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Purpose All patients living with cancer, including those with metastatic cancer, are encouraged to be physically active. This paper examines the secondary endpoints of an aerobic exercise intervention for men with metastatic prostate cancer. Methods ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells), was a multi-centre randomised control trial with a 6-month aerobic exercise intervention arm or a standard care control arm. Exercise adherence data was collected via heart rate monitors. Quality of life (FACT-P) and physical activity (self-administered questionnaire) assessments were completed at baseline, at 3 months and at 6 months. Results A total of 61 patients were included (69.4 ± 7.3 yr, body mass index 29.2 ± 5.8 kg/m2). The median time since diagnosis was 34 months (IQR 7–54). A total of 35 (55%) of participants had > 1 region affected by metastatic disease. No adverse events were reported by participants. There was no effect of exercise on quality of life (Cohen’s d = − 0.082). Overall adherence to the supervised sessions was 83% (329 out of 396 possible sessions attended by participants). Overall adherence to the non-supervised home exercise sessions was 72% (months 1–3) and 67% (months 3–6). Modelling results for overall physical activity scores showed no significant main effect for the group (p-value = 0.25) or for time (p-value = 0.24). Conclusion In a group of patients with a high burden of metastatic prostate cancer, a 6-month aerobic exercise intervention did not lead to change in quality of life. Further exercise studies examining the role of exercise for people living with metastatic prostate cancer are needed. Trial Registration The trial was registered at clinicaltrials.gov (NCT02453139) on May 25th 2015.

Purpose: Variants at chromosomal loci 8q24 and 17q are established risk factors for prostate cancer. Many studies have confirmed the findings for risk, but few have examined aggressiveness and other clinical variables in detail. Additionally, Gleason score is typically used as a surrogate for the primary end point of prostate cancer mortality. We investigated whether the 8q24 and 17q risk variants are associated with clinical variables as well as prostate cancer mortality.Experimental Design: In the Physicians' Health Study (1,347 cases and 1,462 controls), the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center; 3,714 cases), and the Fred Hutchinson Cancer Research Center King County Case-Control Studies (1,308 cases and 1,266 controls), we examined eight previously identified 8q24 and 17q risk variants for association with prostate cancer mortality in men of European ancestry. We considered associations with other surrogate markers of prostate cancer aggressiveness, such as Gleason score, pathologic stage, prostate-specific antigen at diagnosis, and age at diagnosis.Results: Six of the eight variants were confirmed as prostate cancer risk factors. Several variants were nominally associated with age at diagnosis; when totaling all alleles for single nucleotide polymorphisms significantly associated with risk, each additional allele decreased age at diagnosis by an average of 6 months in the Physicians' Health Study (P = 0.0005) and 4 months in the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center) cohort (P = 0.0016). However, there were no statistically significant associations with prostate cancer mortality.Conclusions: Our results suggest that the 8q24 and 17q prostate cancer risk variants may influence age at diagnosis but not disease aggressiveness.

Supplementary Data from Evaluation of 8q24 and 17q Risk Loci and Prostate Cancer Mortality

Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus. [Cancer Res 2009;69(13):5568–74]

Supplementary Figure 1 from Evaluation of the 8q24 Prostate Cancer Risk Locus and MYC Expression

Background: Although polygenic risk score (PRS), which estimates an individual’s genetic risk to a given trait/disease, has been considered as a promising tool for precision medicine, the individual-level uncertainty in lung cancer PRS and the extent to which its effect on downstream clinical applications remains largely unexplored. Method: Lung cancer PRSs with confidence interval (CI) were constructed via two approaches for each individual - 1) a GWAS-based cross-validation and bootstrapping method (PRS-CV) based on 16 SNP loci that have been validated in Caucasian population, and 2) a Bayesian method using LDPred2 (PRS-Bayes), among 18,146 lung cancer cases and 12,894 cancer-free controls of European ancestry in the International Lung Cancer Consortium (ILCCO). Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Multivariable analyses controlling for age, gender and smoking history were conducted to discover the relative risk of lung cancer for different PRS risk subgroups. Lung cancer risk prediction models incorporating both PRS risk subgroups and non-genetic risk factors were constructed and evaluated using five-fold cross-validation. Results: Considerable variance in PRS point estimates at the individual level was observed for both methods, with an average standard deviation (s.d.) of 0.12 (95% CI = 0.09-0.15) for PRS-CV and a much larger s.d. of 0.88 (95% CI = 0.68-1.11) for PRS-Bayes. With a credible level p = 95%, PRS-CV only classified 24.3% of the low genetic risk and 15.6% of the high genetic risk population with certainty, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were commonly identified as high genetic risk using the two PRS estimators. An increased relative risk of lung cancer was observed for PRS risk subgroups identified by PRS CI approach (OR = 2.92, 95% CI = 2.26-3.78, p-value = 2.5*10−16) compared to by PRS mean (OR = 2.20, 95% CI = 1.99-2.45, p-value = 1.6*10−50). Similar improvement was observed in stratified analyses by gender, lung cancer histologies and smoking history, with the largest increase observed in never smokers. Improved risk prediction performance was consistently observed in individuals identified by PRS CI approach and it achieved the best performance when incorporating age, gender and smoking packyears (AUC: 0.73, 95% CI = 0.72-0.74). Conclusion: Our study first characterized the uncertainty of lung cancer PRS for individuals and evaluated the potential impacts on subsequent risk stratification and prediction in populations with European ancestry. Lung cancer PRS estimated using different methods have modest correlations at the individual level, highlighting the importance of taking serious considerations integrating PRS in clinical interpretation and implementation in precision medicine. Citation Format: Xinan Wang, Ziwei Zhang, Yi Ding, Tony Chen, Lorelei Mucci, Christopher I. Amos, Xihong Lin, David C. Christiani. Impact of individual level uncertainty of lung cancer polygenic risk score on risk stratification and prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1184.

Background: Prostate cancer genome-wide association studies have identified >260 germline risk variants which provide strong risk prediction for prostate cancer. Functional interpretation and biological mechanisms of these risk variants are not always clear. Many of the prostate cancer risk variants are expression quantitative trait loci (eQTLs), but studies have mostly been performed in tumor or epithelial-enriched normal prostate tissue. Given emerging evidence supporting that stroma contributes to the carcinogenic process, we examined the associations of prostate cancer risk variants with the expression of genes in prostate stroma. Methods: We generated mRNA expression data for 13,577 genes with the Illumina TruSeq RNA Exome library preparation kit from stromal samples in specimens from participants of the Health Professionals Follow-up Study and Physicians’ Health Study cohorts. Specifically, we profiled 172 stromal samples adjacent to tumor and 86 paired stroma distant from tumor. We included 264 prostate cancer risk variants genotyped data and imputed using a common reference panel (1,000 Genomes Phase I release). We performed cis- (≤1 Mb from the SNP (single nucleotide polymorphism) to the gene) and trans- eQTL analyses using a linear regression model in the R package Matrix eQTL. Results: Thirty-four SNPs were significantly (P < 0.01) associated with cis-expression of 41 nearby genes in prostate stroma adjacent to tumor, and 41 SNPs with 52 nearby genes for stroma distant from tumor. Genome-wide, 86 SNPs were significantly (FDR < 0.10) associated with the expression of 126 genes in stroma adjacent to tumor, and 64 SNPs with 291 genes for stroma distant from tumor. Conclusions: This is the first study to comprehensively examine associations between prostate cancer risk variants and gene expression in prostate stroma. We observed some previous reported associations but also novel associations which may suggest genes that contribute to prostate cancer risk within the stromal tissue. Identifications of eQTLs within prostate stroma may suggest potential mechanisms in specific cell types for their effect on disease. Citation Format: Chaoran Ma, Yinglu Zhou, Anna Plym, Giuseppe Nicolò Fanelli, Massimo Loda, Lorelei Mucci, Svitlana Tyekucheva, Kathryn Penney. Association of prostate cancer risk variants with gene expression in prostate stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6242.

