Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation, in part through modulation of epigenetic aging.

Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as tumor grade. To interrogate the evolutionary origins of prostate cancer heterogeneity, we analyzed 666 prostate tumor whole genomes. We identified a compendium of 223 recurrently mutated driver regions, most influencing downstream mutational processes and gene expression. We identified and validated individual germline variants that predispose tumors to acquire specific somatic driver mutations: these explain heterogeneity in disease presentation and ancestry differences. High-grade tumors have a superset of the drivers in lower-grade tumors, including increased frequency of BRCA2 and MYC mutations. Grade-associated driver mutations occur early in tumor evolution, and their earlier occurrence strongly predicts cancer relapse and metastasis. Our data suggest high- and low-grade prostate tumors both emerge from a common premalignant field, influenced by germline genomic context and stochastic mutation timing.Significance: This study uncovered 223 recurrently mutated driver regions using the largest cohort of prostate tumors to date. It reveals associations between germline SNPs, somatic drivers, and tumor aggression, offering significant insights into how prostate tumor evolution is shaped by germline factors and the timing of somatic mutations.

PURPOSE:With the availability of prostate-specific membrane antigen positron emission tomography scans, it is controversial whether pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP) is still the most reliable and accurate staging modality for lymph node assessment. Furthermore, the oncological benefit of PLND remains unclear. The aim of this study was to assess whether omitting PLND in patients undergoing RP for prostate cancer (PCa) is associated with the risk of tumor recurrence and progression to metastasis. MATERIALS AND METHODS:In this longitudinal multicenter cohort study, we reviewed data of 2346 consecutive patients with PCa who underwent RP with (n = 1650) and without (n = 696) extended PLND between January 1996 and December 2021. Recurrence-free survival and metastasis-free survival (MFS) were analyzed as a time-to-event outcome using Kaplan-Meier analyses with log-rank tests. To assess the effect of PLND, we created multivariable Cox proportional hazards models adjusting for relevant clinical and demographic characteristics. RESULTS:Median follow-up was 44 months. There was no difference in recurrence-free survival between men who had a PLND and those who did not (HR, 1.07, 95% CI, 0.87-1.32, P = .52). Patients with D'Amico high-risk disease (PSA >20 µg/L and/or International Society of Urological Pathology grade group ≥4) demonstrated a significantly prolonged MFS if they underwent PLND (HR, 0.57, 95% CI, 0.36-0.91, P = .02). PLND also improved MFS in patients with intermediate-risk disease (HR, 0.48, 95% CI, 0.25-0.90, P = .023). Further significant prognostic variables for MFS on multivariable Cox proportional hazards regression were PSA, International Society of Urological Pathology grade group, and pathological T-stage. CONCLUSIONS:PLND improves MFS in patients with D'Amico intermediate-risk and high-risk PCa and may therefore be considered in men undergoing RP.

INTRODUCTION:Brain-derived tau (BD-tau) measures tau specifically from brain-derived sources and can differentiate Alzheimer's disease (AD) from other diseases. This study investigated BD-tau as a potential biomarker of treatment effect. METHODS:BD-tau and phosphorylated tau-217 (p-tau217) levels were measured after treatment with an anti-tau drug in AD and behavioral variant frontotemporal dementia (bvFTD) clinical trials, and the association with total tau (t-tau), p-tau181, and amyloid beta 42 (Aβ42) was examined. RESULTS:Cerebrospinal fluid (CSF) BD-tau decreased after treatment in the AD cohort; however, no change was seen in bvFTD or p-tau217 in either cohort. CSF t-tau and p-tau181 correlated with BD-tau in AD (r = 0.9113 and 0.7746, p < 0.0001) and bvFTD (r = 1.0 and r = 0.79, p < 0.05). CSF BD-tau did not correlate with serum or plasma BD-tau in bvFTD. DISCUSSION:CSF BD-tau shows potential as a biomarker of treatment effect in AD but not bvFTD. Further research is needed to investigate this effect in blood-based samples and in other neurodegenerative diseases. Trial registration: ACTRN12611001200976, ACTRN12617001218381. Highlights:Cerebrospinal fluid (CSF) brain-derived tau (BD-tau) levels decreased with sodium selenate treatment in patients with Alzheimer's disease (AD).CSF BD-tau levels did not change with sodium selenate treatment in bvFTD.Baseline CSF BD-tau correlated with CSF total tau (t-tau) and phosphorylated tau-181 (p-tau181) in AD and behavioral variant frontotemporal dementia (bvFTD).Baseline serum and plasma BD-tau levels did not correlate with CSF BD-tau in bvFTD.CSF p-tau217 did not change with sodium selenate treatment in AD or bvFTD.

Cancer progression involves the sequential accumulation of genetic alterations that cumulatively shape the tumour phenotype. In prostate cancer, tumours can follow divergent evolutionary trajectories that lead to distinct subtypes, but the causes of this divergence remain unclear. While causal inference could elucidate the factors involved, conventional methods are unsuitable due to the possibility of unobserved confounders and ambiguity in the direction of causality. Here, we propose a method that circumvents these issues and apply it to genomic data from 829 prostate cancer patients. We identify several genetic alterations that drive divergence as well as others that prevent this transition, locking tumours into one trajectory. Further analysis reveals that these genetic alterations may cause each other, implying a positive-feedback loop that accelerates divergence. Our findings provide insights into how cancer subtypes emerge and offer a foundation for genomic surveillance strategies aimed at monitoring the progression of prostate cancer.

Greater personalization of cancer medicine continues to shape therapy development and patient selection accordingly. The treatment of prostate cancer has evolved considerably since the discovery of androgen deprivation therapy. The comprehensive profiling of the prostate cancer genome has mapped the targetable molecular landscape of the disease and identified opportunities for the implementation of novel and combination therapies. In this review, we provide an overview of the molecular biology of prostate cancer and tools developed to aid prognostication and prediction of therapy benefit. Modern treatment of advanced prostate cancer is reviewed as a paradigm of increasing precision-informed approach to patient care, and must be considered on a global scale with respect to the state of science and care delivery.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

BACKGROUND:Immunotherapy has demonstrated limited activity in prostate cancer to date. This likely reflects an immune suppressive tumor microenvironment (TME), with previous studies suggesting low PD-L1 expression and a sparse immune cell infiltrate. We aimed to further characterise the immune TME in primary prostate cancer and correlate immune subset densities with clinical outcomes. METHODS:Two distinct cohorts of patients treated with radical prostatectomy were identified, based on the development of biochemical recurrence (BCR), one subgroup with high International Society of Urological Pathologists (ISUP) grade group, recurrent disease and a second with low grade, non-recurrent disease. A prostate immunohistochemical (IHC) antibody cocktail was used to differentiate tumor and peritumoral benign tissue. Specific CD8+, CD4+, FoxP3+, CD20+ and CD68+ cell subsets were identified using IHC staining of consecutive slides. PD-L1 and CD8/PD-L1 dual staining were also performed. Cell subset densities were quantified within tumor and peritumoral regions. We used descriptive statistics to report cell subset densities and T-tests to compare groups by age, grade and the development of BCR. Univariable and multivariable logistic regression were used to analyse risk factors for BCR and the development of metastatic disease. RESULTS:A total of 175 patients were included, with a median age of 63 years and median pre-operative PSA of 8.2ng/ml. BCR occurred in 115 patients (66%) and 56 (32%) developed metastatic disease. CD68+ cells were the most abundant (median 648.8/mm2 intratumoral, 247.6/mm2 peritumoral), while PD-L1+ and PD-L1/CD8+ cell density was low overall (PD-L1+ median 162.4/mm2 intratumoral, 141.7/mm2 peritumoral; PD-L1/CD8+ (median 5.52/mm2 intratumoral, 3.41/mm2 peritumoral). Overall, grade group and T-stage were independently associated with BCR and metastatic disease. Higher density of peritumoral PD-L1+ cells was an independent risk factor for BCR (OR 5.33, 95%CI 1.31-21.61, p = 0.019).Although higher densities of CD8+ and CD4+ cells were observed in higher grade group 3-5 tumors, these were not associated with the development of BCR or metastasis. CONCLUSIONS:In our cohort of prostate cancer patients who underwent radical prostatectomy, higher grade group and T-stage were independent predictors of BCR and metastasis. Despite higher grade group being associated with higher CD8+ cell density, PD-L1+ and PD-L1/CD8+ cell densities were low overall, suggesting lower T cell receptor recognition of tumor antigens. Further understanding of this phenomenon would influence development of future immunotherapeutic strategies in prostate cancer.

Brain metastases pose a formidable challenge in oncology. While certain cancers like lung, breast, and melanoma are known to commonly metastasize to the brain, comprehensive studies spanning cancer types that uncommonly or rarely spread to the brain are limited. This study employs data from the Surveillance, Epidemiology, and End Results (SEER) database to examine incidence, prevalence, and clinical characteristics of brain metastases across nearly all cancers. We conducted a detailed review of SEER-derived patient data, focusing on brain metastases. Statistical analyses, including Kaplan-Meier plots and Gehan-Breslow-Wilcoxon tests, were utilized to compare survival rates and clinical features between cancer types, integrating additional features such as staging. (i.e., T and N grades) Lung cancer is the most common primary source of brain metastases. (~80.5% of cases) Furthermore, cancers traditionally associated with brain metastasis—lung, melanoma, breast, renal, and colorectal—comprise 93% of all brain metastasis cases in SEER. Further analysis showed that brain metastasis patients had worse five-year survival than patients who developed metastasis elsewhere, and those patients with high grade glioma. Recent advancements in treatment have improved survival rates for patients diagnosed with brain metastases between 2015-2019, compared to those diagnosed during 2010-2014. This improvement appears to be driven disproportionately by cancers commonly associated with brain metastasis. Moreover, it can be revealed that there are notable differences in T/N grades and clinical features of the cancers that uncommonly or rarely spread to the brain, compared to those that commonly do so. This study suggests that the pattern of brain metastasis formation may differ between those primary malignancies that commonly, and uncommonly or rarely spread metastatically, highlighting the deficit of our clinical and scientific understanding of this pernicious cancer phenomenon, as well as the need to develop novel, innovative treatment paradigms for patients with brain metastases.

Abstract INTRODUCTION Brain metastases pose a significant and growing challenge in clinical practice, yet the molecular variants of this tumor type has not previously been examined comprehensively across multiple cancer types. In particular, there has been limited focus on contrasting the genetic profiles of common brain metastases originating from primary sites like lung, breast, melanoma, colorectal, and renal cancers, with those arising infrequently such as prostate and others. METHODS We have prospectively collected over 125 fresh frozen brain metastases and matching germline reference samples from 14 different primary tumor types and to date have performed WGS, RNA-Seq and Epic 850k methylation profiling on 60 of these samples spanning both common and rare brain metastases. We have employed machine learning algorithms, network analysis techniques, and integrative bioinformatics pipelines to extract meaningful insights into the biological underpinnings of brain metastasis formation. RESULTS We conducted an in-depth investigation into the genomic, transcriptomic, and epigenomic profiles of brain metastases, spanning both common and rare types. By merging these diverse datasets, we identified distinct molecular modifications linked to brain metastases with low incidence rates compared to those more frequently observed. Notably, we observed heightened alterations in the regulation of Golgi dynamics, sensing of lipid species, chromatin remodeling factors, and cytoskeletal remodeling in rare brain metastases. These changes likely influence cell migration and invasion dynamics, elucidating the potential for unique characteristics of less common brain metastasis types. CONCLUSIONS This research indicates that the molecular mechanisms driving the formation of brain metastases may vary depending on whether the primary malignancy frequently or infrequently spreads to the brain. Studies such as these, will aid in eventually driving innovations in precision oncology and ultimately improving patient outcomes.

PDF file - 6KB, Table S1. List of genes used for geneset enrichment analysis.

Lymphovascular invasion, whereby tumour cells or cell clusters are identified in the lumen of lymphatic or blood vessels, is thought to be an essential step in disease dissemination. It has been established as an independent negative prognostic indicator in a range of cancers. We therefore aimed to assess the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes. We performed a multicentre, retrospective cohort study of 3495 men who underwent radical prostatectomy for localised prostate cancer. Only men with negative preoperative staging were included. We assessed the relationship between lymphovascular invasion and adverse pathological features using multivariable logistic regression models. Kaplan–Meier curves and Cox proportional hazard models were created to evaluate the impact of lymphovascular invasion on oncological outcomes. Lymphovascular invasion was identified in 19% (n = 653) of men undergoing prostatectomy. There was an increased incidence of lymphovascular invasion-positive disease in men with high International Society of Urological Pathology (ISUP) grade and non-organ-confined disease (p < 0.01). The presence of lymphovascular invasion significantly increased the likelihood of pathological node-positive disease on multivariable logistic regression analysis (OR 15, 95%CI 9.7–23.6). The presence of lymphovascular invasion at radical prostatectomy significantly increased the risk of biochemical recurrence (HR 2.0, 95%CI 1.6–2.4). Furthermore, lymphovascular invasion significantly increased the risk of metastasis in the whole cohort (HR 2.2, 95%CI 1.6–3.0). The same relationship was seen across D’Amico risk groups. The presence of lymphovascular invasion at the time of radical prostatectomy is associated with aggressive prostate cancer disease features and is an indicator of poor oncological prognosis.

Inherited genetic variation profoundly influences cancer risk and outcome. While the impact of germline single nucleotide polymorphisms has been well-studied in several cancer types, the effects of germline structural variants (gSVs) on cancer biology and clinical outcomes is largely unknown. From our cohort of 300 men with localized, intermediate risk prostate cancer, we identified 6,003 gSVs present in at least 3% of patients; 48 were associated with recurrent somatic alterations or clinical outcome. Of these, approximately 50% were associated with expression of nearby genes or intersected with exons or regulatory regions. Using external cohorts, we validated three gSVs that were strongly associated with poor clinical outcomes, including an inversion at chr14q24.1 present in ~20% of patients. Notably, a strong synergistic effect on outcome was observed in patients with somatic TP53 alterations or high genomic instability, defining a new aggressive prostate cancer subtype with chr14INV as a novel, recurrent biomarker. Citation Format: Nicholas K. Wang, Alexandre Rouette, Kathleen E. Houlahan, Takafumi N. Yamaguchi, Julie Livingstone, Chol-Hee Jung, Peter Georgeson, Michael Fraser, Yu-Jia Shiah, Cindy Q. Yao, Vincent Huang, Natalie S. Fox, Natalie Kurganovs, Katayoon Kasaian, Veronica Y. Sabelnykova, Jay Jayalath, Kenneth Weke, Helen Zhu, Theodorus van der Kwast, Tony Papenfuss, Housheng H. He, Niall M. Corcoran, Robert G. Bristow, Alexandre R. Zlotta, Christopher Hovens, Paul C. Boutros. Germline structural variants shape prostate cancer clinical and molecular evolution. [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 4305.

Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

INTRODUCTION:Epilepsy is one of the most common neurological conditions worldwide. Despite many antiseizure medications (ASMs) being available, up to one-third of patients do not achieve seizure control. Preclinical studies have shown treatment with sodium selenate to have a disease-modifying effect in a rat model of chronic temporal lobe epilepsy (TLE).AIM:This randomised placebo-controlled trial aims to evaluate the antiseizure and disease-modifying effects of sodium selenate in people with drug-resistant TLE.METHODS:This will be a randomised placebo-controlled trial of sodium selenate. One hundred and twenty-four adults with drug-resistant TLE and ≥4 countable seizures/month will be recruited. Outcomes of interest will be measured at baseline, week 26 and week 52 and include an 8-week seizure diary, 24-hour electroencephalogram and cognitive, neuropsychiatric and quality of life measures. Participants will then be randomised to receive a sustained release formulation of sodium selenate (initially 10 mg three times a day, increasing to 15 mg three times a day at week 4 if tolerated) or a matching placebo for 26 weeks.OUTCOMES:The primary outcome will be a consumer codesigned epilepsy-Desirability of Outcome Rank (DOOR), combining change in seizure frequency, adverse events, quality of life and ASM burden measures into a single outcome measure, compared between treatment arms over the whole 52-week period. Secondary outcomes will compare baseline measures to week 26 (antiseizure) and week 52 (disease modification). Exploratory measures will include biomarkers of treatment response.ETHICS AND DISSEMINATION:The study has been approved by the lead site, Alfred Hospital Ethics Committee (594/20). Each participant will provide written informed consent prior to any trial procedures. The results of the study will be presented at national and international conferences, published in peer-reviewed journals and disseminated through consumer organisations.CONCLUSION:This study will be the first disease-modification randomised controlled trial in patients with drug-resistant TLE.TRIAL REGISTRATION NUMBER:ANZCTR; ACTRN12623000446662.

PDF file - 148KB, Figure S1. Mean + SEM concentration of indicated steroids measured in the conditioned media derived from BPH, hormone nave CaP or HRPC when cultured in the presence of cholesterol, progesterone, DHEA or testosterone at a concentration of 10 ng/ml for 96 hr.

Introduction:Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open-label Phase 1b study of sodium selenate as a disease-modifying treatment for behavioral variant frontotemporal dementia (bvFTD).Methods:Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52.Results:Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t-tau, p-tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study-one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12-month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction).Conclusion:Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized-controlled trials are warranted to investigate potential efficacy.

Background: Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting. Methods: We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing. Results: Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation. Conclusions: Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naive prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting.

Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies; however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain.