Risk Of Aggressive Prostate Cancer Research Articles

Abstract 7056: The role of aggressive prostate cancer risk gene ANO7 in prostate metabolism

Abstract Prostate cancer (PCa), the most common male cancer worldwide, causes about 10% of cancer related deaths in Europe. It has a wide spectrum of clinical behavior that ranges from decades of indolence to rapid metastatic progression and lethality. However, the molecular mechanisms involved in aggressive PCa progression are still poorly understood. In PCa the expression of anoctamin 7 (ANO7) has been shown to diminish as the cancer progresses. We have previously linked single-nucleotide polymorphisms in the ANO7 gene to the risk of aggressive prostate cancer and shown that in homozygous carriers of rs77559646, the variant leads to a total loss of ANO7 protein. ANO7 is a prostate-specific gene and is highly expressed in the luminal cells of the human prostate. ANO7 belongs to a family of calcium-activated chloride channels and select members of the anoctamin family have phospholipid scramblase activity. To uncover the cellular functions of ANO7 has proven challenging because ANO7 is not expressed in commercially available cell lines. To study the cellular functions of ANO7, we have generated stable prostate cell lines overexpressing ANO7 using lentiviral transduction. To gain information into what pathways ANO7 is affecting, we performed RNA-sequencing and gene set enrichment analysis. Interestingly, we found enrichment and downregulation of mitochondrial genes participating in oxidative phosphorylation in ANO7 cells. We assessed the mitochondrial function by measuring the oxidative phosphorylation capability of the cells and showed that the basal and maximal respiratory capacity of ANO7 overexpressing cells is indeed reduced. We also analyzed which of the three major mitochondrial fuels (glucose, glutamine and fatty acids) are not used as efficiently for oxidative phosphorylation in ANO7 overexpressing cells. The result proves that ANO7 cells are not utilizing glucose as effectively as control cells. Furthermore, the glycolysis stress assay showed that glycolytic capacity is increased in ANO7 overexpressing cells. In addition, a targeted metabolite screening revealed that aspartate is decreased in ANO7 cells, which again points towards perturbed mitochondrial function as aspartate is produced from a tricarboxylic acid cycle intermediate. By inhibiting the uptake of extracellular aspartate, we measured slower proliferation of ANO7 expressing cells, while inhibiting aspartate had no effect on control cells. Interestingly, preliminary results also suggest ANO7's involvement in regulation of phospholipid acyl chain length and saturation, offering insights into altered signaling observed in ANO7 cells. Taken together, this study shows for the first time that ANO7 rewires prostate mitochondrial functions and thus cellular metabolism, which could explain why it is beneficial for cancer cells to lose ANO7 expression. Citation Format: Christoffer Löf, Nasrin Sultana, Neha Goel, Gudrun Wahlström, Johanna Schleutker. The role of aggressive prostate cancer risk gene ANO7 in prostate metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7056.

Abstract 6280: Vitamin D enhances luminal differentiation of prostate organoids more than androgens

Abstract Background: Prostate Cancer (PCa) is a prevalent disease affecting over two million men worldwide. Vitamin D is a fat-soluble hormone that is well-known for its role in the maintenance of strong bones and has anti-cancer effects in prostate cancer. Vitamin D is synthesized in the skin in response to sun exposure and may be supplemented with diet. However, since melanin hinders this synthesis many African Americans are deficient in vitamin D. Vitamin D circulates as 25-hydroxyvitamin D3 (25D) and 25-dihydroxyvitamin D3 (1,25D). Hydroxylation of 25D by the kidney or within tissues forms the active hormone 1,25D. 1,25D binds the vitamin D receptor (VDR), a steroid transcription factor. Androgens are the main regulatory hormones involved in prostate growth and differentiation. Epithelial differentiation is the process in which progenitor or stem cells become specialized cells, such as basal or luminal. In the prostate, luminal epithelial cells are the most differentiated and are the origin of PCa. We used mouse prostate organoids to replicate the differentiation process in vitro and to help identify the role of 1,25D on epithelial differentiation in the presence and absence of other androgens. Methods: Primary mouse prostate cells were isolated from dorsal lateral lobes and grown as organoids. Over two weeks, we treated these organoids with concentrations of 1,25D and androgen (dihydrotestosterone, DHT). The four treatment groups were control, 1,25D only, DHT only and 1,25D+DHT. Organoids were imaged and analyzed for number, size and phenotype. Phenotypes were identified as luminal, acinar, or solid. Results: Luminal phenotypes were more prevalent in 1,25D conditions compared to control or DHT alone. The number, size and percent of luminal organoids was highest in 1,25D + DHT compared to all other groups. Ongoing studies include examination of prostate organoids from mice with a vitamin D-deficient diet and staining of the organoids for differentiation markers. Conclusions/Significance: We observed that 1,25D enhanced luminal epithelial differentiation in mouse prostate organoids. These findings suggest that chronic vitamin D deficiency may increase risk of aggressive prostate cancer, due to decreased epithelial differentiation. This has implications for the disparity of aggressive PCa observed in African American men who have lower vitamin D levels compared to their white counterparts. Citation Format: Oscar Fernando Cerna, Larisa Nonn, Mike Schlicht, Kirty Krieger. Vitamin D enhances luminal differentiation of prostate organoids more than androgens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6280.