Introduction: Advances in cancer screening, diagnosis, and treatment have resulted in an increasing population of cancer survivors, many of whom experience persistent cancer-related side effects. Multiple studies have found that cancer survivors report poorer sleep than the general population. More than 3 million men in the US are prostate cancer survivors, yet few existing studies have focused on sleep in this population, especially among men with metastatic disease. Thus, a better understanding of sleep problems among prostate cancer survivors could help characterize how sleep affects the quality of life among men with prostate cancer. Aim: To describe sleep behaviors and problems among prostate cancer survivors overall and specifically among those with metastatic disease. Methods: Self-reported sleep data, including sleep disruption, sleep apnea, and insomnia, were obtained from the 2018 Prostate Cancer Follow-up Survey (PCFS) administered to participants of the Health Professionals Follow-Up Study with a diagnosis of prostate cancer. We evaluated each item individually and calculated a score for clinical insomnia using the validated Women’s Health Initiative Insomnia Rating Scale (range 1-20; score >10 indicative of clinically relevant insomnia). Descriptive analyses on sleep measures were conducted overall and stratified by metastatic disease. We utilized multivariable linear regression models to compare metastatic disease status and insomnia score, adjusting for age, race, body mass index, physical activity, smoking, and other health information. Results: Of 2,431 men (median age: 83 years) who completed the 2018 survey, 87 had metastatic disease, de novo or men who progressed after diagnosis. Sleep disturbances were relatively common in this population. Among all men with prostate cancer, 33% (n=290) reported waking up several times a night five or more times a week, 14% (n=337) rated their sleep quality as restless, and 15% (n=368) reported a clinical diagnosis with sleep apnea. The Insomnia Rating Scale scores were relatively high among all prostate cancer survivors with a mean score of 9.0 (95% CI 6.0-12.0). Scores significantly differed by metastatic disease status and men with metastatic disease had scores that were 1.30 (95% CI 0.19-2.41) points higher than men without metastatic disease. Conclusion: The growing global number of prostate cancer survivors with metastatic disease and the potentially high prevalence of negative cancer-related quality of life effects pose pressing challenges to health systems. Our findings suggest that sleep disturbances are common among prostate cancer survivors. Men with metastatic disease had poorer sleep overall and higher rates of clinical insomnia than men without metastatic disease. These results could highlight the importance of sleep among men with prostate cancer and could increase the clinical treatment of sleep problems. Citation Format: Alaina H. Shreves, Lorelei Mucci, Unnur Valdimarsdottir, Sarah Markt, Kathryn Penney. Sleep disruption among prostate cancer survivors by metastatic disease status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3226.

Introduction: The COVID-19 pandemic has disrupted the lives of cancer survivors who may be at higher risk than people without cancer of other adverse health outcomes. For many individuals, a cancer diagnosis leads to lower physical activity and change in mental health status. Modifiable health behaviors, such as consumption of a healthy diet, can positively affect cancer survivorship outcomes. Aim: To investigate the individual-level changes in diet and supplement use among male cancer survivors during the COVID-19 pandemic and compared to men without cancer. Methods: Participants of the Health Professionals Follow-up Study, enrolled since 1986, were asked to self-report health behaviors during the pandemic on three web-based questionnaires administered during the COVID-19 pandemic (baseline COVID: October 2020, first follow-up: January 2021, second follow-up: April 2021). Diet and supplement use were analyzed descriptively between cancer survivors and individuals without a history of cancer. Further, outcomes were dichotomized to reflect whether a change was healthful or unchanged/unhealthful; for example, lower fast food consumption was classified as a healthful change. To assess the associations between cancer survivors and other men, logistic regression was used, adjusting for age, race, pre-pandemic body mass index, pre-pandemic physical activity, and other health information. Results: Of 4,416 men who completed the baseline COVID-19 questionnaire, 962 were cancer survivors (after excluding those with non-melanoma skin cancer). Across all eligible men (median age: 78 years), there were considerable proportions of men engaging in healthful changes following the start of the pandemic in intake of fast food (19% decreased), sugary drinks (14% decreased), fresh fruit (26% increased), fresh vegetables (19% increased), fish (13% increased), and red meat (12% decreased) consumption. Similar changes in diet were reported on the second follow-up questionnaire. For most foods, a similar percentage of cancer survivors and individuals without a history of cancer increased healthy eating. Findings from multivariable logistic regression models were reflective of higher odds of cancer survivors to engage in a healthful diet change for unhealthy food categories (i.e., less fast food, less frozen food), though none of which were statistically significant. There was little change in supplement use during the pandemic, except for 6% who started use of vitamin D supplements between the baseline and first follow-up questionnaire. Conclusion: Our findings suggest that older men engaged in healthful diet changes during the COVID-19 pandemic, without noticeable differences among cancer survivors. Citation Format: Alaina H. Shreves, Colleen B. McGrath, Konrad Stopsack, Lilian Cheung, Ann Fisher, Edward Giovannucci, Sarah Markt, Eric Rimm, Lorelei Mucci. Diet and supplement use changes among male cancer survivors during the COVID-19 pandemic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 440.

