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BACKGROUND: Active surveillance (AS) is recommended for low-risk and some intermediate-risk prostate cancer. Uptake and practice of AS vary significantly across different settings, as does the experience of surveillance-from which tests are offered, and to the levels of psychological support. OBJECTIVE: To explore the current best practice and determine the most important research priorities in AS for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A formal consensus process was followed, with an international expert panel of purposively sampled participants across a range of health care professionals and researchers, and those with lived experience of prostate cancer. Statements regarding the practice of AS and potential research priorities spanning the patient journey from surveillance to initiating treatment were developed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Panel members scored each statement on a Likert scale. The group median score and measure of consensus were presented to participants prior to discussion and rescoring at panel meetings. Current best practice and future research priorities were identified, agreed upon, and finally ranked by panel members. RESULTS AND LIMITATIONS: There was consensus agreement that best practice includes the use of high-quality magnetic resonance imaging (MRI), which allows digital rectal examination (DRE) to be omitted, that repeat standard biopsy can be omitted when MRI and prostate-specific antigen (PSA) kinetics are stable, and that changes in PSA or DRE should prompt MRI ± biopsy rather than immediate active treatment. The highest ranked research priority was a dynamic, risk-adjusted AS approach, reducing testing for those at the least risk of progression. Improving the tests used in surveillance, ensuring equity of access and experience across different patients and settings, and improving information and communication between and within clinicians and patients were also high priorities. Limitations include the use of a limited number of panel members for practical reasons. CONCLUSIONS: The current best practice in AS includes the use of high-quality MRI to avoid DRE and as the first assessment for changes in PSA, with omission of repeat standard biopsy when PSA and MRI are stable. Development of a robust, dynamic, risk-adapted approach to surveillance is the highest research priority in AS for prostate cancer. PATIENT SUMMARY: A diverse group of experts in active surveillance, including a broad range of health care professionals and researchers and those with lived experience of prostate cancer, agreed that best practice includes the use of high-quality magnetic resonance imaging, which can allow digital rectal examination and some biopsies to be omitted. The highest research priority in active surveillance research was identified as the development of a dynamic, risk-adjusted approach.

Prostate cancer (PCa) is a leading cause of death and partially heritable. Genetic risk prediction might be useful for strategies to reduce PCa mortality through early detection and prevention.To review evidence for genetic risk prediction for PCa.A collaborative literature review was conducted using PubMed and Google Scholar. Search terms included genetic, risk, prediction, and "prostate cancer". Articles addressing screening, early detection, or prevention were prioritized, as were studies involving diverse populations.Rare pathogenic mutations (RPMs), especially in DNA damage repair genes, increase PCa risk. RPMs in BRCA2 are most clearly deleterious, conferring 2-8.6 times higher risk of PCa and a higher risk of aggressive disease. Common genetic variants can be combined into genetic risk scores (GRSs). A high GRS (top 20-25% of the population) confers two to three times higher risk of PCa than average; a very high GRS (top 1-5%) confers six to eight times higher risk. GRSs are not specific for aggressive PCa, possibly due to methodological limitations and/or a field effect of an elevated risk for both low- and high-grade PCa. It is challenging to disentangle genetics from structural racism and social determinants of health to understand PCa racial disparities. GRSs are independently associated with a lethal PCa risk after accounting for family history and race/ancestry. Healthy lifestyle might partially mitigate the risk of lethal PCa.Genetic risk assessment is becoming more common; implementation studies are needed to understand the implications and to avoid exacerbating healthcare disparities. Men with a high genetic risk of PCa can reasonably be encouraged to adhere to a healthy lifestyle.Prostate cancer risk is inherited through rare mutations and through the combination of hundreds of common genetic markers. Some men with a high genetic risk (especially BRCA2 mutations) likely benefit from early screening for prostate cancer. The risk of lethal prostate cancer can be reduced through a healthy lifestyle.

PURPOSE: Compared with conventional external-beam radiation therapy (cEBRT) for patients with breast cancer (BC) and prostate cancer (PC), shorter radiation regimens may be associated with lower treatment noncompletion rates. We assess disparities in receipt of shorter radiation regimens and treatment noncompletion for BC and PC. PATIENTS AND METHODS: The 2004-2017 National Cancer Database was queried for adjuvant cEBRT or hypofractionated EBRT (hEBRT) for nonmetastatic BC; and definitive cEBRT, moderate hypofractionation (mEBRT), or stereotactic body radiotherapy (SBRT) for localized PC. Multivariable logistic regression identified factors associated with treatment noncompletion and receipt of shorter regimens. FINDINGS: We identified 170,386 men with PC (median age [interquartile range], 70 [64-75] years; Black, 17.5%; White, 82.5%) and 306,846 women with BC (61 [52-69] years; Black, 12.3%; White, 87.7%). Among patients who received cEBRT for PC, Black men had higher treatment noncompletion rates compared with White (14.1% v 13.0%; odds ratio [95% CI] 1.07 [1.03 to 1.12]; P < .001). In contrast, treatment noncompletion was not disparate with SBRT (Black 1.6% v White 1.3%; 1.20 [0.72 to 2.00], P = .49) or mEBRT (Black 9.0% v White 7.1%; 1.05 [0.72 to 1.54], P = .79). From 2004 to 2017, SBRT (0.07% to 11.8%; 1.32 [1.31 to 1.33]) and mEBRT (0.35% to 9.1%; 1.27 [1.25 to 1.28]) increased (both P < .001); however, Black men were consistently less likely to receive SBRT (7.4% v White, 8.3%; 0.84 [0.79 to 0.89], P < .001). Among women with BC, there were no racial differences in treatment noncompletion; however, hEBRT was associated with lower treatment noncompletion rates (1.0% v cEBRT 2.3%; 0.39 [0.35 to 0.44], P < .001). Although hEBRT for BC increased (0.8% to 35.6%) between 2004 and 2017, Black women were less likely to receive hEBRT (10.4% v 15.3%; 0.78 [0.75 to 0.81], P < .001). INTERPRETATION: Black patients were consistently less likely to receive hypofractionated radiation for PC or BC, despite evidence suggesting that shorter regimens may lower rates of treatment noncompletion with similar oncologic outcomes.

Black men are disproportionately affected by prostate cancer (PCa), with earlier presentation, more aggressive disease, and higher mortality rates versus White men. Furthermore, Black men have less access to PCa treatment and experience longer delays between diagnosis and treatment. In this review, the authors discuss the factors contributing to racial disparities and present solutions to improve access to care and increase clinical trial participation among Black men with PCa. Racial disparities observed among Black men with PCa are multifaceted, evolving from institutional racism. Cultural factors include generalized mistrust of the health care system, poor physician-patient communication, lack of information on PCa and treatment options, fear of PCa diagnosis, and perceived societal stigma of the disease. In the United States, geographic trends in racial disparities have been observed. Economic factors, e.g., cost of care, recovery time, and cancer debt, play an important role in racial disparities observed in PCa treatment and outcomes. Racial diversity is often lacking in genomic and precision medicine studies. Black men are largely underrepresented in key phase 3 PCa trials and may be less willing to enroll in clinical trials due to lack of awareness, lack of diversity in clinical trial research teams, and bias of health care providers to recommend clinical research. The authors propose solutions to address these factors that include educating clinicians and institutions on the barriers Black men experience, increasing the diversity of health care providers and clinical research teams, and empowering Black men to be involved in their treatment, which are keys to creating equity for Black men with PCa. LAY SUMMARY: Prostate cancer negatively affects Black men more than men of other races. The history of segregation and mistreatment in the health care system may contribute to mistrust among Black men. Outcomes are worse for Black men because they are less likely to be screened or to receive treatment for prostate cancer. Black men also are unlikely to participate in clinical research, making it difficult for investigators to understand how Black men are affected by prostate cancer. Suggestions for addressing these differences include teaching physicians and nurses about the issues Black men experience getting treatment and improving how Black men get information on prostate cancer.

Immune checkpoint blockade (ICB) has shown immense promise for treating patients with various cancer types, but its effectiveness relies on our ability to identify likely responders. Here, we examined the association between mutations in 25 core DNA repair genes and ICB outcomes in 6619 patients across 9 cancer types with advanced disease and MSK-IMPACT tumor sequencing. Notably, we observed that mutations in 7 of the DNA repair genes (ATM, ATR, POLE, ERCC4, NBN, RAD50, PARP1) were significantly associated with improved overall survival in ICB-treated patients (p0.05 for all) and had significant interaction with treatment (p

Currently, Black men in the United States are greater than 1.5 times as likely to be diagnosed with prostate cancer and more than twice as likely to succumb to the disease. While racial disparities in prostate cancer have been well documented, we must analyze these disparities in the correct context. Discussion of these disparities without correctly describing race as a social construct and acknowledging the impact of structural racism is insufficient. This article reviews the disparities seen in screening, treatment, outcomes, and clinical trial participation. We conclude by outlining future steps to help understand and study disparities, as we strive toward equitable outcomes.

To assess publishing trends regarding the contribution of societal systems on health disparities within the urology literature.We performed a bibliometric analysis of the top 15 urology journals for titles and abstracts with the term race or ethnicity between 2000-2021. Articles were graded by the presence of (1) race, (2) disparities secondary to race, or (3) racial disparities secondary to structural biases. Frequencies were tabulated and logistic regression was used to determine odds of disparities publishing.Our query returned 934 articles for review. In 484 (52%) articles, race was mentioned as a demographic/covariate. 110 (12%) abstracts noted a racial health disparity and only 2 articles implicated racism. Rates of more direct language varied significantly by journal and year of publication. Discussion of disparities increased over time, ranging from 0% in 2002 to 25% in 2020 (P-trend.001). Logistic regression demonstrated an 11% annual increase in the likelihood of disparity publishing (OR=1.11, 95%CI=1.08-1.14; P.001).While it is widely acknowledged that race is a determinant of health, often "race" itself is ascribed the risk when societal inequities are largely at fault. Despite the frequent use of race as a key covariate within the urologic literature, health-disparities relating to structural racism are rarely explicitly named. In order to address the systemic biases that underpin these inequities, increased awareness through clear language in publishing is needed.

Supplemental Tables 1-7

Purpose:Carcinomas originate from epithelial tissues, which have apical (luminal) and basal orientations. The degree of luminal versus basal differentiation in cancer has been shown to be biologically important in some carcinomas and impacts treatment response.Experimental Design:Although prior studies have focused on individual cancer types, we used a modified clinical-grade classifier (PAM50) to subtype 8,764 tumors across 22 different carcinomas into luminal A, luminal B, and basal-like tumors.Results:We found that all epithelial tumors demonstrated similar gene expression–based luminal/basal subtypes. As expected, basal-like tumors were associated with increased expression of the basal markers KRT5/6 and KRT14, and luminal-like tumors were associated with increased expression of the luminal markers KRT20. Luminal A tumors consistently had improved outcomes compared with basal across many tumor types, with luminal B tumors falling between the two. Basal tumors had the highest rates of TP53 and RB1 mutations and copy number loss. Luminal breast, cervical, ovarian, and endometrial tumors had increased ESR1 expression, and luminal prostate, breast, cervical, and bladder tumors had increased androgen receptor (AR) expression. Furthermore, luminal B tumors had the highest rates of AR and ESR1 mutations and had increased sensitivity in vitro to bicalutamide and tamoxifen. Luminal B tumors were more sensitive to gemcitabine, and basal tumors were more sensitive to docetaxel.Conclusions:This first pan-carcinoma luminal/basal subtyping across epithelial tumors reveals global similarities across carcinomas in the transcriptome, genome, clinical outcomes, and drug sensitivity, emphasizing the biological and translational importance of these luminal versus basal subtypes.

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Purpose:Rb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting biallelic RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale.Experimental Design:We utilized data from the Cancer Cell Line Encyclopedia (N = 995) to develop the first pan-cancer transcriptomic signature for predicting biallelic RB1 loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (N = 11,007). RBS was then used to assess the clinical relevance of biallelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort.Results:RBS outperformed the leading existing signature for detecting RB1 biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (RB1 biallelic loss) was associated with promoter hypermethylation (P = 0.008) and gene body hypomethylation (P = 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free (P < 0.00001), overall (P = 0.0004), and disease-specific (P < 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer (P = 0.03) and of shorter overall survival in mCRPC (P = 0.004) independently of the number of DNA alterations in RB1.Conclusions:Our study provides the first validated tool to assess RB1 biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption.See related commentary by Choudhury and Beltran, p. 4199

Table S1-3

Supplementary Figures 1-8 with legends

Genes differentially expressed in RB1 loss tumors with two or more RB1 mutations

Purpose:Perineural invasion (PNI) is associated with aggressive tumor behavior, recurrence, and metastasis, and can influence the administration of adjuvant treatment. However, standard histopathologic examination has limited sensitivity in detecting PNI and does not provide insights into its mechanistic underpinnings.Experimental Design:A multivariate Cox regression was performed to validate associations between PNI and survival in 2,029 patients across 12 cancer types. Differential expression and gene set enrichment analysis were used to learn PNI-associated programs. Machine learning models were applied to build a PNI gene expression classifier. A blinded re-review of hematoxylin and eosin (H&E) slides by a board-certified pathologist helped determine whether the classifier could improve occult histopathologic detection of PNI.Results:PNI associated with both poor overall survival [HR, 1.73; 95% confidence interval (CI), 1.27–2.36; P < 0.001] and disease-free survival (HR, 1.79; 95% CI, 1.38–2.32; P < 0.001). Neural-like, prosurvival, and invasive programs were enriched in PNI-positive tumors (Padj < 0.001). Although PNI-associated features likely reflect in part the increased presence of nerves, many differentially expressed genes mapped specifically to malignant cells from single-cell atlases. A PNI gene expression classifier was derived using random forest and evaluated as a tool for occult histopathologic detection. On a blinded H&E re-review of sections initially described as PNI negative, more specimens were reannotated as PNI positive in the high classifier score cohort compared with the low-scoring cohort (P = 0.03, Fisher exact test).Conclusions:This study provides salient biological insights regarding PNI and demonstrates a role for gene expression classifiers to augment detection of histopathologic features.

Supplementary Data Legends

Published manuscripts supporting 23 of the 26 approvals were retrieved (as of March 2020) and the eligibility criteria specifics for each trial were extracted from each manuscript.

Purpose:In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population.Experimental Design:Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation.Results:In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria.Conclusions:Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations.See related commentary by Giantonio, p. 2369

Supplementary Figure S1

Tumor suppressors selected for methylation analysis null model

Supplementary Table 1

PURPOSE: We identified (1) differences in localized prostate cancer (PCa) risk group at presentation and (2) disparities in access to initial treatment for Asian American, Native Hawaiian, and Pacific Islander (AANHPI) men with PCa after controlling for sociodemographic factors. METHODS: We assessed all patients in the National Cancer Database with localized PCa with low-, intermediate-, and high-risk disease who identified as Thai, White, Asian Indian, Chinese, Vietnamese, Korean, Japanese, Filipino, Hawaiian, Pacific Islander, Laotian, Pakistani, Kampuchean, and Hmong. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CI of (1) presenting at progressively higher risk group and (2) receiving treatment or active surveillance with intermediate- or high-risk disease, adjusting for sociodemographic and clinical factors. RESULTS: Among 980,889 men (median age 66 years), all AANHPI subgroups with the exception of Thai (AOR = 0.84 [95% CI, 0.58 to 1.21], P > .05), Asian Indian (AOR = 1.12 [95% CI, 1.00 to 1.25], P > .05), and Pakistani (AOR = 1.34 [95% CI, 0.98 to 1.83], P > .05) men had greater odds of presenting at a progressively higher PCa risk group compared with White patients (Chinese AOR = 1.18 [95% CI, 1.11 to 1.25], P < .001; Japanese AOR = 1.36 [95% CI, 1.26 to 1.47], P < .001; Filipino AOR = 1.37 [95% CI, 1.29 to 1.46], P < .001; Korean AOR = 1.32 [95% CI, 1.18 to 1.48], P < .001; Vietnamese AOR = 1.20 [95% CI, 1.07 to 1.35], P = .002; Laotian AOR = 1.60 [95% CI, 1.08 to 2.36], P = .018; Hmong AOR = 4.07 [95% CI, 1.54 to 10.81], P = .005; Kampuchean AOR = 1.55 [95% CI, 1.03 to 2.34], P = .036; Asian Indian or Pakistani AOR = 1.15 [95% CI, 1.07 to 1.24], P < .001; Native Hawaiians AOR = 1.58 [95% CI, 1.38 to 1.80], P < .001; and Pacific Islanders AOR = 1.58 [95% CI, 1.37 to 1.82], P < .001). Additionally, Japanese Americans (AOR = 1.46 [95% CI, 1.09 to 1.97], P = .013) were more likely to receive treatment compared with White patients. CONCLUSION: Our findings suggest that there are differences in PCa risk group at presentation by race or ethnicity among Asian American, Native Hawaiian, and Pacific Islander subgroups and that there exist disparities in treatment patterns. Although AANHPI are often studied as a homogenous group, heterogeneity upon subgroup disaggregation underscores the importance of further study to assess and address barriers to PCa care.

Contains fulltext : 291600.pdf (Publisher’s version ) (Open Access) BACKGROUND: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management. OBJECTIVE: To present consensus voting results for select questions from APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. RESULTS AND LIMITATIONS: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis. CONCLUSIONS: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions.

PURPOSE: We assessed sociodemographic factors associated with and survival implications of refusal of potentially survival-prolonging locoregional treatment (LT, including radiotherapy and surgery) despite provider recommendation among men with localized prostate adenocarcinoma. METHODS: The National Cancer Database (2004-2015) identified men with TxN0M0 prostate cancer who either received or refused LT despite provider recommendation. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CI of refusing LT, with sociodemographic and clinical covariates. Models were stratified by low-risk and intermediate- or high-risk (IR or HR) disease, with a separate interaction analysis between race and risk group. Multivariable Cox proportional hazard ratios compared overall survival (OS) among men who received versus refused LT. RESULTS: Of 887,839 men (median age 64 years, median follow-up 6.14 years), 2,487 (0.28%) refused LT. Among men with IR or HR disease (n = 651,345), Black and Asian patients were more likely to refuse LT than White patients (0.35% v 0.29% v 0.17%; Black v White AOR, 1.75; 95% CI, 1.52 to 2.01; P < .001; Asian v White AOR, 1.47; 95% CI, 1.05 to 2.06; P = .027, race * risk group interaction P < .001). Later year of diagnosis, community facility type, noninsurance or Medicaid, and older age were also associated with increased odds of LT refusal, overall and when stratifying by risk group. For men with IR or HR disease, LT refusal was associated with worse OS (5-year OS 80.1% v 91.5%, HR, 1.65, P < .001). CONCLUSION: LT refusal has increased over time; racial disparities were greater in higher-risk disease. Refusal despite provider recommendation highlights populations that may benefit from efforts to assess and reduce barriers to care.

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant for endocrine resistance and ER+ breast cancer plasticity. In endocrine sensitive cells, CoREST is recruited to ERα/FOXA1 co-bound regulatory regions to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit, LSD1. Genetic and pharmacological CoREST inhibition reduce tumorigenesis and metastasis of endocrine sensitive and resistant xenografts models. Consistently, CoREST controls a gene signature in clinical breast tumors resistant to endocrine therapies involved in invasiveness. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.

BACKGROUND Native African men (NAM) experience a disproportionate burden of prostate cancer (PCa) and have higher mortality rates compared to European American men (EAM). While socioeconomic status has been implicated as a driver of this disparity, little is known about the genomic mechanisms and distinct biological pathways that are associated with PCa of native men of African origin. METHODS To understand biological factors that contribute to this disparity we utilized a total of 406 multi-institutional localized PCa samples, collected by Men of African Descent and Carcinoma of the Prostate biospecimen network and Moffitt Cancer Center/University of Pennsylvania Health science system. We performed comparative genomics and immunohistochemistry to identify the biomarkers that are highly enriched in NAM from west Africa and compared them with African American Men (AAM) and EAM. Quantified messenger RNA expression and Median H scores based on immune reactivity of staining cells, were compared using Mann Whitney test. For gene expression analysis, p values were further adjusted for multiple comparisons using false discovery rates. RESULTS Immunohistochemical analysis on selected biomarkers showed a consistent association between ETS related gene (ERG) status and race with 83% of NAM exhibiting tumors that lacked TMPRSS2-ERG translocation (ERGnegative ) as compared to AAM (71%) and EAM (52%). A higher proportion of NAM (29%) were also found to be double negative (ERGnegative and PTENLoss ) as compared to AAM (6%) and EAM (7%). NAM tumors had significantly higher immunoreactivity (H-score) for PSMA, and EZH2, whereas they have lower H-score for PTEN, MYC, AR, RB and Racemase, (all p

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P, Walter Rayford, Alp Tuna Beksac et al. investigated gene expression alterations in African-American and European-American men who underwent radical prostatectomy for prostate cancer. The observed differences include higher expression of inflammation genes and lower expression of mismatch repair genes in African-American men.

Background For men with radiation-managed prostate cancer, there is conflicting evidence regarding the association between androgen deprivation therapy (ADT) and cardiovascular mortality (CVM), particularly among those who have with preexisting comorbidities. The objective of this study was to analyze the association between ADT and CVM across patient comorbidity status using prospectively collected data from a large clinical trial. Methods In total, 1463 men were identified who were diagnosed with clinically localized, intermediate-risk/high-risk prostate cancer (T2b-T4, Gleason 7-10, or prostate-specific antigen >10 ng/mL) from 1993 to 2001 and managed with either radiation therapy (RT) alone or RT plus ADT during the randomized Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial. Adjusted hazard ratios (aHRs) for cause-specific mortality (prostate cancer-specific mortality vs other-cause mortality-including the primary end point of CVM [death from ischemic heart disease, cerebrovascular accident, or other circulatory disease]) were determined using Fine and Gray competing-risk regression analysis and stratified by comorbidity history. Results There was no difference in the risk of 5-year CVM between ADT plus RT and RT alone (2.3% vs 3.3%, respectively; aHR, 0.69; 95% CI, 0.38-1.24; P = .21) overall or on subgroup analysis among men with a history of ≥1 preexisting comorbidities (3.2% vs 5.3%, respectively; aHR, 0.83; 95% CI, 0.43-1.60; P = .58), ≥2 preexisting comorbidities (6.9% vs 8.3%, respectively; aHR, 0.95; 95% CI, 0.40-2.25; P = .90), or cardiovascular disease/risk factors (3.6% vs 4.3%, respectively; aHR, 0.85; 95% CI, 0.44-1.65; P = .63). These results were all similar when each component of CVM was analyzed separately-either cardiac, stroke, or other vascular mortality (P > .05). Conclusions This study provides prospectively collected evidence that the use of ADT plus RT, compared with RT alone, is not associated with an increased risk of CVM, even among subgroups of men who have preexisting comorbidities and cardiovascular disease.

Summary Background The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. Methods For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. Findings 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7–10·6). Biochemical failure (R2 0·38 [95% CI 0·11–0·64]), biochemical failure-free survival (R2 0·12 [0·0030–0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045–0·65]), and local failure (R2 0·085 [0·00–0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22–0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59–0·89]) correlated strongly. Interpretation Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. Funding Prostate Cancer Foundation and National Institutes of Health.

Patients diagnosed with cancer as adolescent and young adult (AYA) are at risk for a range of long-term psychosocial sequelae, which have been poorly studied. We sought to characterize the prevalence of cognitive dysfunction and psychological distress among long-term AYA cancer survivors. Using data from the National Health Interview Survey between 2010 and 2018, multivariable logistic regression analyses defined the association between AYA cancer diagnosis and cognitive dysfunction and psychological distress, as defined by the 6-item Kessler Psychological Distress Scale. Among AYA cancer survivors, the association between psychological distress and cognitive dysfunction was assessed via multivariable logistic regression. Among 230,675 participants, 2646 (1.1%) were AYA cancer survivors diagnosed > 10 years prior to survey administration. Prior AYA cancer diagnosis was associated with greater odds of cognitive dysfunction (AOR 1.61, 95% CI 1.41–1.82; 27.8% vs. 16.4%) and psychological distress (AOR 1.60, 95% CI 1.41–1.83; 26.6 vs. 15.3%) as compared to individuals without a cancer history. Among survey participants reporting a cancer diagnosis, greater psychological distress was associated with greater odds of cognitive dysfunction (AOR 12.31, 95% CI 7.51–20.18 for severe psychological distress) and cognitive dysfunction was associated with having psychological distress (AOR 4.97, 95% CI 3.66–6.73). Long-term survivors of AYA cancer have higher rates of cognitive dysfunction and psychological distress as compared to the general population. Additional services addressing psychosocial and neurocognitive issues should be integrated into standard AYA cancer survivorship care. Cancer survivors should be aware of self-reported high rates of long-term cognitive dysfunction and psychologic distress and actively seek out formal evaluation and services such as mental health counseling

Background and purposeThe optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens.Materials and methodsIn 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35Gy/5 fractions [35/5, n=265, 13.4%], 36.25Gy/5 fractions [36.25/5, n=711, 37.3%], 40Gy/5 fractions [40/5, n=684, 35.8%], and 38Gy/4 fractions [38/4, n=257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5ng/mL, and BCR-free survival (BCRFS).ResultsMedian follow-up was 72.3months. Median nPSA was 0.01ng/mL for 38/4, and 0.17-0.20ng/mL for 5-fraction regimens (p&nbsp

Chromosome 8q arm (chr8q) is the most amplified chromosomal segment in advanced metastatic castration-resistant prostate cancer after chXq12. These regions harbor important oncogenes driving prostate cancer progression, including MYC that plays a role in various hallmarks of cancer, including cell cycle progression and immune surveillance. Herein we characterize the co-expression patterns of chr8q genes and their clinical utility in more than 7,000 radical prostatectomy samples.Copy Number alterations of 336 genes on chr8q21 to chr8q24 were extracted from 2 primary prostate cancer cohorts (TCGA, n = 492; MSK-primary, n = 856) and 3 metastatic prostate cancer cohorts (MSK-met, N = 432; MSK-mCSPC, N = 424; SU2CPNAS, n = 444) from cBioPortal. Expression data for the 336 genes was extracted from 6,135 radical prostatectomy samples from Decipher GRID registry. For survival analysis, patients were grouped into top 10% and top 25% by band expression and were compared with the remaining cohort. Hazard ratios were calculated using Cox proportional hazards models.Genes on chr8q were highly co-amplified and co-expressed. Copy number alterations and overexpression of chr8q genes in primary disease were associated with higher Gleason scores, increased risk of metastases, and increased prostate cancer specific mortality. Additionally, our data demonstrated high expression of MYC alone was not associated with differences in metastases free survival while high expression of other chr8q bands was associated with decreased metastases free survival. By combining chr8q data with an established genomic classifier like Decipher, we were able to develop a new model that was better at predicting metastases than Decipher alone.Our findings highlight the clinical utility of chr8q data, which can be used to improve prognostication and risk prediction in localized prostate cancer.

BACKGROUND Current guidelines endorse shared decision making (SDM) for prostate-specific antigen (PSA) screening. The relationship between a patient's health literacy (HL) and SDM remains unclear. In the current study, the authors sought to identify the impact of HL on the rates of PSA screening and on the relationship between HL and SDM following the 2012 US Preventive Services Task Force recommendations against PSA screening. METHODS Using data from the 2016 Behavioral Risk Factor Surveillance System, the authors examined PSA screening in the 13 states that administered the optional "Health Literacy" module. Men aged ≥50 years were examined. Complex samples multivariable logistic regression models were computed to assess the odds of undergoing PSA screening. The interactions between HL and SDM were also examined. RESULTS A weighted sample of 12.249 million men with a rate of PSA screening of 33.4% were identified. Approximately one-third self-identified as having optimal HL. Rates of PSA screening were found to be highest amongst the highest HL group (42.2%). Being in this group was a significant predictor of undergoing PSA screening (odds ratio, 1.214; 95% confidence interval, 1.051-1.403). There was a significant interaction observed between HL and SDM (P for interaction

Background The 2012 US Preventive Services Task Force recommendation against routine prostate-specific antigen (PSA) testing led to a decrease in prostate cancer screening, but the heterogeneity of its impact by race and ethnicity remains unclear. Methods The proportion of 40- to 74-year-old men who self-reported receiving a routine PSA test in the past year was estimated in the Behavioral Risk Factor Surveillance System (2012-2018). Odds ratios (ORs) of undergoing screening by race and ethnicity were estimated, adjusting for healthcare–related factors. Prostate cancer incidence rates and rate ratios (IRRs) by race and ethnicity were estimated using Surveillance, Epidemiology, and End Results registry data (2004-2017). Results PSA testing frequencies were 32.3% (95% confidence interval [CI] = 31.7% to 32.8%) among non-Hispanic White (NHW), 30.3% (95% CI = 28.3% to 32.3%) among non-Hispanic Black (NHB), 21.8% (95% CI = 19.9% to 23.7%) among Hispanic, and 17.7% (95% CI = 14.1% to 21.3%) among Asian and Pacific Islander men in 2012. The absolute screening frequency declined by 9.5% from 2012 to 2018, with a larger decline among NHB (11.6%) than NHW men (9.3%). The relative annual decrease was greater among NHB (OR = 0.86, 95% CI = 0.84 to 0.88) than NHW men (OR = 0.89, 95% CI = 0.89 to 0.90; Pheterogeneity = .005), driven by a larger decline among NHB men ages 40-54 years. The NHB to NHW IRR for total prostate cancer increased from 1.73 (95% CI = 1.69 to 1.76) in 2011 to 1.87 (95% CI = 1.83 to 1.92) in 2012 and has remained elevated, driven by differences in localized tumor incidence. Metastatic disease incidence is rising across all racial and ethnic groups. Conclusions The frequency of prostate cancer screening varies by race and ethnicity, and there was a modestly steeper decline in PSA testing among younger NHB men relative to NHW men since 2012. The NHB to NHW IRR for localized prostate cancer modestly increased following 2012.

To inform treatment decisions for patients with high-risk prostate cancer (PCa), we determined rates of adverse pathologic factors and overall survival (OS) among subgroups of high-risk men.Using the National Cancer Database, 89,450 patients with clinical N0M0 unfavorable intermediate-risk, favorable high-risk (cT1c, Gleason 6, prostate-specific antigen [PSA]20 ng/mL or cT1c, biopsy Gleason 8, PSA10 ng/mL), standard high-risk (all other cT3a, biopsy Gleason ≥ 8, or PSA20 ng/mL), or very high-risk (cT3b-T4 or biopsy primary Gleason pattern 5) PCa treated with radical prostatectomy were identified. Rates of adverse pathologic factors (positive surgical margins, T4 disease, or pathologic lymph node involvement) were compared across subgroups.Patients with unfavorable intermediate-risk (n = 31,381) and favorable high-risk (n = 10,296) disease had similar rates of adverse features (7.6% vs 8.2%, adjusted odds ratio 1.00, 95% confidence interval 0.92-1.08, P= .974). Patients with standard high-risk (n = 30,260) or very high-risk (n = 7513) disease were significantly more likely to have adverse pathologic factors (15.9% and 26.5%, P.001 for both). Patients with unfavorable intermediate-risk and favorable high-risk disease had similar 5-year OS (95.7% vs 95.1%, adjusted hazard ratio 1.06, 95% confidence interval 0.92-1.21, P = .411) but better OS compared to standard and very high-risk patients (93.4% and 88.1%, respectively; P.001).Unfavorable intermediate-risk or favorable high-risk PCa patients had low rates of adverse pathologic factors and similar OS. In contrast, standard and very high-risk PCa patients had significantly higher rates of adverse pathologic factors and worse OS. This 3-tiered subclassification of high-risk disease may allow for improved treatment selection among patients considering surgery.

PURPOSE Pretreatment estimates of seminal vesicle invasion (SVI) are challenging and significantly influence the management of prostate cancer. We sought to improve current models to predict SVI through the development of an SVI prediction genomic signature. PATIENTS AND METHODS A total of 15,889 patients who underwent radical prostatectomy (RP) with available baseline clinical, pathology, and transcriptome data were retrieved from the GRID registry (ClinicalTrials.gov identifier: NCT02609269 ) and other retrospective cohorts. These data were divided into a training (n = 6,766), test (n = 3,363), and two validation (n = 5,062 and 698) cohorts. Multivariable logistic regression was performed to assess the predictive effect of the genomic SVI (gSVI) classifier in the presence of established nomograms (Partin Tables and Memorial Sloan Kettering Cancer Center [MSKCC]). RESULTS In the training cohort, univariable filtering identified 2,132 genes that were differentially expressed between RP tumors with and without SVI. Model parameters were tuned to maximize the area under the curve (AUC) in the testing cohort, resulting in a logistic generalized linear model with 581 genes. The gSVI model scores range from 0 to 1. In the first validation set, gSVI showed superior discrimination of patients with and without SVI at RP compared with other prognostic signatures trained to predict distant metastasis or clinical recurrence. Of the 698 patients in the second validation set, gSVI combined with the MSKCC nomogram had a superior AUC (0.86) compared with either nomogram individually (0.81). CONCLUSION The gSVI represents a novel and validated expression signature to predict the presence of SVI before treatment with surgery. This genomic tool adds discriminatory power to existing clinical predictive nomograms and may help with pretreatment counseling and decision making.