Abstract 7320: Expression of circadian rhythm genes and lethal prostate cancer

Abstract Background: The circadian rhythm regulates diverse physiological and oncologic processes. We have previously shown in epidemiology studies that disruption of the circadian rhythm may be associated with increased risk of aggressive prostate cancer, including germline polymorphisms in certain circadian rhythm genes. This study sought to investigate the relationship between tumor circadian rhythm gene expression and lethal prostate cancer. Methods: We studied patients with primary prostate cancer in the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). We created a composite score of mRNA expression using principal components that incorporated 11 circadian rhythm genes: AANAT, ARNTL, CLOCK, CRY1, CSNK1E, MTNR1A, MTNR1B, NPAS2, PER1, PER2, PER3. An age-stratified analysis was performed, and the mean differences of the score both by Gleason score and compared to normal tissue were calculated. The relationship between the score in prostate tumor tissue and lethal prostate cancer (metastases/prostate cancer-specific death) vs. indolent disease (no metastases after >8 years of follow-up) was assessed using logistic regression. The contribution of each gene was evaluated by leave-one-out analysis, generating scores leaving out one gene and assessing the relationship between the modified score and lethal disease. Results: Among 404 cancer patients in HPFS/PHS, there were 119 lethal events over 30 years of follow-up (median: 17 years). The circadian rhythm gene score was lower in tumor tissue compared to tumor-adjacent, histologically normal tissue (mean difference in units of standard deviation [SD] of gene score: -0.31, 95% confidence interval [CI]: -0.48 to -0.15). In addition, the score was lower in Gleason 9-10 compared to Gleason 6 tumors (mean difference in SD units: -1.05, 95% CI: -1.55 to -0.54). The three PER genes were the most strongly correlated with each other and with the score (Spearman correlation coefficients from 0.52-0.88 for the score and 0.31-0.63 between PER genes). Higher circadian rhythm gene scores were inversely associated with lethal prostate cancer (odds ratio [OR] for highest vs. lowest quartile: 0.43, 95% CI: 0.20 to 0.90) in a dose-response fashion and after adjusting for clinical and pathologic factors. The association appeared to be stronger in patients aged ≥65 years (OR for highest vs. lowest quartile: 0.21, 95% CI: 0.08 to 0.47) compared to <65 years at diagnosis (OR: 0.78, 95% CI: 0.29, 2.17). Results were consistent in the leave-one-out analysis for all genes except PER2 (OR for highest vs. lowest quartile: 1.00, 95% CI: 0.55 to 1.83) and PER1 (OR: 0.55, 95% CI: 0.30 to 1). Conclusion: This study examining intratumoral circadian rhythm gene expression contributes further evidence in support of the relationship between circadian rhythm disruption and aggressive prostate cancer. Tumor expression of PER1 and PER2 may be a predominant factor in the association. Citation Format: Jane Bailey Vaselkiv, Sarah C. Markt, Hannah E. Guard, Anqi Wang, Kathryn L. Penney, Konrad H. Stopsack, Lorelei A. Mucci. Expression of circadian rhythm genes and lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7320.

Abstract 3751: Diagnostic assessment of Filamin A (FLNA) as a serum biomarker for identification of benign prostatic hyperplasia vs aggressive prostate cancer in a prospective Mexican cohort

Abstract Prostate cancer (PCa) exhibits a significant health risk to aging men, in which effective diagnosis of high gleason (Gleason >7) cancers is of critical need. Currently, the main screening tool utilized for detection of prostate cancer is prostate specific antigen (PSA), however, PSA exhibits limited utility in men with benign prostatic hyperplasia (BPH) due to inherent elevated PSA as the result of an enlarged prostate, resulting in increasing unnecessary biopsies. In Mexico, there is currently a higher incidence of aggressive PCa due to the risk within the overall population as well as the need for increased screening tools. Since, there is a critical unmet need to evaluate novel PCa diagnostic test that could serve as a reflex test within the screening paradigm, we evaluated the recently developed test, pSTATEdx, which measures the cleaved portion of Filamin A (FLNA) via IP-MRM mass spectrometry in conjunction with the patients age, to determine the overall risk of aggressive prostate cancer. In the current study, we analyzed a prospective cohort from Mexico City and Guadalajara evaluating 34 BPH and 44 PCa in men exhibiting symptoms with PSA levels between 4-10 ng/mL, who were all referred for 12 core prostate biopsies due to suspicion of prostate cancer. Additionally, we assessed 41 non-diseased men as controls who had PSA below 1.5 ng/mL, who were not assessed further. Comparison of non-diseased controls with BPH/PCa men exhibited an AUC of 0.99, PPV 0.96, NPV 0.89, OR 118, and P value 2 e-20, thus demonstrating that pSTATEdx had significant utility in assessing prostate health independent of PSA. In comparison with previously published data, FLNA mean levels were 24 ng/mL in previously published American study cohort and 55 ng/mL in the Mexican BPH/PCa cohort with a P value of <0.001. Assessment of patient populations revealed that there was superior diagnostic performance of FLNA for patients between PSA 4-7, which represents an increased unmet need for biopsy decision support. Analysis of BPH compared to all PCa exhibited a sensitivity of 0.94 and specificity of 0.53, PPV 0.64, NPV of 0.91, and OR of 16.4. Diagnostic analysis of BPH compared to high gleason PCa exhibited a sensitivity of 1, specificity of 0.21, PPV 0.38, NPV of 1, and OR of inf in this pilot study. This assessment revealed promising insight that aggressive PCa was not missed using pSTATEdx. pSTATEdx demonstrated diagnostic utility in prevention of unnecessary biopsies in the Mexican population as a reflex test to those patients with PSA levels between 4-7 as well as demonstrated that aggressive prostate cancers were not missed with the risk score. Additional studies are planned in the future to expand the utility of pSTATEdx in Latin America. Citation Format: Arturo Rodriguez, Arturo Mendoza, Matthew Rosenburg, José de J. Castaneda, Alejandro A. Melgar, Bernardo Ciseros, Adrian G. Gangemi, Nischal M. Chand, Poornima Tekumalla, Greg Miller, Anjan Thakurta, Diego Banuelos, Juan J. Real, Diego A. Joya, Alejandro Romero, Juan D. Farias, Eduardo Cabeza, Hector H. Remess, Julio J. Delgado, Hector M. Sanchez, Ignacio Barragan, Mabel Rodriguez, Barbara Garcia, David A. Sanchez, Juan Izquierdo, Elizabeth M. Lopez, Juan Hanao, Jeronimo G. Frusch, Niven R. Narain, Michael A. Kiebish. Diagnostic assessment of Filamin A (FLNA) as a serum biomarker for identification of benign prostatic hyperplasia vs aggressive prostate cancer in a prospective Mexican cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3751.