Leukemias are a diverse group of acute and chronic haematological malignancies, that account for 2% to 3% of cancers globally. Recent advances in molecular biology and therapy have transformed the landscape for several leukemia subtypes changing some, but by no means all, from rapidly fatal diseases to treatable conditions with a good prognosis. In general, however, this progress has not been matched by new aetiological insights. Albeit accounting for a relatively small proportion, genetic predisposition syndromes such as neurofibromatosis, Li-Fraumeni and Trisomy 21, have the biggest impact in children and young adults. At older ages, established chemical, physical and biological risk factors, which explain only a small proportion of the total disease burden, include chemotherapy for a preceding cancer, ionizing radiation, and the viral infections human T-cell lymphotropic virus type 1 (HTLV-1) which causes the rare adult T-cell leukemia/lymphoma (ATLL) and the human immunodeficiency virus (HIV) which is associated with an increased risk of acute lymphoid leukaemias. Workplace exposures to potential carcinogens such as benzene, butadiene, and styrene have also been linked to increased risk of leukemia.

Prostate cancer is among the most commonly diagnosed cancers among men, ranking second in cancer globally and first in Western countries. There are marked variations in incidence globally, and its incidence must be interpreted in the context of diagnostic intensity and screening. The uptake of prostate-specific antigen screening since the 1990s has led to dramatic increases in incidence in many countries, resulting in an increased proportion of indolent cancers that would never have come to light clinically in the absence of screening. Risk factors differ when studying prostate cancer overall versus advanced disease. Older age, African ancestry, and family history are established risk factors for prostate cancer. Obesity and smoking are not associated with risk overall, but are associated with increased risk of advanced prostate cancer. Several additional lifestyle factors, medications, and dietary factors are now emerging as risk factors for advanced disease.

cBrain tumors constitute an array of histologic types, the most common being meningioma and glioma. Unlike other cancers, both benign and malignant brain tumors are concerning for survival because of their anatomic location. Two-thirds of brain tumors are benign. The most well established risk factor is high dose ionizing radiation, based on studies of atomic bomb survivors as well as children treated for tinea capitis. In contrast, nonionizing radiation including from cellular telephones, is not a risk factor. Tobacco use does not appear to be associated with glioma or meningioma. There is fairly consistent evidence of an inverse association between allergies and asthma with risk of glioma, potentially through levels of IgE. Finally, occupational epidemiology studies suggest potential positive associations with specific exposures. The identification of modifiable risk factors for brain tumors has been challenging, due in part to the diversity of tumor subtypes.

In 2012, more than 337,000 pancreatic cancer cases were diagnosed globally, ranking twelfth in cancer incidence. Pancreatic cancer has one of the highest fatality rates of any cancer, and as such ranks higher in cancer mortality, including in the United States, where it is the third most common cause of cancer death. There are concerning increases in incidence rates in the United States, although the reason for this is not known. Smoking is the strongest established risk factor for pancreatic cancer. Risk decreases after smoking cessation, and is similar to that of nonsmokers within 15 years of smoking cessation. Early epidemiological studies had suggested a positive association between coffee intake and pancreatic cancer risk, but subsequently the association was found to be due to bias. Obesity has emerged as a consistent risk factor for pancreatic cancer risk. Finally, conditions such as hereditary pancreatitis are strongly associated with cancer risk.

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (p pathway < 0.00625). The two most significant genes were NPAS2 (p gene =0.0062) and AANAT (p gene =0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (p pathway =0.021); this association was not confirmed in GECCO (p pathway =0.76) or the combined data (p pathway =0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

Background: Converging evidence points to a potential role of disruption of the circadian rhythm in prostate cancer progression. There is limited human data in prostate tissue examining the biological consequences of alterations in genes involved in circadian rhythm on outcomes among prostate cancer patients. Methods: To test the hypothesis that tissue expression of circadian-related genes was associated with prostate cancer outcomes, we leveraged data from the Physicians' Health Study (PHS) and the Health Professionals Follow-Up Study (HPFS) prostate tumor cohorts. Whole transcriptome expression profiling was performed on 404 prostate cancer cases, including 113 lethal cases (metastatic disease or prostate cancer death) and 291 indolent cases (>8 years from diagnosis without evidence of metastasis). Using logistic regression models, we assessed whether mRNA expression levels in tumor (N=404) or paired normal prostate tissue (N=202) of eleven circadian-related genes (AANAT, CLOCK, CRY1, CRY2, CSNK1E, MTNR1B, NPAS2, OPN4, PER1, PER2, PER3) were associated with lethal prostate cancer, stage (T2 vs. T3+), Gleason grade at diagnosis ( Results: Pathway analyses showed a statistically significant association between the eleven circadian genes and lethal disease (global test p-value = 5.1e-05). On an individual gene level, men with higher tumor expression of Period Circadian Regulator 1 (PER1) gene had a reduced risk of lethal disease, independent of grade and stage (OR: 0.75, 95% CI: 0.59-0.97). High tumor expression of PER1 (OR: 0.72, 95% CI: 0.57-0.91) and Cryptochrome Circadian Regulator 2 (CRY2) (OR: 0.79, 95% CI: 0.63-1.00) were associated with lower Gleason grade tumors. High tumor expression of PER1 was associated with lower levels of cell proliferation and lower levels of angiogenesis markers; Neuronal PAS Domain Protein 2 (NPAS2) was associated with markers of apoptosis. For none of the genes was expression in normal prostate tissue associated with lethal prostate cancer (global test p-value = 0.06). Discussion: We found higher expression of several of the circadian related genes were associated with less aggressive prostate cancer features. In line with these findings, PER1 has been suggested to be a tumor suppressor in previous studies. This supports the idea that maintenance of circadian clock function may protect tumor progression. Citation Format: Sarah C. Markt, Ericka Ebot, Iona Cheng, Lynne Wilkens, Ayesha Shafi, Karen Knudsen, Kathryn Penney, Lorelei Mucci, Travis Gerke. Circadian clock gene expression and lethal prostate cancer outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1574.

Background: The parenchyma of the pineal gland, an endocrine gland in the brain, produces the circadian hormone melatonin. Previously, we found low levels of melatonin were associated with an increased risk for advanced prostate cancer. This study used data from men in the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) Study to evaluate the relationship between pineal volume, melatonin levels, and prostate cancer risk. Methods: Participants were enrolled in the AGES-Reykjavik Study from 2002 to 2006 and underwent detailed clinical assessments at baseline that included biospecimen collection, MRI of the brain, medical history, and health questionnaires on dietary and lifestyle factors. We included 802 men who had information on pineal size, where parenchyma, calcification, and cyst volume were estimated individually and manually from the MRIs. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for risk of prostate cancer during follow-up through 2014, comparing parenchyma volume tertiles. Results: There was a positive association between pineal parenchyma volume and urinary levels of melatonin. During follow-up, 135 men were diagnosed with prostate cancer, 30 of which were advanced prostate cancer. Men with volumes in the upper tertile had no statistically significant increased risk of prostate cancer compared to men with volumes in the lowest tertile (HR: 1.0, 95% CI: 0.7, 1.5), and men with volumes in the middle tertile had only a borderline statistically significant decreased risk of prostate cancer compared to men with volumes in the lowest tertile (HR: 0.7, 95% CI: 0.4, 1.0). Compared to men without pineal cysts, there was a borderline statistically significant association between men with pineal cysts and decreased risk of prostate cancer (HR: 0.7, 95% CI: 0.5, 1.0). Compared to men without pineal calcifications, there was no statistically significant association between men with pineal calcifications and increased risk of prostate cancer (HR: 1.1, 95% CI: 0.7, 1.6). Conclusions: Pineal parenchyma volume was associated with melatonin levels, but there was no statistically significant association between parenchyma volume alone and prostate cancer risk. Further studies are needed to investigate the relationship between pineal parenchyma volume, presence of calcifications and cysts, melatonin, and prostate cancer. Citation Format: Latifa A. Bazzi, Lara Sigurdardottir, Sigurdur Sigurdsson, Unnur Valdimarsdottir, Johanna Torfadottir, Thor Aspelund, Lenore Launer, Tamara Harris, Vilmundur Gudnason, Lorelei Mucci, Sarah Markt. Pineal gland volume and risk of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5045.

Chemokines and cytokines have been implicated in progression to castration-resistant prostate cancer (CRPC).Retrospective data were accessed from 122 men with serum samples drawn at a median of 0.5 months after starting ADT for metastatic prostate cancer. MCP-1, IL-1-β, IL-2, IL-8, IL-6, and TNF-α levels were measured by multiplex electrochemiluminescence assays. A multivariable Cox model assessed the association of time to CRPC and overall survival by the protein levels and adjusted for clinical variables (age and prostate specific antigen (PSA) levels at start of ADT, race, ECOG status, and extent of metastases). Associations were reported as hazard ratio (HR) with 95% confidence interval (CI).Median follow-up and overall survival were 44 and 42.2 months, respectively. ECOG performance status (≥1 vs. 0) was negatively associated with overall survival [HR = 2.8 (1.1-7.0), P = 0.03], and PSA nadir 0.2 was predictive of longer time to development of CRPC [HR = 0.3 (0.2-0.5), P 0.0001]. The HR for time to CRPC by protein above the median was 1.4 (95% CI: 0.9, 2.2, P = 0.13) for IL-8; 1.3 (95% CI: 0.8, 2, P = 0.18) for TNF-α; 1.0 (95% CI: 0.7, 1.6, P = 0.95) for MCP-1. The HR for median overall survival for protein levels above the median was: 1.9 (95% CI: 1.0, 3.5, P = 0.04) for IL-8; 2.0 (95% CI: 1.1, 3.5, P = 0.02) for TNF-α; 1.7 (95% CI: 1.7, 3.0, P = 0.08) for MCP-1. There was no association with IL-1-β, IL-2, or IL-6.Higher levels of inflammation-associated cytokines correlate with poorer prostate cancer outcomes and may guide strategies to improve prostate cancer therapy.

Insulin-like growth factor (IGF) and adipokines have been implicated in prostate cancer carcinogenesis.Data from 122 men with serum samples drawn within 3 months of starting ADT for metastatic prostate cancer was accessed retrospectively. IGF-1, IGF binding protein (BP)-1, leptin, and adiponectin levels were measured by multiplex electrochemiluminescence assays. A multivariable Cox model assessed the association of time to castration resistant prostate cancer (CRPC) and overall survival by the protein levels, adjusted for clinical variables, age and prostate specific antigen (PSA) levels at start of ADT, race, ECOG status, extent of metastases and were reported as hazard ratio (HR) with 95% confidence interval (CI).Median follow-up and overall survival were 44 and 42.2 months, respectively. ECOG performance status (≥ 1 vs. 0) was negatively associated with overall survival [H = 2.8 (1.1-7.0), P = 0.03], and PSA nadir0.2 was predictive of longer time to CRPC [HR = 0.3 (0.2-0.5), P0.0001]. The median time to CRPC by low, middle, and top IGFBP-1 tertile distribution was 20.7, 18.1, and 12.4 months, respectively, with HR for middle versus low tertile levels 3.1 (1.7-5), P = 0.0003, and for top versus low tertile levels was 2.4 (1.3-4.2), P = 0.003. The median overall survival by low, middle and top tertile IGFBP-1 level was 48.5, 46.4, and 32.8 months, respectively, with HR for top versus low tertile 2.5 (1.2-5.1), P = 0.01. There was no association with IGF-1, adiponectin and leptin.Elevated IGFBP-1 appears to be associated with shorter time to CRPC and lower overall survival in men with metastatic prostate cancer.

