RAD21 promotes oncogenesis and lethal progression of prostate cancer.

Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, RAD21, with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by the TMPRSS2-ERG oncogenic fusion, found in about half of all prostate tumors, we found that increased RAD21 alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

SLCO1B3 and SLCO2B1 genotypes, androgen deprivation therapy, and prostate cancer outcomes: a prospective cohort study and meta-analysis.

Solute carrier organic anion (SLCO) transporters (OATP transporters) are involved in cellular uptake of drugs and hormones. Germline variants in SLCO1B3 and SLCO2B1 have been implicated in prostate cancer progression and therapy response, including to androgen deprivation and statin medications, but results have appeared heterogeneous. We conducted a cohort study of five single-nucleotide polymorphisms (SNPs) in SLCO1B3 and SLCO2B1 with prior evidence among 3208 men with prostate cancer who participated in the Health Professionals Follow-up Study or the Physicians' Health Study, following participants prospectively after diagnosis over 32 years (median, 14 years) for development of metastases and cancer-specific death (lethal disease, 382 events). Results were suggestive of, but not conclusive for, associations between some SNPs and lethal disease and differences by androgen deprivation and statin use. All candidate SNPs were associated with SLCO mRNA expression in tumor-adjacent prostate tissue. We also conducted a systematic review and harmonized estimates for a dose-response meta-analysis of all available data, including 9 further studies, for a total of 5598 patients and 1473 clinical events. The A allele of the exonic SNP rs12422149 (14% prevalence), which leads to lower cellular testosterone precursor uptake via SLCO2B1, was associated with lower rates of prostate cancer progression (hazard ratio per A allele, 0.80; 95% confidence interval, 0.69-0.93), with little heterogeneity between studies (I2, 0.27). Collectively, the totality of evidence suggests a strong association between inherited genetic variation in SLCO2B1 and prostate cancer prognosis, with potential clinical use in risk stratification related to androgen deprivation therapy.

Intratumoral vitamin D signaling and lethal prostate cancer.

High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21-0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.

Healthy dietary patterns and risk of prostate cancer in men at high genetic risk.

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow-up Study (1993-2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk-reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer-specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow-up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk-reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58-0.94]) and lethal prostate cancer (0.43 [0.21-0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60-0.95]; lethal, 0.46 [0.23-0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13-0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%-5.0%) among those with healthy lifestyles and 9.5% (5.3%-16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer.

Evaluating recommendation-based dietary and physical activity strategies for prostate cancer prevention: a target trial emulation in the Health Professionals Follow-up Study.

The 2018 World Cancer Research Fund/American Institute for Cancer Research recommends sustained strategies of physical activity and diet for cancer prevention, but evidence for long-term prostate cancer risk is limited. Using observational data from 27,859 men in the Health Professionals Follow-up Study, we emulated a target trial of recommendation-based physical activity and dietary strategies and 26-year risks of prostate cancer, adjusting for risk factors via the parametric g-formula. Compared with no intervention, limiting sugar-sweetened beverages showed a 0.4% (0.0-0.9%) lower risk of lethal (metastatic or fatal) disease and 0.5% (0.1-0.9%) lower risk of fatal disease. Restricting consumption of processed foods showed a 0.4-0.9% higher risk of all prostate cancer outcomes. Estimated risk differences for clinically significant disease were close to null for strategies involving fruits and non-starchy vegetables, whole grains and legumes, red meat, and processed meat, as well as under a joint strategy of physical activity and diet. Compared with a "low adherence" strategy, maintaining recommended physical activity levels showed a 0.4% (0.1-0.8%) lower risk of lethal and 0.5% (0.2-0.8%) lower risk of fatal disease. Adhering to specific components of current physical activity and dietary recommendations may help to prevent lethal and fatal prostate cancer over 26 years.

Plant-based diet associated with better quality of life in prostate cancer survivors.

BACKGROUND: Plant-based diets have many health benefits, including a lower risk of fatal prostate cancer, and greater environmental sustainability. However, less is known regarding the impact of plant-based diets on quality of life among individuals diagnosed with prostate cancer. The authors' objective was to examine the relationship between plant-based diet indices postdiagnosis with quality of life. METHODS: This prospective cohort study included 3505 participants in the Health Professionals Follow-Up Study (1986-2016) with nonmetastatic prostate cancer. Food-frequency questionnaires were used to calculate overall and healthful plant-based diet indices. Quality-of-life scores were calculated using the Expanded Prostate Cancer Index Composite. Generalized estimating equations were used to examine associations over time between plant-based diet indices and quality-of-life domains (sexual functioning, urinary irritation/obstruction, urinary incontinence, bowel functioning, hormonal/vitality), adjusted for demographics, oncologic history, body mass index, caloric intake, health-related behaviors, and comorbidities. RESULTS: The median age at prostate cancer diagnosis was 68 years; 48% of patients underwent radical prostatectomy, and 35% received radiation as primary therapy. The median time from diagnosis/treatment to first the quality-of-life questionnaire was 7.0 years. A higher plant-based diet index was associated with better scores for sexual function, urinary irritation/obstruction, urinary incontinence, and hormonal/vitality. Consuming more healthful plant-based foods was also associated with better sexual and bowel function, as well as urinary incontinence and hormonal/vitality scores in the age-adjusted analysis, but not in the multivariable analysis. CONCLUSIONS: This prospective study provides supportive evidence that greater consumption of healthful plant-based foods is associated with modestly higher scores in quality-of-life domains among patients with prostate cancer.

Multivitamin use after diagnosis and prostate cancer survival among men with nonmetastatic prostate cancer.

BACKGROUND: Multivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests potential harm. METHODS: We prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986-2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality. RESULTS: We observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR [95% CI], 0.98 [0.74-1.30]) or all-cause mortality (1.00 [0.88-1.12]), after adjustment for potential confounders. Similarly, null associations were observed across various categories of use frequency. Compared to non-users, men who used multivitamins regularly (6-9 tablets/week) after cancer diagnosis had similar risk of lethal prostate cancer (0.96 [0.72-1.28]) and all-cause mortality (0.99 [0.88-1.12]). CONCLUSIONS: We found no evidence that post-diagnostic multivitamin use among men with nonmetastatic prostate cancer was associated with better or worse survival in a well-nourished population.

A prospective study of birth weight and prostate cancer risk and mortality in the Health Professionals Follow-up Study.

BACKGROUND: Previous studies have observed inconsistent associations between birth weight and aggressive prostate cancer risk. This study aimed to prospectively analyse this association in the Health Professionals Follow-up Study (HPFS). METHODS: Birth weight was self-reported in 1994, and prostate cancer diagnoses were assessed biennially through January 2017 and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to evaluate the association between birth weight and prostate cancer risk and mortality. RESULTS: Among 19,889 eligible men, 2520 were diagnosed with prostate cancer, including 643 with higher-grade/advanced stage, 296 with lethal, and 248 with fatal disease. Overall, no association was observed for increasing birth weight with risk of overall prostate cancer, lower-grade, and organ-confined disease. However, a borderline statistically significant positive trend was observed for increasing birth weight with risk of higher-grade and/or advanced-stage prostate cancer (adjusted hazard ratio [HRadj] per pound: 1.05; 95% confidence interval [CI]: 0.99-1.11; P-trend = 0.08), but no associations were observed with risk of lethal or fatal disease (HRadj: 0.99, 95% CI: 0.91-1.08; P-trend = 0.83; and HRadj: 0.99, 95% CI: 0.90-1.08; P-trend = 0.82, respectively). CONCLUSION: No consistent associations were observed between birth weight and prostate cancer risk or mortality in this 22-year prospective cohort study.

All-cause and cause-specific mortality risk and loss in life expectancy associated with incident type 2 diabetes onset age and duration.

BACKGROUND: Evidence on type 2 diabetes onset age and duration on mortality risk has been limited by short follow-up, inadequate control for confounding, missing repeated measurements, and inability to cover the full range of onset age, duration, and major causes of death. Moreover, scarce data dissect how type 2 diabetes onset age and duration shape life expectancy. METHODS: We evaluate prospectively these topics based on 270,075 eligible participants in the Nurses' Health Studies and Health Professionals Follow-up Study, leveraging repeated measurements throughout up to 40 years of follow-up. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted analyses, incident early onset type 2 diabetes (diagnosed <40 years of age) was associated with significantly higher mortality from all-causes (HR, 95% CI was 3.16, 2.64-3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27-10.1), respiratory disease (3.43, 1.38-8.51), neurodegenerative disease (5.13, 2.09-12.6), and kidney disease (8.55, 1.98-36.9). The relative risk elevations declined dramatically with each higher decade of age at diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Longer disease duration was associated with generally higher relative and absolute risk of mortality. CONCLUSION: Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all-cause and cause-specific mortality and greater loss in life expectancy.

Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer.

PURPOSE: Family history and germline genetic risk single nucleotide polymorphisms (SNPs) have been separately shown to stratify lifetime risk of prostate cancer. Here, we evaluate the combined prognostic value of family history of prostate and other related cancers and germline risk SNPs among patients with favorable-risk prostate cancer. MATERIALS AND METHODS: A total of 1367 participants from the prospective Health Professionals Follow-up Study diagnosed with low- or favorable intermediate-risk prostate cancer from 1986 to 2017 underwent genome-wide SNP genotyping. Multivariable Cox regression was used to estimate the association between family history, specific germline risk variants, and a 269 SNP polygenic risk score with prostate cancer‒specific death. RESULTS: Family history of prostate, breast, and/or pancreatic cancer was observed in 489 (36%) participants. With median follow-up from diagnosis of 14.9 years, participants with favorable-risk prostate cancer with a positive family history had a significantly higher risk of prostate cancer‒specific death (HR 1.95, 95% CI 1.15-3.32, P = .014) compared to those without any family history. The rs2735839 (19q13) risk allele was associated with prostate cancer‒specific death (HR 1.81 per risk allele, 95% CI 1.04-3.17, P = .037), whereas the polygenic risk score was not. Combined family history and rs2735839 risk allele were each associated with an additive risk of prostate cancer‒specific death (HR 1.78 per risk factor, 95% CI 1.25-2.53, P = .001). CONCLUSIONS: Family history of prostate, breast, or pancreatic cancer and/or a 19q13 germline risk allele are associated with an elevated risk of prostate cancer‒specific death among favorable-risk patients. These findings have implications for how family history and germline genetic risk SNPs should be factored into clinical decision-making around favorable-risk prostate cancer.

Neighborhood greenness and long-term physical and psychosocial quality of life among prostate cancer survivors in the Health Professionals Follow-up Study.

INTRODUCTION: Neighborhood greenness may benefit long-term prostate cancer survivorship by promoting physical activity and social integration, and reducing stress and exposure to air pollution, noise, and extreme temperatures. We examined associations of neighborhood greenness and long-term physical and psychosocial quality of life in prostate cancer survivors in the Health Professionals Follow-up Study. METHODS: We included 1437 individuals diagnosed with non-metastatic prostate cancer between 2008 and 2016 across the United States. Neighborhood greenness within a 1230m buffer of each individual's mailing address was measured using the Landsat satellite image-based Normalized Difference Vegetation Index (NDVI). We fit generalized linear mixed effect models to assess associations of greenness (in quintiles) with longitudinal patient reported outcome measures on prostate cancer-specific physical and psychosocial quality of life, adjusting for time-varying individual- and neighborhood-level demographic factors and clinical factors. RESULTS: The greatest symptom burden was in the sexual domain. More than half of survivors reported good memory function and the lack of depressive signs at diagnosis. In fully adjusted models, cumulative average greenness since diagnosis was associated with fewer vitality/hormonal symptoms (highest quintile, Q5, vs lowest quintile, Q1: mean difference: 0.46, 95% confidence interval [CI]: 0.81, -0.12). Other domains of physical quality of life (bowel symptoms, urinary incontinence, urinary irritation, and sexual symptoms) did not differ by greenness overall. Psychosocial quality of life did not differ by greenness overall (Q5 vs Q1, odds ratio [95% CI]: memory function: 1.01 [0.61, 1.73]; lack of depressive signs: 1.10 [0.63, 1.95]; and wellbeing: 1.17 [0.71, 1.91]). CONCLUSION: During long-term prostate cancer survivorship, cumulative average 1230m greenness since diagnosis was associated with fewer vitality/hormonal symptoms. Other domains of physical quality of life and psychosocial quality of life did not differ by greenness overall. Limitations included potential non-differential exposure measurement error and NDVI's lack of time-activity pattern.

Influence of Neighborhood Social and Natural Environment on Prostate Tumor Histology in a Cohort of Male Health Professionals.

Adverse neighborhood social and natural (green space) environments may contribute to the etiology of prostate cancer (CaP), but mechanisms are unclear. We examined associations between neighborhood environment and prostate intratumoral inflammation in 967 men diagnosed with CaP with available tissue samples from 1986-2009 in the Health Professionals Follow-up Study. Exposures were linked to work or residential addresses in 1988. We estimated indices of neighborhood socioeconomic status (nSES) and segregation (Index of Concentration at the Extremes (ICE)) using US Census tract-level data. Surrounding greenness was estimated using seasonal averaged Normalized Difference Vegetation Index (NDVI) data. Surgical tissue underwent pathological review for acute and chronic inflammation, corpora amylacea, and focal atrophic lesions. Adjusted odds ratios (aORs) for inflammation (ordinal) and focal atrophy (binary) were estimated using logistic regression. No associations were observed for acute or chronic inflammation. Each interquartile-range increase in NDVI within 1,230 m of the participant's work or home address (aOR = 0.74, 95% confidence interval (CI): 0.59, 0.93), in ICE-income (aOR = 0.79, 95% CI: 0.61, 1.04), and in ICE-race/income (aOR = 0.79, 95% CI: 0.63, 0.99) was associated with lower odds of postatrophic hyperplasia. Interquartile-range increases in nSES (aOR = 0.76, 95% CI: 0.57, 1.02) and ICE-race/income (aOR = 0.73, 95% CI: 0.54, 0.99) were associated with lower odds of tumor corpora amylacea. Histopathological inflammatory features of prostate tumors may be influenced by neighborhood.

Experience with the US health care system for Black and White patients with advanced prostate cancer.

OBJECTIVE: The purpose of this study was to assess differences in reported information about treatment, integration into care, and respect by self-identified Black and White individuals with advanced prostate cancer in the United States. PATIENTS AND METHODS: This is a prospective cohort study of 701 participants (20% identifying as Black) enrolled in the International Registry for Men with Advanced Prostate Cancer at 37 US sites from 2017 to 2022. Participants were asked six questions from the Cancer Australia National Cancer Control Indicators about their experience with care at study enrollment. Prevalence differences by self-reported race were estimated using marginal standardization of logistic-normal mixed effects models (adjusted for age at enrollment and disease state at enrollment), and 95% CIs were estimated using parametric bootstrapping. RESULTS: Most participants reported a high quality of care for each question. Black participants generally reported higher care quality compared with White participants. Black participants reported more frequently that they were offered a written assessment and care plan (71%) compared with White participants (58%; adjusted difference, 13 percentage points; 95% CI, 4-23). Black participants also reported more frequently being given the name of nonphysician personnel who would support them (64%) than White participants (52%; adjusted difference, 10; 95% CI, 1-20). Prevalence differences did not differ by disease state at enrollment. CONCLUSIONS: Black participants generally reported a higher quality of care compared with White participants. This study calls attention to the need to study potential mediating factors and interpersonal aspects of care in this population to improve survivorship.

Modifiable risk factors for subsequent lethal prostate cancer among men with an initially negative prostate biopsy.

BACKGROUND: Previously suggested modifiable risk factors for prostate cancer could have resulted from detection bias because diagnosis requires a biopsy. We investigated modifiable risk factors for a subsequent cancer diagnosis among men with an initially negative prostate biopsy. METHODS: In total, 10,396 participants of the Health Professionals Follow-up Study with an initial negative prostate biopsy after 1994 were followed for incident prostate cancer until 2017. Potential risk factors were based on previous studies in the general population. Outcomes included localised, advanced, and lethal prostate cancer. RESULTS: With 1851 prostate cancer cases (168 lethal) diagnosed over 23 years of follow-up, the 20-year risk of any prostate cancer diagnosis was 18.5% (95% CI: 17.7-19.3). Higher BMI and lower alcohol intake tended to be associated with lower rates of localised disease. Coffee, lycopene intake and statin use tended to be associated with lower rates of lethal prostate cancer. Results for other risk factors were less precise but compatible with and of similar direction as for men in the overall cohort. CONCLUSIONS: Risk factors for future prostate cancer among men with a negative biopsy were generally consistent with those for the general population, supporting their validity given reduced detection bias, and could be actionable, if confirmed.

Different operationalizations of the 2018 WCRF/AICR cancer prevention recommendations and risk of cancer.

BACKGROUND: The standardized scoring system assessing adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations assigns equal weight for each recommendation, thereby giving higher weight to dietary factors collectively (5 points) than adiposity (1 point) and physical activity (1 point). An alternative score assigning equal weights to the adiposity, physical activity, alcohol, and other dietary (composite) recommendations may better predict cancer associations. METHODS: We examined associations between standardized and alternative scores with cancer risk in two US prospective cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. RESULTS: During 28 years of follow-up, 16,342 incident cancer cases in women and 8729 cases in men occurred. Individuals in the highest versus lowest quintile of the standardized score had a reduced overall cancer risk (women: HR = 0.89, 95% CI: 0.85, 0.94; men: HR = 0.87, 95% CI: 0.81, 0.94). Results were slightly stronger for the alternative score (women: HR = 0.83, 95% CI: 0.79, 0.87; men: HR = 0.81, 95% CI: 0.75, 0.86). Similar patterns were observed for obesity-related, alcohol-related, smoking-related, and digestive system cancers. CONCLUSIONS: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with lower cancer risk. A score assigning equal weights to the adiposity, physical activity, alcohol, and all remaining diet components yielded stronger associations than the standardized score.

Post-diagnostic Zinc Supplement Use and Prostate Cancer Survival Among Men With Nonmetastatic Prostate Cancer.

PURPOSE: Biological and experimental evidence support restoration of normal zinc levels in malignant prostate cells as a promising prostate cancer treatment, yet the influence of zinc supplementation after diagnosis on prostate cancer survival in a human population is unknown. MATERIALS AND METHODS: We prospectively assessed post-diagnostic zinc supplementation in relation to prostate cancer survival among 5,788 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2019). We used Cox regression models to estimate the multivariable hazard ratios and 95% confidence intervals of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality according to post-diagnostic zinc supplement use and dosage. RESULTS: During a median follow-up of 11 years, we documented 527 lethal prostate cancer events and 3,198 all-cause deaths. Fifteen percent of men reported zinc supplement use post-diagnosis. Compared to nonusers, post-diagnostic zinc supplement use was associated suggestively with a lower risk of lethal prostate cancer (HR [95% CI], 0.82 [0.60-1.13]) and significantly with all-cause mortality (0.84 [0.74-0.96]). The inverse association was mostly observed among men who used post-diagnostic zinc supplements of 1-24 mg/d (lethal prostate cancer: 0.55 [0.32-0.96]; all-cause mortality: 0.77 [0.64-0.93]), while higher dosage did not show a lower risk. CONCLUSIONS: Post-diagnostic low-dose zinc supplement use among nonmetastatic prostate cancer patients was associated with lower risk of lethal prostate cancer and all-cause mortality. A potential benefit of low-dose post-diagnostic zinc supplement for prostate cancer survival merits further study.

Promoting Reproducibility and Integrity in Observational Research: One Approach of an Epidemiology Research Community.

To increase research reproducibility, sharing of study data, analysis code, and use of standardized reporting are increasingly advocated. However, beyond reproducibility, few initiatives have addressed the integrity of how research is conducted before manuscripts are submitted. We describe a decades-long experience with a comprehensive approach based in an academic research community around prospective cohort studies that is aimed at promoting a culture of integrity in observational research. The approach includes prespecifying hypotheses and analysis plans, which are discussed in the research community and posted; presentation and discussion of analysis results; mandatory analysis code review by a programmer; review of concordance between analysis output and manuscripts by a technical reviewer; and checks of adherence to the process, including compliance with institutional review board requirements and reporting stipulations by the National Institutes of Health. The technical core is based in shared computing and analytic environments with long-term archiving. More than simply a list of rules, our approach promotes research integrity through integrated educational elements, making it part of the "hidden curriculum," by fostering a sense of belonging, and by providing efficiency gains to the research community. Unlike reproducibility checklists, such long-term investments into research integrity require substantial and sustained funding for research personnel and computing infrastructure. Our experiences suggest avenues for how institutions, research communities, and funders involved in observational research can strengthen integrity within the research process.

Quality of life in the year after new diagnosis with advanced prostate cancer for Black and White individuals living in the US.

PURPOSE: To assess differences in baseline and longitudinal quality of life among Black and White individuals in the US with advanced prostate cancer. METHODS: Secondary analysis of data from the International Registry for Men with Advanced Prostate Cancer (IRONMAN) including US participants newly diagnosed with advanced prostate cancer and identifying their race as Black or White from 2017 to 2023. Participants completed the EORTC QLQ-C30 Quality of Life (QoL) Survey at study enrollment and every 3 months thereafter for up to 1 year of follow-up reporting 15 scale scores ranging from 0 to 100 (higher functioning and lower symptom scores represent better quality of life). Linear mixed effects models with race and month of questionnaire completion were fit for each scale, and model coefficients were used to assess differences in baseline and longitudinal QoL by race. RESULTS: Eight hundred and seventy-nine participants were included (20% identifying as Black) at 38 US sites. Compared to White participants at baseline, Black participants had worse constipation (mean 6.3 percentage points higher; 95% CI 2.9-9.8), financial insecurity (5.7 (1.4-10.0)), and pain (5.1 (0.9-9.3)). QoL decreased over time similarly by race; most notably, role functioning decreased by 0.7 percentage points (95% CI -0.8, -0.5) per month. CONCLUSION: There are notable differences in quality of life at new diagnosis of advanced prostate cancer for Black and White individuals, and quality of life declines similarly in the first year for both groups. Interventions that address specific aspects of quality of life in these patients could meaningfully improve the overall survivorship experience.