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

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). 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. 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). No consistent associations were observed between birth weight and prostate cancer risk or mortality in this 22-year prospective cohort study.

An Updated Evaluation of Atrazine-Cancer Incidence Associations among Pesticide Applicators in the Agricultural Health Study Cohort.

Atrazine is a common agricultural herbicide in the United States. Few epidemiologic studies have evaluated cancer risks. Previous analyses within the Agricultural Health Study (AHS) have found some evidence of associations with cancer at some sites. We updated exposure information, incident cases, and follow-up time to assess the associations between atrazine use and cancer at specific sites in the AHS. Information about lifetime pesticide use was reported at enrollment (1993-1997) and follow-up (1999-2005). Among 53,562 pesticide applicators in North Carolina and Iowa, we identified 8,915 incident cases through cancer registry linkages through 2014 (North Carolina)/2017 (Iowa). We used Poisson regression to evaluate the association between ever/never and intensity-weighted lifetime days of atrazine use and incident cancer risk controlling for several confounders. We also evaluated lagged exposures and age-stratified risk. Approximately 71.2% of applicators reported ever using atrazine, which was associated with lung cancer [; 95% confidence interval (CI): 1.04, 1.46]. Aggressive prostate cancer risk was increased in the highest quartile (; 95% CI: 0.95, 1.52; ), particularly among those years old (; 95% CI: 1.61, 5.75; ; ). Among applicators years of age, ever-atrazine use was associated with non-Hodgkin lymphoma (NHL) (; 95% CI: 1.10, 5.38; ). For soft tissue sarcoma, there was an elevated risk in the highest tertile of exposure (: 2.54; 95% CI: 0.97, 6.62; ). In analyses with exposure lagged by 25 years, there was an elevated risk of pharyngeal (; 95% CI: 1.45, 6.36; ) and kidney (; 95% CI: 1.15, 2.29; ) cancers. We observed suggestive associations with some malignancies in overall, age-specific, and lagged analyses. Associations with aggressive prostate cancer and NHL were apparent among those diagnosed at younger ages and with cancers of the pharynx and kidney, and soft tissue sarcomas were observed in lagged analyses. Further work is needed to confirm these observed associations and elucidate potential underlying mechanisms. https://doi.org/10.1289/EHP13684.

Epidemiological description and trajectories of patients with prostate cancer in Denmark: an observational study of 7448 patients

ObjectiveIdentification of patients at high risk of aggressive prostate cancer is a major clinical challenge. With the view of developing artificial intelligence-based methods for identification of these patients, we are constructing a comprehensive clinical database including 7448 prostate cancer (PCa) Danish patients. In this paper we provide an epidemiological description and patients’ trajectories of this retrospective observational population, to contribute to the understanding of the characteristics and pathways of PCa patients in Denmark.ResultsIndividuals receiving a PCa diagnosis during 2008–2014 in Region Southern Denmark were identified, and all diagnoses, operations, investigations, and biochemistry analyses, from 4 years prior, to 5 years after PCa diagnosis were obtained. About 85.1% were not diagnosed with metastatic PCa during the study period (unaggressive PCa); 9.2% were simultaneously diagnosed with PCa and metastasis (aggressive-advanced PCa), while 5.7% were not diagnosed with metastatic PCa at first, but they were diagnosed with metastasis at some point during the 5 years follow-up (aggressive-not advanced PCa). Patients with unaggressive PCa had more clinical investigations directly related to PCa detection (prostate ultrasounds and biopsies) during the 4 years prior to PCa diagnosis, compared to patients with aggressive PCa, which may have contributed to the early detection of PCa.

Joint associations between established genetic susceptibility loci, pesticide exposures, and risk of prostate cancer

More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06–1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09–2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.

Defining aggressive prostate cancer: a geospatial perspective

BackgroundSpatial analysis can identify communities where men are at risk for aggressive prostate cancer (PCan) and need intervention. However, there are several definitions for aggressive PCan. In this study, we evaluate geospatial patterns of 3 different aggressive PCan definitions in relation to PCan-specific mortality and provide methodologic and practical insights into how each definition may affect intervention targets.MethodsUsing the Pennsylvania State Cancer Registry data (2005–2015), we used 3 definitions to assign “aggressive” status to patients diagnosed with PCan. Definition one (D1, recently recommended as the primary definition, given high correlation with PCan death) was based on staging criteria T4/N1/M1 or Gleason score ≥ 8. Definition two (D2, most frequently-used definition in geospatial studies) included distant SEER summary stage. Definition three (D3) included Gleason score ≥ 7 only. Using Bayesian spatial models, we identified geographic clusters of elevated odds ratios for aggressive PCan (binomial model) for each definition and compared overlap between those clusters to clusters of elevated hazard ratios for PCan-specific mortality (Cox regression).ResultsThe number of “aggressive” PCan cases varied by definition, and influenced quantity, location, and extent/size of geographic clusters in binomial models. While spatial patterns overlapped across all three definitions, using D2 in binomial models provided results most akin to PCan-specific mortality clusters as identified through Cox regression. This approach resulted in fewer clusters for targeted intervention and less sensitive to missing data compared to definitions that rely on clinical TNM staging.ConclusionsUsing D2, based on distant SEER summary stage, in future research may facilitate consistency and allow for standardized comparison across geospatial studies.

Genetic predisposition to metabolically unfavourable adiposity and prostate cancer risk: A Mendelian randomization analysis.

The associations of adiposity with aggressive prostate cancer risk are unclear. Using two-sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer. We examined the association of these genetically predicted adiposity-related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases). In inverse-variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61-1.19), 0.80 (0.53-1.23) and 0.97 (0.88-1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer. We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies.

Abstract A020: Unraveling the role of ANO7 in prostate cancer metabolism

Abstract Prostate cancer (PCa), the most common male cancer worldwide, causes about 10% of cancer related deaths in Europe. It has a wide spectrum of clinical behavior that ranges from decades of indolence to rapid metastatic progression and lethality. However, the molecular mechanisms involved in aggressive PCa progression are still poorly understood. We have previously linked single-nucleotide polymorphisms in the anoctamin 7 (ANO7) gene to the risk of aggressive prostate cancer and shown that carriers of a rs77559646 variant have improved treatment response to docetaxel. The expression of ANO7 is lost when prostate cancer progresses and is completely lacking in prostate cancer metastases. ANO7 is a prostate specific gene and is highly expressed in the luminal cells of the human prostate. ANO7 belongs to a family of calcium-activated chloride channels and select members of the anoctamin family have phospholipid scramblase activity. Whether ANO7 has any of these capabilities is unclear. To uncover the cellular functions of ANO7 has proven challenging because the expression of ANO7 at protein level is either minimal or nonexistent in all commercially available cell lines. To overcome this and to study the cellular functions of ANO7, we have generated stable prostate cell lines overexpressing ANO7 using lentiviral transduction. The characterization of the RWPE-1 cells overexpressing ANO7 showed that the viability and proliferation was increased both in 2D and 3D. To gain information into what pathways ANO7 is affecting, we performed RNA-sequencing and pathway analysis. Interestingly, we found enrichment of mitochondrial genes participating in oxidative phosphorylation in cells overexpressing ANO7. The genes expressed from the mitochondrial genome were upregulated and the nuclear genes encoding for proteins involved in mitochondrial functions were mostly downregulated. This suggests that the mitochondrial metabolism has changed. We assessed the mitochondrial function by measuring the oxidative phosphorylation capability of the cells and showed that the maximal respiratory capacity of ANO7 overexpressing cells is indeed reduced compared to control cells. We also analyzed which of the three major mitochondrial fuels (glucose, glutamine and fatty acids) are not used as efficiently for oxidative phosphorylation in ANO7 overexpressing cells. The result proves that ANO7 cells are not utilizing glucose as effectively as control cells as there were no differences in maximal respiratory capacity when we treated the cells with the UK5099 inhibitor, which inhibits pyruvate import to mitochondria. Furthermore, preliminary results from the glycolysis stress assay indicates that glycolysis is increased in ANO7 overexpressing cells. In addition, electron microscopy study suggests that ANO7 overexpressing cells have less cristae compared to control. This study shows for the first time that ANO7 rewires prostate mitochondrial functions and thus cellular metabolism. Citation Format: Nasrin Sultana, Christoffer Lof, Neha Goel, Johanna Schleutker. Unraveling the role of ANO7 in prostate cancer metabolism [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A020.

Total-, LDL-, and HDL-cholesterol, apolipoproteins, and triglycerides with risk of total and fatal prostate cancer in Black and White men in the ARIC study.

Cholesterol reduction is considered a mechanism through which cholesterol-lowering drugs including statins are associated with a reduced aggressive prostate cancer risk. While prior cohort studies found positive associations between total cholesterol and more advanced stage and grade in White men, whether associations for total cholesterol, low (LDL)- and high (HDL)-density lipoprotein cholesterol, apolipoprotein B (LDL particle) and A1 (HDL particle), and triglycerides are similar for fatal prostate cancer and in Black men, who experience a disproportionate burden of total and fatal prostate cancer, is unknown. We conducted a prospective study of 1553 Black and 5071 White cancer-free men attending visit 1 (1987-1989) of the Atherosclerosis Risk in Communities Study. A total of 885 incident prostate cancer cases were ascertained through 2015, and 128 prostate cancer deaths through 2018. We estimated multivariable-adjusted hazard ratios (HRs) of total and fatal prostate cancer per 1-standard deviation increments and for tertiles (T1-T3) of time-updated lipid biomarkers overall and in Black and White men. Greater total cholesterol concentration (HR per-1 SD = 1.25; 95% CI = 1.00-1.58) and LDL cholesterol (HR per-1 SD = 1.26; 95% CI = 0.99-1.60) were associated with higher fatal prostate cancer risk in White men only. Apolipoprotein B was nonlinearly associated with fatal prostate cancer overall (T2 vs. T1: HR = 1.66; 95% CI = 1.05-2.64) and in Black men (HR = 3.59; 95% CI = 1.53-8.40) but not White men (HR = 1.13; 95% CI = 0.65-1.97). Tests for interaction by race were not statistically significant. These findings may improve the understanding of lipid metabolism in prostate carcinogenesis by disease aggressiveness, and by race while emphasizing the importance of cholesterol control.

MP17-10 DEVELOPMENT AND UTILIZATION OF AN AT HOME URINE EXOSOME BIOMARKER COLLECTION TEST KIT TO SUPPORT UROLOGIC TELEHEALTH

You have accessJournal of UrologyCME1 Apr 2023MP17-10 DEVELOPMENT AND UTILIZATION OF AN AT HOME URINE EXOSOME BIOMARKER COLLECTION TEST KIT TO SUPPORT UROLOGIC TELEHEALTH Ali Kasraeian, David Albala, Grannum Sant, Judd Moul, Liam Hurley, Sanoj Punnen, Jason Alter, and Ronald Tutrone Ali KasraeianAli Kasraeian More articles by this author , David AlbalaDavid Albala More articles by this author , Grannum SantGrannum Sant More articles by this author , Judd MoulJudd Moul More articles by this author , Liam HurleyLiam Hurley More articles by this author , Sanoj PunnenSanoj Punnen More articles by this author , Jason AlterJason Alter More articles by this author , and Ronald TutroneRonald Tutrone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003237.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: COVID-19 led to paradigm shifts in telemedicine due to patient’s fear of office visits and travel avoidance. With widespread cancellation of office visits and reduction of diagnostic biopsy procedures in men with elevated PSAs, the need for a non-invasive/non-DRE At Home Collection Kit for assessing risk of aggressive prostate cancer and to prioritize biopsy procedures became apparent. We adapted the existing ExoDx Prostate (EPI) office liquid biomarker kit into an At Home Collection Kit physician/patient shared decisions for prostate biopsy. METHODS: A 2-stage program for an At Home Collection Testing Kit program for the ExoDx Test was initiated in April 2020 at the onset of the COVID-19 pandemic. The Phase 1 Pilot study (100 patients, 6 sites) was completed in June 2020. Based on the findings in the pilot, the program was streamlined based on feedback from physicians, patients, and office mangers before making it available in Phase 2 to all urologists in the US. The utilization of the At Home Collection Kits have been measured. RESULTS: Extensive feedback from the pilot program led to improvements and streamlining before the Phase 2 rollout. As of October 31st, 2022, >30% of all the ExoDx Prostate Tests are At Home Collection Kits. EPI Score distributions are identical (mean 28.4 and 29.7), (median 23.0 and 24.7) in home or clinic sample collection respectively (Figure 1). CONCLUSIONS: The COVID-19 pandemic accelerated major shifts to telehealth and increased use of At Home Testing. The ExoDx Prostate (EPI) At Home Collection Kit was successfully developed and employed to help men (>50 years old) with elevated PSAs (2 – 10 ng/ml) considering initial or repeat diagnostic biopsy but with pandemic-related fears of visiting offices/hospitals or wanting to avoid long distance travel from rural areas. As COVID becomes manageable and clinical practices have opened, some pandemic-adopted approaches remain relevant: the ExoDx™ Prostate, (EPI) At Home Collection Kit is one such approach. Source of Funding: Exosome Diagnostics, a Bio-Techne Brand, Waltham, MA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e216 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ali Kasraeian More articles by this author David Albala More articles by this author Grannum Sant More articles by this author Judd Moul More articles by this author Liam Hurley More articles by this author Sanoj Punnen More articles by this author Jason Alter More articles by this author Ronald Tutrone More articles by this author Expand All Advertisement PDF downloadLoading ...