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The use of MRI for prostate cancer diagnosis and staging is increasing. Indications for prostate MRI are not defined and many clinicians are unsure of how best to use MRI to aid clinical decisions. This evidence-based medicine article addresses the clinical utility of prostate MRI for preoperative staging. Based on a common patient scenario, a guide to calculating the probability of extraprostatic extension is provided.

The aim of this study is to prospectively assess pregnancy hormone levels as correlates of subsequent development of pre-eclampsia, a condition that has been shown to be inversely associated with breast cancer risk in the offspring. A cohort of 260 Caucasian women in Boston, Massachusetts, was followed through pregnancy. Maternal blood was collected at the 16th and 27th weeks of gestation, and 18 women were diagnosed with pre-eclampsia after blood collection. Information on sociodemographic variables and risk factors of pre-eclampsia was collected through an interviewer-administered questionnaire and review of medical records. At the 16th week, there was a nonsignificant positive association between progesterone levels and pre-eclampsia [relative risk (RR) = 1.63, 95% confidence interval (CI), 0.97-2.74, per 1 SD increase]. By the 27th week, the association between progesterone and pre-eclampsia was strengthened (RR = 2.65, 95% CI, 1.46-4.81, per SD), and sex hormone-binding globulin levels were somewhat inversely related to pre-eclampsia (RR = 0.61, 95% CI, 0.31-1.20, per SD). No difference was found with respect to prolactin, estradiol, and estriol levels. Our findings indicate that progesterone may have a role in the late manifestation of pre-eclampsia pathology but are also compatible with the hypothesis that increases in progesterone represent an early compensatory mechanism.

Background: The TMPRSS2:ERG gene fusion is a distinct molecular subtype of prostate cancer characterized by chromosomal rearrangements joining the androgen responsive TMPRSS gene with ERG, an oncogenic member of the ETS gene family. TMPRSS2:ERG is thought to be an early pathologic event occurring in 50% of prostate tumors and resulting in more than 100,000 fusion positive cancer cases each year in the US. No studies to date have examined underlying risk factors associated with development of the fusion. Oxidative stress and the production of free radicals may result in chromosomal instability and predispose to the formation of TMPRSS2:ERG positive prostate cancer. Higher levels of serum antioxidants prior to prostate cancer diagnosis may therefore be protective against later development of fusion positive cancer. Methods: We undertook a case-control analysis nested within the prospective Physicians' Health Study and the Health Professionals Follow-up Study among men with prostate cancer (n=331) and age-matched controls (n=2139). The cohorts include pre-diagnostic bloods with antioxidant levels at baseline as well as tumor tissue to characterize TMPRSS2:ERG status among prostate cancer cases. We used multivariate logistic regression analysis to determine if plasma antioxidant levels influenced the development of the TMPRSS2:ERG fusion. Results: Of seven antioxidants examined (alpha-tocopherol, alpha-carotene, beta-carotene, beta-cryptoxanthin, gamma-tocopherol, lutein, and lycopene), levels of beta-carotene above the lowest quartile were protective against fusion positive vs. fusion negative prostate cancer (OR 0.49, 95% CL 0.28-0.86, p = 0.01). This association was driven by a non-significantly decreased risk of fusion positive cancer vs. controls (OR 0.75, 95% CL 0.51-1.09, p = 0.13) and a significantly increased risk of fusion negative cancer vs. controls (OR 1.58, 95% CL 1.03-2.41, p = 0.03). None of the six other antioxidants were associated with fusion status, and none of the antioxidants, including beta-carotene, predicted overall prostate cancer risk. Discussion: Previous studies examining antioxidant status and overall prostate cancer risk have been inconclusive. This is the first study to examine pre-diagnostic serum antioxidant levels in relationship to fusion status. We find that beta-carotene levels may alter prostate cancer risk based on molecular subtype. Citation Format: Gregory Judson, Andreas Pettersson, Allison Meisner, Lorelei Mucci. Prediagnostic serum antioxidant levels and prediction of TMPRSS2:ERG fusion status in prostate cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A18.