Calibrating Observational Health Record Data Against a Randomized Trial.

Importance: The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this. Objective: To pilot an emulation of the KEYNOTE-189 RCT using a commercially available electronic health record (EHR) data source. Design, Setting, and Participants: This retrospective cohort study used an EHR database spanning from April 2007 to February 2023. Follow-up began on treatment initiation and proceeded until an outcome event, loss to follow-up, end of data, or end of study period (640 days). The population-based cohort was ascertained from EHRs provided by 52 health systems across the US. Eligibility criteria were defined as closely as possible to the benchmark RCT. Patients with non-small cell lung cancer initiating first-line treatment for metastatic disease were included. Patients with evidence of squamous non-small cell lung cancer, primary nonlung malignant neoplasms, or identified EGFR/ALK variations were excluded. Data were analyzed from June to October 2023. Exposures: Initiation of first-line pembrolizumab and chemotherapy and chemotherapy alone. Chemotherapy in both groups was defined as a combination of pemetrexed and platinum-based (carboplatin or cisplatin) therapy. Main Outcomes and Measures: Outcomes of interest were 12-month survival probability and mortality hazard ratio (HR). Results: A total of 1854 patients (mean [SD] age, 63.7 [9.6] years; 971 [52.4%] men) were eligible, including 589 patients who initiated pembrolizumab and chemotherapy and 1265 patients who initiated chemotherapy only. The cohort included 364 Black patients (19.6%) and 1445 White patients (77.9%). The 12-month survival probabilities were 0.60 (95% CI, 0.54-0.65) in the pembrolizumab group and 0.58 (95% CI, 0.55-0.62) in the chemotherapy-only group, compared with 0.69 (95% CI, 0.64-0.74) in the KEYNOTE-189 pembrolizumab group and 0.49 (95% CI, 0.42-0.56) in the KEYNOTE-189 chemotherapy-only group. The mortality HR was 0.95 (95% CI, 0.78-1.16), compared with 0.49 (95% CI, 0.38-0.64) in the KEYNOTE-189 RCT. Conclusions and Relevance: In this cohort study piloting an RCT emulation, results were incongruous with the benchmark trial. Differences in patient treatment and data capture between the RCT and EHR populations, confounding by indication, treatment crossover, and accuracy of captured diagnoses may explain these findings. Future feasibility assessments will require data sources to have important oncology-specific measures curated.

Emulations of Oncology Trials Using Real-World Data: A Systematic Literature Review.

By evaluating published emulations of oncology RCTs studies in which both the active and comparator groups are sourced from RWD and target trial results are available for benchmarking, this systematic review aims to gain insight into factors related to emulation performance. Thirteen oncology emulation studies using various types of RWD were identified through an online database search of PubMed through 2022. Based on the ROBINS-I tool, most studies (N=8) had a serious risk of overall bias driven by risk of bias from confounding. Approximately half of the studies (N=6) fully proxied the RCT entry criteria. Of 11 RWD studies that provided sufficient detail to quantify emulation performance, the emulation HR estimate fell within the 95% CI of the trial estimate in 9 of the studies. There were no clear trends between risk of bias or degree to which the entry criteria were proxied and emulation performance. Findings may have been influenced by publication bias and researcher degrees of freedom, as only one emulation study pre-registered its protocol. Tools for comprehensively characterizing factors that affect emulation performance, including the real-world clinical context as it relates to the RCT research question, are needed to evaluate the feasibility of a RCT emulation.

Counterfactual mediation analysis in the multistate model framework for surrogate and clinical time-to-event outcomes in randomized controlled trials.

In cancer randomized controlled trials, surrogate endpoints are frequently time-to-event endpoints, subject to the competing risk from the time-to-event clinical outcome. In this context, we introduce a counterfactual-based mediation analysis for a causal assessment of surrogacy. We use a multistate model for risk prediction to account for both direct transitions towards the clinical outcome and indirect transitions through the surrogate outcome. Within the counterfactual framework, we define natural direct and indirect effects with a causal interpretation. Based on these measures, we define the proportion of the treatment effect on the clinical outcome mediated by the surrogate outcome. We estimate the proportion for both the cumulative risk and restricted mean time lost. We illustrate our approach by using 18-year follow-up data from the SPCG-4 randomized trial of radical prostatectomy for prostate cancer. We assess time to metastasis as a surrogate outcome for prostate cancer-specific mortality.