MP17-08 CLINICAL VALIDATION OF A NOVEL SIX-GENE RISK-STRATIFICATION SIGNATURE TO SUPPORT TREATMENT DECISIONS FOR MEN DIAGNOSED WITH PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023MP17-08 CLINICAL VALIDATION OF A NOVEL SIX-GENE RISK-STRATIFICATION SIGNATURE TO SUPPORT TREATMENT DECISIONS FOR MEN DIAGNOSED WITH PROSTATE CANCER Agnieszka Krzyzanowska, Stephen Barron, Debra F. Higgins, Tony Loughman, Katherine M. Sheehan, Angel Chan-Ju Wang, Bozena Fender, Leah M. McGuire, David Galvin, Amanda O'Neil, Joanna Fay, Anthony O'Grady, Desmond O'Leary, R. William. G. Watson, Anders Bjartell, and William M. Gallagher Agnieszka KrzyzanowskaAgnieszka Krzyzanowska More articles by this author , Stephen BarronStephen Barron More articles by this author , Debra F. HigginsDebra F. Higgins More articles by this author , Tony LoughmanTony Loughman More articles by this author , Katherine M. SheehanKatherine M. Sheehan More articles by this author , Angel Chan-Ju WangAngel Chan-Ju Wang More articles by this author , Bozena FenderBozena Fender More articles by this author , Leah M. McGuireLeah M. McGuire More articles by this author , David GalvinDavid Galvin More articles by this author , Amanda O'NeilAmanda O'Neil More articles by this author , Joanna FayJoanna Fay More articles by this author , Anthony O'GradyAnthony O'Grady More articles by this author , Desmond O'LearyDesmond O'Leary More articles by this author , R. William. G. WatsonR. William. G. Watson More articles by this author , Anders BjartellAnders Bjartell More articles by this author , and William M. GallagherWilliam M. Gallagher More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003237.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is diagnosed in over 1.2 million men worldwide annually. Most men have indolent PCa and can safely defer treatment with active surveillance. However, many men are commonly treated with surgery or radiation therapy which are associated with reduced quality of life. Clinicians are increasingly using molecular information to further understand a patient’s risk of aggressive PCa, and while these signatures have shown promise, there remains a significant opportunity for improving prognostic capacity. METHODS: Expression of a novel six-gene signature was measured by RT-qPCR in prostate samples from an Irish cohort of men diagnosed with PCa and treated with radical prostatectomy (RP) (PCRC, n=426). Cross-validated logistic regression identified a six-gene molecular risk score (MRS) with strong prognostic performance to predict aggressive PCa. The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score to create a molecular plus clinical risk score (MCRS). The MRS and MCRS were clinically validated in an independent Swedish cohort of men diagnosed with PCa and treated by RP (UPCA, n=203 RP and n=100 biopsy samples). RESULTS: We identified a six-gene signature, four prognostic and two reference genes, with improved prognostic value over clinical features. In the clinical biopsy validation study, the AUC of the signature for AP was 0.72 (MRS) and 0.82 (MCRS) versus 0.72 (EAU) and 0.82 (CAPRA), and for high primary Gleason was 0.75 (MRS) and 0.85 (MCRS) versus 0.77 (EAU) and 0.83 (CAPRA). The C index for BCR was 0.62 (MRS) and 0.74 (MCRS) versus 0.65 (EAU) and 0.73 (CAPRA). In bivariable analysis, the six-gene signature added statistically significant (p<0.001) prognostic value to EAU and CAPRA. In the RP clinical validation study, the C index for BCR was 0.74 (MRS) and 0.83 (MCRS) versus 0.69 (EAU) and 0.77 (CAPRA). In bivariable analysis, the six-gene signature added statistically significant (p<0.0001) prognostic value to EAU and CAPRA. CONCLUSIONS: The six-gene molecular prognostic signature has strong performance for AP, high primary Gleason and BCR in independent clinical validation studies when tested on prostate biopsy or RP tissue. MCRS provides improved prognostic stratification and can inform optimal patient management post-diagnosis and post-treatment. Source of Funding: Support is acknowledged from the Swedish Cancer Society, the Swedish Scientific Council and Government Funding of Clinical Research within the Swedish National Health Service (ALF), the Irish Cancer Society, and OncoAssure Ltd © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e215 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Agnieszka Krzyzanowska More articles by this author Stephen Barron More articles by this author Debra F. Higgins More articles by this author Tony Loughman More articles by this author Katherine M. Sheehan More articles by this author Angel Chan-Ju Wang More articles by this author Bozena Fender More articles by this author Leah M. McGuire More articles by this author David Galvin More articles by this author Amanda O'Neil More articles by this author Joanna Fay More articles by this author Anthony O'Grady More articles by this author Desmond O'Leary More articles by this author R. William. G. Watson More articles by this author Anders Bjartell More articles by this author William M. Gallagher More articles by this author Expand All Advertisement PDF downloadLoading ...

MP44-13 GENETIC RISK ASSESSMENT OF LETHAL PROSTATE CANCER USING BENIGN PROSTATIC HYPERPLASIA OR PROSTATE VOLUME-RELATED POLYGENIC RISK SCORE AND HEREDITARY CANCER SUSCEPTIBILITY GENES

You have accessJournal of UrologyCME1 Apr 2023MP44-13 GENETIC RISK ASSESSMENT OF LETHAL PROSTATE CANCER USING BENIGN PROSTATIC HYPERPLASIA OR PROSTATE VOLUME-RELATED POLYGENIC RISK SCORE AND HEREDITARY CANCER SUSCEPTIBILITY GENES Xiaohao Ruan, Da Huang, Jingyi Huang, Danfeng Xu, Shanghai, People's Republic of China, James Tsu, Rong Na, Hong Kong, and People's Republic Of China Xiaohao RuanXiaohao Ruan More articles by this author , Da HuangDa Huang More articles by this author , Jingyi HuangJingyi Huang More articles by this author , Danfeng XuDanfeng Xu More articles by this author , Shanghai Shanghai More articles by this author , People's Republic of ChinaPeople's Republic of China More articles by this author , James TsuJames Tsu More articles by this author , Rong NaRong Na More articles by this author , Hong KongHong Kong More articles by this author , and People's Republic Of ChinaPeople's Republic Of China More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003290.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Genetic risk of aggressive prostate cancer (PCa) is hard to be assessed due to the lack of aggressiveness-related single-nucleotide polymorphisms (SNPs). Prostate volume (PV) is a potential well-established risk factor for aggressive PCa, we hypothesize that polygenic risk score (PRS) based on benign prostate hyperplasia (BPH) or PV-related SNPs may also predict the risk of aggressive PCa or PCa death. METHODS: A PRS using 27 BPH/PV-associated SNPs, two established PCa risk-related PRS (PRATICAL PRS and PHS) and 10 guideline-recommended hereditary cancer susceptibility genes were evaluated and compared in the population-based UK Biobank cohort. Multivariable logistic regression and Cox regression analyses were applied to evaluate the association with the primary outcome (PCa death), adjusting for age at onset, charlson comorbidity index score and 10 principal components. Survival time after PCa diagnosis and the differences across PRS categories were estimated with restricted mean survival time (RMST). RESULTS: The study included a total of 14,564 males were diagnosed with PCa, of which 959 (8.2%) died of PCa, 1,173 (8.1%) died due to other reasons and 12,193 (83.7%) survived till the latest follow-up in Jan 1st, 2022. The BPH/PV PRS was significantly inversely associated with the incidence of lethal PCa as well as the natural progress in PCa patients (hazard ratio, HR=0.92, 95% confidence interval, 95%CI: 0.85–0.99, p=0.03; HR=0.92, 95%CI: 0.86-0.99, p=0.02, Table). Compared with men at top 25th PRS, PCa patients with bottom 25th PRS would have a 1.40-fold (HR, 95%CI: 1.16-1.69, p=0.001) increased PCa fatal risk and shorter survival time at 0.37 yr (RMST, 95%CI: 0.14-0.61, p=0.002). On the contrary, PRACTICAL PRS and PHS showed poor prognostic value (p>0.05). Importantly, BPH/PV PRS could further distinguish the risk of PCa death in addition to the pathogenic mutations in known genes (ie. BRCA2/PALB2), especially in non-carriers. CONCLUSIONS: BPH/PV PRS and germline pathogenic mutation in BRCA2/PALB2 were significantly associated with PCa death and cancer-specific survival. Source of Funding: This work was in supported by grants from National Natural Science Foundation of China (Grant No. 81972645), Innovative research team of high-level local universities in Shanghai, Shanghai Youth Talent Support Program, intramural grant of The University of Hong Kong to Dr. Rong Na, and Shanghai Sailing Program (22YF1440500) to Dr. Da Huang. All the funders had no role in study design, data collection, data analysis, interpretation, and writing of the report © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e616 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Xiaohao Ruan More articles by this author Da Huang More articles by this author Jingyi Huang More articles by this author Danfeng Xu More articles by this author Shanghai More articles by this author People's Republic of China More articles by this author James Tsu More articles by this author Rong Na More articles by this author Hong Kong More articles by this author People's Republic Of China More articles by this author Expand All Advertisement PDF downloadLoading ...

A prospective nested case-control study of serum concentrations of per- and polyfluoroalkyl substances and aggressive prostate cancer risk

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent organic pollutants detectable in the serum of most U.S. adults. Some studies of highly-exposed individuals have suggested an association between PFAS and prostate cancer, but evidence from population-based studies is limited. We investigated the association between pre-diagnostic serum PFAS concentrations and aggressive prostate cancer risk in a large prospective study. We measured pre-diagnostic serum concentrations of eight PFAS, including perfluorooctanoate (PFOA), for 750 aggressive prostate cancer cases and 750 individually matched controls within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We assessed the reproducibility of PFAS concentrations in serial samples collected up to six years apart among 60 controls using intraclass correlation coefficients (ICCs). Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with prostate cancer, adjusting for other PFAS and potential confounders. Concentrations of most PFAS were consistent (ICC>0.7) across the serial samples over time. We observed an inverse association between PFOA and aggressive prostate cancer (ORcontinuous = 0.79, 95% CI = 0.63, 0.99), but the association was limited to cases diagnosed ≤3 years after blood collection and became statistically non-significant for cases diagnosed with later follow-up (>3 years, ORcontinuous = 0.90, 95% CI = 0.79, 1.03). Other PFAS were not associated with aggressive prostate cancer risk. Although we cannot rule out an increased risk at higher levels, our findings from a population with PFAS serum concentrations comparable to the general population do not support an association with increased risk of aggressive prostate cancer.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

BackgroundGenetic factors play an important role in prostate cancer (PCa) susceptibility. ObjectiveTo discover common genetic variants contributing to the risk of PCa in men of African ancestry. Design, setting, and participantsWe conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. Outcome measurements and statistical analysisCommon genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. Results and limitationsNine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40–60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10–1.38, p = 4.4 × 10–4). ConclusionsThis study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. Patient summaryIn this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Development and clinical validation of a novel biopsy-based six-gene signature to accurately risk-stratify men with early-stage prostate cancer to aid treatment decision making.

374 Background: Prostate cancer (PCa) is diagnosed in over 1.2 million men worldwide annually, making it the second-most common non-cutaneous cancer in men. Most men have indolent PCa and can safely defer treatment with active surveillance. However, many patients are commonly treated with surgery (radical prostatectomy, RP) or radiation therapy, which are associated with a significant reduction in quality of life. Molecular signatures have been developed to assist clinicians in stratifying patients based on their risk of aggressive PCa; while these have shown promise, there remains a significant opportunity for improving prognostic capacity. Methods: A panel of fourteen prognostic genes was identified from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) database. Gene expression was measured by reverse-transcription quantitative polymerase chain reaction in RP samples from an Irish cohort of men diagnosed with PCa and treated with RP (PCRC, n=426). Cross-validated logistic regression analysis identified a six-gene molecular risk score (MRS) with strong prognostic performance to predict aggressive PCa, i.e., adverse pathology (AP) at RP or biochemical recurrence (BCR). The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score to create a molecular plus clinical risk score (MCRS). The MRS and MCRS were clinically validated in biopsy samples from an independent Swedish cohort of men diagnosed with PCa and treated by RP (UPCA, n=100). Results: We identified a six-gene signature, consisting of four prognostic and two reference genes, with improved prognostic value over clinical features. In the clinical biopsy validation study univariable analysis, the AUC of the signature for AP was 0.72 (MRS) and 0.82 (MCRS) versus 0.72 for EAU risk categories and 0.82 for CAPRA. The C-index for BCR was 0.62 (MRS) and 0.74 (MCRS) versus 0.65 for EAU risk categories and 0.73 for CAPRA. Furthermore, in bivariable analysis, the six-gene signature added statistically significant (p &lt; 0.001) prognostic value to EAU risk categories and CAPRA. Conclusions: The six-gene prognostic signature has strong performance for AP and BCR in an independent clinical biopsy validation study. MCRS can provide improved prognostic stratification and inform optimal patient management post-diagnosis.

A phase 2 study of ibrutinib as neoadjuvant therapy in patients with localized prostate cancer.

387 Background: Treatment of localized prostate cancer (PCa) with surgery or radiotherapy remains suboptimal with failure rates of 35-40%. Bruton’s Tyrosine Kinase (BTK) is seen elevated in PCa tissues compared to normal prostate tissue. Malignant B-cell density has been correlated with higher risk of aggressive PCa and mitigating that through the BTK has been proposed in mouse models. Ibrutinib is a potent BTK inhibitor which targets B-cell signaling pathways, has an established safety profile, and has been shown to inhibit in vivo prostate tumor growth pre-clinically. Therefore, we hypothesized that ibrutinib will augment anti-tumor immune responses through inhibiting tumor-intrinsic growth via blocking BTK B-cell signaling pathways, while also inducing favorable T-cell profiles in localized PCa. Methods: We performed a neoadjuvant clinical trial (NCT02643667) studying ibrutinib in PCa. Eligible patients had localized PCa with no prior treatment, and deemed suitable for undergoing a radical prostatectomy. Patients received 840mg/day oral ibrutinib for 28 days followed by a radical prostatectomy 7-12 days later. Patients were assessed 4 weeks after surgery. The primary objectives are to assess safety of ibrutinib and characterize B and T cell infiltration. Correlative pre- and post- treatment tissue and blood samples were collected; BTK and PD-L1 expression in tumor and immune-infiltrating immune cells will be examined, and BCR and TCR clonality and diversity will be evaluated. Results: 22 patients were registered and underwent treatment to date. 4 patients had early termination of ibrutinib treatment with 3 due to adverse effects and 1 due to discovery of surgically unresectable disease. A total of 21 of 22 patients received radical prostatectomies. There were no intra-operative complications attributed to ibrutinib. The treatment was generally well tolerated with 7.1% grade 3 treatment related adverse effects. 2% experienced a grade 4 treatment adverse effects of hepatic dysfunction. The most common grade 1-2 adverse effects were diarrhea (8.2%), fatigue (7.1%), and anemia (6.1%). The median follow-up time was 23.9 months. Median overall survival and median failure free survival have not been reached and the two-year milestone is 100%. Sample collection is complete and immune correlative analyses are ongoing. Safety/tolerability, clinical outcomes, and preliminary correlative data will be reported. Conclusions: This is the first clinical trial of ibrutinib in PCa, and lays the foundation for larger future studies. Clinical trial information: NCT02643667 .

Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants.

The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels.