men in the lowest quintile of vigorous activity. The association was independent of screening history. Vigorous activity was not associated with total PCa in the overall cohort but was inversely associated among highly screened men (top vs bottom quintile, HR: 0.83, 95% CI: 0.70-0.97). Of all cases, 945 were assayed for ERG (48% ERG-positive). Men with higher vigorous activity had a lower risk of ERG-positive PCa (top vs bottom quintile, HR: 0.71, 95% CI: 0.52-0.97). There was no significant association with the risk of ERG-negative disease (p heterogeneity=0.09). CONCLUSIONS: Our study confirms that vigorous physical activity is associated with lower risk of advanced and lethal PCa and provides novel evidence for a lower risk of TMPRSS2:ERG-positive disease. PATIENT SUMMARY: The identification of modifiable lifestyle factors for prevention of clinically important prostate cancer (PCa) is needed. In this report, we compared risk of PCa in men with different levels of physical activity. Men with higher vigorous activity had a lower risk of developing advanced and lethal PCa and PCa with the common TMPRSS2:ERG gene fusion.