Disparities in precision medicine-Examining germline genetic counseling and testing patterns among men with prostate cancer.

INTRODUCTION: This study sought to examine whether germline genetic counseling and testing were employed differentially among men with prostate cancer by race and/or ethnicity and other social factors. METHODS: In this retrospective analysis, all patients with prostate cancer listed as a visit diagnosis during the study period (April 2011 to August 2020) were identified from electronic health records. Patient characteristics were collected along with genetic counselor visits and germline genetic testing results in electronic health records. Multivariable analyses were performed with the primary outcome defined as the receipt of a genetic counseling visit and receipt of genetic testing. RESULTS: A total of 14,610 patients with a prostate cancer diagnosis code were identified. The majority of patients were White (72%), aged >=65 years (62.7%), English-speaking (95%), married (71.4%), and publicly insured (58.7%). A total of 667 patients completed an appointment with a genetic counselor. A total of 439 patients received germline genetic test result, of whom 403 (91.8%) had also completed an appointment with a genetic counselor. Patients that were 65 years or older (adjusted odds ratio 0.53, 95%CI 0.44-0.65) and non-English proficient (adjusted odds ratio 0.71, 95%CI 0.42-1.21) were less likely to receive genetic counseling. Receiving genetic counseling was the strongest independent predictor of receipt of genetic testing. CONCLUSIONS: The results of the current study highlight that the role of social factors in contributing to disparities in genetic counseling and testing among men with prostate cancer. These results underscore the importance of developing novel strategies to tackle contributors of observed disparities including language, age, and insurance status.

Family Member Incarceration, Psychological Stress, and Subclinical Cardiovascular Disease in Mexican Women (2012-2016).

Objectives. To examine the association between family member incarceration, psychological stress, and subclinical cardiovascular disease (CVD).Methods. Between 2012 and 2016, 1849 CVD-free women from the Mexican Teachers' Cohort responded to questions on family incarceration from the Life Stressor Checklist. Perceived stress and hair cortisol levels were measured in a subset of participants. Carotid intima-media thickness was measured, and carotid atherosclerosis was determined in all participants. We used multivariable quantile, linear, and logistic regression models to evaluate the association between family member incarceration, stress, and subclinical CVD.Results. Among women with a mean age of 49.7 years (SD ±5.2), 15.3% reported family member incarceration. We found that both perceived stress and hair cortisol levels were significantly higher in women with an incarcerated family member relative to women without one. After multivariable adjustment, women who reported family member incarceration had 41% (95% confidence interval = 1.04, 2.00) higher odds of carotid atherosclerosis compared with those who did not.Conclusions. Family member incarceration was associated with robust markers of stress and cardiovascular risk. Mass incarceration may have a long-lasting impact on physical health of affected families.

Impact of age at diagnosis of de novo metastatic prostate cancer on survival.

BACKGROUND: An older age at the diagnosis of prostate cancer has been linked to worse prostate cancer-specific survival (PCSS). However, these studies were conducted before the approval of many life-prolonging drugs. This study was aimed at describing outcomes in a contemporary cohort of men diagnosed with de novo metastatic prostate cancer (mPCa) and assessing associations with the age at diagnosis while controlling for known prognostic factors. METHODS: The Surveillance, Epidemiology, and End Results registry was used to identify men diagnosed with mPCa from 2004 to 2014. Men were classified by 4 age groups: ≤54, 55 to 64, 65 to 74, and ≥75 years. The median overall survival, PCSS, and restricted mean survival times for any-cause mortality and prostate cancer-specific mortality (PCSM) were calculated. Multivariable and subdistribution hazard ratios for PCSM according to age group and with controlling for race, marital status, and income were estimated. RESULTS: Compared with men aged ≤54 years, men aged ≥75 years experienced a mean PCSS at 5 years that was 6.7 months shorter (95% confidence interval [CI], 5.5-7.8 months). In multivariable analyses, men aged ≥75 years had a 49% increase in the rate of PCSM in comparison with those aged ≤54 years (95% CI, 1.39-1.60). The subdistribution hazard ratio for PCSM between these groups was 1.41 (95% CI, 1.32-1.50). CONCLUSIONS: Age was found to be an independent predictor of shorter PCSS in men diagnosed with de novo mPCa even in an era with more effective therapies. Further work is needed to determine the reason for poor outcomes in older men with mPCa.

Statin Use Is Associated with Lower Risk of PTEN-Null and Lethal Prostate Cancer.

PURPOSE: Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms. EXPERIMENTAL DESIGN: Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue. RESULTS: During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60-0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19-0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95-1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever (n = 10) versus never users (n = 103). CONCLUSIONS: Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials.

Socioenvironmental adversity and risk of prostate cancer in non-Hispanic black and white men.

Non-Hispanic black (NHB) men experience higher risk of prostate cancer than other racial/ethnic groups, and it is possible that socioenvironmental (SE) adversity and resulting stress may contribute to this disparity. Data from the Southern Community Cohort Study were used to evaluate associations between SE adversity and perceived stress in relation to prostate cancer risk, overall and by race/ethnicity and grade. Between 2002 and 2009, 26,741 men completed a questionnaire, from which an 8-item SE adversity composite was created (covering socioeconomic status, residential environment, and social support/buffers). Two items from the Perceived Stress Scale were assessed. With follow-up through 2011, 527 prostate cancer cases were diagnosed. In multivariable models, each one-unit increase in the SE adversity composite was associated with increased prostate cancer risk among non-Hispanic white (NHW) men (HR 1.23; 95% CI 1.02-1.48) and reduced risk among NHB men (HR 0.89; 95% CI 0.82-0.95) (p interaction: 0.001). This pattern held for low grade, but not high grade, cancers although power was limited for the latter. Perceived stress variables were associated with increased risk of prostate cancer among NHW men, but not among NHB men. Results do not support the hypothesis that SE adversity my underlay the racial disparity in prostate cancer, over and above that of covariates, including healthcare utilization.

Restricted Mean Survival Times to Improve Communication of Evidence from Cancer Randomized Trials and Observational Studies.

Hazard ratios (HRs) are frequently misinterpreted. We describe an easily estimated complementary measure, the difference in restricted mean survival time (RMST), that requires fewer assumptions than the HR and is more readily interpretable. Reporting RMST-based measures may benefit shared decision-making.

Elevated Serum Cytokines and Trichomonas vaginalis Serology at Diagnosis Are Not Associated With Higher Gleason Grade or Lethal Prostate Cancer.

BACKGROUND: Inflammation and infections have been associated with prostate cancer progression. We assessed whether elevated serum cytokines or T. vaginalis seropositivity at the time of diagnosis was associated with higher grade or lethal prostate cancer. PATIENTS AND METHODS: Men with localized or metastatic prostate cancer were included in this study. Cytokine serum levels including interleukin (IL)-1α, IL-1ß, IL-2, IL-6, IL-8, monocyte chemotactic protein 1 (CCL-2), tumor necrosis factor α, and growth-regulated oncogene α (CXCL-1) using a multiplex enzyme-linked immunosorbent assay and T. vaginalis serology were measured in blood samples at diagnosis. RESULTS: A total of 324 patients were identified at time of localized disease and 118 at time of metastatic disease. Of the 189 patients with localized disease and clinical follow-up data (median, 73 months), 28 developed lethal disease. There was no association between circulating cytokine levels above median concentrations nor T. vaginalis seropositivity and risk of intermediate- to high-risk or lethal prostate cancer. CONCLUSION: Higher levels of serum cytokine levels and T. vaginalis seropositivity at diagnosis are not associated with high-grade or lethal prostate cancer and do not aid risk stratification of localized prostate cancer.

Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease.

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Corpora amylacea in prostatectomy tissue and associations with molecular, histological, and lifestyle factors.

BACKGROUND: Corpora amylacea are amyloid bodies commonly found adjacent to damaged prostate epithelium. Little is known about their formation or function. The current study sought to characterize corpora amylacea in prostate tissue and to describe their relationship with clinical, histological, molecular, and lifestyle factors, especially with chronic inflammation which is associated with aggressive disease. METHODS: We studied a cohort of 355 men with prostate cancer and tissue specimens from the Health Professionals Follow-Up Study. Pathologists examined H&E slides and undertook a standardized review for histologic data and inflammation. Trained observers counted corpora amylacea within the benign and predominately tumor areas. Immunohistochemistry biomarkers were available from tissue microarrays. We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) to assess associations of chronic inflammation, clinical, histological, molecular, and lifestyle factors with the presence of corpora amylacea. RESULTS: Corpora amylacea were present in benign tissue area for 298 men (84%). Specimens with moderate-to-severe chronic inflammation were more likely to have corpora amylacea in benign regions (OR = 5.4 95%CI 1.9, 15.6). Moreover, corpora amylacea were more common in men with higher body mass index (OR = 1.13 95%CI 1.01, 1.26). In contrast, Gleason grade (OR = 0.4 95%CI 0.2, 0.8), proliferation index (OR = 0.6 95%CI 0.3, 1.2) and the presence of the TMPRSS2:ERG fusion (OR = 0.4 95%CI 0.2, 0.8) were inversely associated with corpora amylacea presence. TURP specimens were less likely to have corpora amylacea than prostatectomy specimens (OR = 0.12 95%CI 0.03, 0.47). Age, PSA, stage, biomarkers of angiogenesis and PTEN, and vasectomy were not significantly associated with corpora amylacea. CONCLUSION: Corpora amylacea were common among men with prostate cancer and were associated with pro-inflammatory factors, some markers of less aggressive disease, and lack of the TMPRSS2:ERG fusion.

Regular aspirin use and gene expression profiles in prostate cancer patients.

PURPOSE: Pharmacoepidemiology studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that aspirin induces transcriptional changes in tumors or normal prostate tissue. METHODS: We analyzed the prostatic transcriptome from men diagnosed with prostate cancer during follow-up of the Physicians' Health Study 1 (PHS, n = 149), initially a randomized controlled trial of aspirin. Aspirin target genes were identified through systematic literature review and a drug target database. We compared target gene expression according to regular aspirin use at cancer diagnosis and used whole-transcriptome gene set enrichment analysis to identify gene sets associated with aspirin use. Results were validated in the Health Professionals Follow-up Study (HPFS, n = 254) and in Connectivity Map. RESULTS: Of 12 target genes identified from prior studies and 540 genes from the drug target database, none were associated with aspirin use. Twenty-one gene sets were enriched in tumor tissue of aspirin users, 18 of which were clustered around ribosome function and translation. These gene sets were associated with exposure to cyclooxygenase inhibitors in Connectivity Map. Their association with cancer prognosis was U-shaped in both cohorts. No gene sets were enriched in normal tissue. In HPFS, neither the target genes nor the gene sets were associated with aspirin use. CONCLUSIONS: Regular aspirin use may affect ribosome function in prostate tumors. Other putative target genes had similar expression in tumors from aspirin users and non-users. If results are corroborated by experimental studies, a potential benefit of aspirin may be limited to a subset of prostate cancer patients.

Differential Gene Expression in Prostate Tissue According to Ejaculation Frequency.

In a prospective study of 31 925 men with 18 yr of follow-up, higher ejaculation frequency (EF) throughout adulthood was associated with lower rates of prostate cancer. To further explore this association, we evaluated whole transcriptome gene expression in the prostate tissue from study participants who developed prostate cancer between 1992 and 2004 (n=157 tumor tissue, n=85 adjacent normal). We tested for trends in gene expression according to the level of EF as self-reported in 1992 for ages 20-29 yr, 40-49 yr, and the year prior to the questionnaire, 1991. There were no associations between EF and gene expression in areas of tumor after accounting for multiple testing. In contrast, in the adjacent normal tissue, 409 genes and six pathways were differentially expressed at a false discovery rate ≤0.2 across categories of EF in 1991. These results suggest that ejaculation affects the expression of genes in the normal prostate tissue. The identified genes and pathways provide potential biological links between EF and prostate tumorigenesis. PATIENT SUMMARY: To explore previous findings that men who ejaculate more frequently have lower risk of prostate cancer, we evaluated molecular alterations in the prostate tissue according to each man's frequency of ejaculation prior to diagnosis. We identified biological processes that could link ejaculation frequency and prostate cancer.

High inducible nitric oxide synthase in prostate tumor epithelium is associated with lethal prostate cancer.

OBJECTIVE: The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) in lethal prostate cancer (PCa) by studying the iNOS immunoreactivity in tumor tissue from men diagnosed with localized PCa. MATERIALS AND METHODS: This study is nested within a cohort of men diagnosed with incidental PCa undergoing transurethral resection of the prostate (the Swedish Watchful Waiting Cohort). To investigate molecular determinants of lethal PCa, men who died from PCa (n = 132) were selected as cases; controls (n = 168) comprised men with PCa who survived for at least 10 years without dying from PCa during follow-up. The immunoreactivity of iNOS in prostate tumor epithelial cells and in cells of the surrounding stroma was scored as low/negative, moderate or high. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for lethal PCa according to iNOS category. RESULTS: There was no association between iNOS immunoreactivity in stroma and lethal disease. However, when comparing high versus low/negative iNOS immunoreactivity in epithelial cells, the OR for lethal PCa was 3.80 (95% CI 1.45-9.97). CONCLUSION: Patients with localized PCa have variable outcomes, especially those with moderately differentiated tumors. Identifying factors associated with long-term PCa outcomes can elucidate PCa tumor biology and identify new candidate prognostic markers. These findings support the hypothesis that high iNOS in tumor epithelium of the prostate is associated with lethal disease.

FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer.

BACKGROUND: The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer. METHODS: Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmans test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area. RESULTS: In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart. CONCLUSIONS: Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established.

A Walking Intervention Among Men With Prostate Cancer: A Pilot Study.

BACKGROUND: Men diagnosed with prostate cancer have increased risk for disease progression, cardiovascular events, and impairments in quality of life. This pilot study evaluated the feasibility of a randomized walking group intervention to improve quality of life, circulating biomarkers, and morbidity among men with newly diagnosed prostate cancer. METHODS: Men were recruited at Örebro University Hospital, Sweden, and randomized to an 11-week walking group intervention (n = 21) or usual care (n = 20). The intervention included weekly 1-hour walking group sessions and maintenance of 10,000 steps/day. Outcomes were changes in body composition, clinical factors, biomarkers of cardiovascular health, and quality of life between baseline and end of study. Analysis of covariance was used to compare outcomes in each group adjusted for baseline values. RESULTS: All 41 men randomized completed the 11-week trial. Men assigned to the intervention walked on average 10,644 steps/day, and 92% reported missing 2 or fewer sessions. Both groups experienced similar weight loss at 11 weeks. Men in the intervention had a significant adjusted mean change in high-density lipoprotein of 0.14 mmol/L (95% confidence interval [CI], 0.01-0.27; P = .04), and suggestive adjusted mean changes in low-density lipoprotein of -0.22 mmol/L (95% CI, -0.47 to 0.03; P = .08) and in systolic blood pressure of -8.5 mm Hg (95% CI, -21.2 to 4.2; P = .18), compared with the usual care group. CONCLUSIONS: A walking group intervention among men with recent diagnosis of prostate cancer is feasible and potentially effective in improving cardiovascular health. A larger randomized trial of longer duration is required to elucidate its potential for improvement in longer term outcomes.

Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

BACKGROUND: Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. METHODS: Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. RESULTS: Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10-4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). CONCLUSIONS: This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society.