Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

Discovery and Validation of a 15-Gene Prognostic Signature for Clear Cell Renal Cell Carcinoma.

PURPOSE: Develop and validate gene expression-based biomarker associated with recurrent disease to facilitate risk stratification of clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We retrospectively identified 110 patients who underwent radical nephrectomy for ccRCC (discovery cohort). Patients who recurred were matched on the basis of grade/stage to patients without recurrence. Capture whole-transcriptome sequencing was performed on RNA isolated from archival tissue using the Illumina platform. We developed a gene-expression signature to predict recurrence-free survival/disease-free survival (DFS) using a 15-fold lasso and elastic-net regularized linear Cox model. We derived the 31-gene cell cycle progression (mxCCP) score using RNA-seq data for each patient. Kaplan-Meier (KM) curves and multivariable Cox proportional hazard testing were used to validate the independent prognostic impact of the gene-expression signature on DFS, disease-specific survival (DSS), and overall survival (OS) in two validation data sets (combined n = 761). RESULTS: After quality control, the discovery cohort comprised 50 patients with recurrence and 41 patients without, with a median follow-up of 26 and 36 months, respectively. We developed a 15-gene (15G) signature, which was independently associated with worse DFS and DSS (DFS: hazard ratio [HR], 11.08 [95% CI, 4.9 to 25.1]; DSS: HR, 9.67 [95% CI, 3.4 to 27.7]) in a multivariable model adjusting for clinicopathologic parameters (including stage, size, grade, and necrosis [SSIGN] score and Memorial Sloan Kettering Cancer Center nomogram) and mxCCP score. The 15G signature was also independently associated with worse DFS and DSS in both validation data sets (Validation A [n = 382], DFS: HR, 2.6 [95% CI, 1.6 to 4.3]; DSS: HR, 3 [95% CI, 1.4 to 6.1] and Validation B (n = 379), DFS: HR, 2.1 [95% CI, 1.2 to 3.6]; OS: HR, 3 [95% CI, 1.6 to 5.7]) adjusting for clinicopathologic variables and mxCCP score. CONCLUSION: We developed and validated a novel 15G prognostic signature to improve risk stratification of patients with ccRCC. Pending further validation, this signature has the potential to facilitate optimal treatment allocation.

Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater). Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers. Design, Setting, and Participants: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023. Exposure: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy. Main Outcomes and Measures: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily. Results: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater. Conclusions and Relevance: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

Analysis of the Tumor Immune Microenvironment (TIME) in Clear Cell Renal Cell Carcinoma (ccRCC) Reveals an M0 Macrophage-Enriched Subtype: An Exploration of Prognostic and Biological Characteristics of This Immune Phenotype.

There is a need to optimize the treatment of clear cell renal cell carcinoma (ccRCC) patients at high recurrence risk after nephrectomy. We sought to elucidate the tumor immune microenvironment (TIME) of localized ccRCC and understand the prognostic and predictive characteristics of certain features. The discovery cohort was clinically localized patients in the TCGA-Kidney Renal Clear Cell Carcinoma (KIRC) project (n = 382). We identified an M0 macrophage-enriched cluster (n = 25) in the TCGA-KIRC cohort. This cluster's median progression-free survival (PFS) and overall survival (OS) were 40.4 and 45.3 months, respectively, but this was not reached in the others (p = 0.0003 and <0.0001, respectively). Gene set enrichment (GSEA) analysis revealed an enrichment of epithelial to mesenchymal transition and cell cycle progression genes within this cluster, and these patients also had a lower predicted response to immune checkpoint blockade (ICB) (4% vs. 20-34%). An M0-enriched cluster (n = 9) with shorter PFS (p = 0.0006) was also identified in the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort (n = 94). Through this characterization of the TIME in ccRCC, a cluster of patients defined by enrichment in M0 macrophages was identified that demonstrated poor prognosis and lower predicted ICB response. Pending further validation, this signature can identify localized ccRCC patients at high risk of recurrence after nephrectomy and who may require therapeutic approaches beyond ICB monotherapy.

Role of adenosine deaminase in prostate cancer progression.

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a surrogate for ADA activity was high in PCa patient urine and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in ADA expression during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis revealed that mTOR signaling activation could be associated with this tumor growth. Chronic ADA overexpression shows alterations in the cells' adhesion machinery and a decrease in cells' ability to adhere to the extracellular matrix in vitro. Losing cell-matrix interaction is critical for metastatic dissemination which suggests that ADA could potentially be involved in promoting metastasis. This is supported by the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.

Comparing Patient-reported Functional Outcomes After Radical Prostatectomy in Historical and Contemporary Practice.

PURPOSE: Modifications to surgical technique, particularly the widespread adoption of robotic surgery, have been proposed to improve functional recovery after prostate cancer surgery. However, rigorous comparison of men in historical vs contemporary practice to evaluate the cumulative effect of these changes on urinary and sexual function after radical prostatectomy is lacking. MATERIALS AND METHODS: We compared prospectively collected patient-reported urinary and sexual function from historical (PROSTQA [Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment study], n=235) and contemporary (MUSIC-PRO [Michigan Urological Surgery Improvement Collaborative Patient Reported Outcome] registry, n=1,215) cohorts at the University of Michigan to understand whether modern techniques have resulted in functional improvements for men undergoing prostate cancer surgery. RESULTS: We found significant differences in baseline function, with better urinary (median [IQR]; 100 [93.8-100] vs 93.8 [85.5-100], P < .001) and sexual scores (median [IQR]; 83.3 [66.7-100] vs 74.4 [44.2-87.5], P < .001) prior to treatment in PROSTQA compared to MUSIC-PRO patients, respectively. There was no statistically significant difference in the pattern of urinary incontinence recovery after surgery from 6-24 months between groups (P = .14). However, men in the contemporary MUSIC-PRO group did have significantly better recovery of sexual function compared to men in the historical PROSTQA group (P < .0001). Further, we found that contemporary practice consists of men with more unfavorable demographic and clinical characteristics compared to historical practice. CONCLUSIONS: Our results demonstrate that the widespread alterations in prostate cancer surgery over the past 2 decades have yielded improvements in sexual, but not urinary, function recovery.

Michigan Urology Academy-Our Role in Diversifying the Urology Workforce.

OBJECTIVE: To evaluate the value/utility of developing an online mentorship program for underrepresented in medicine (URiM) students interested in urology. The Michigan Urology Academy (MUA) was launched in 2020 to increase exposure and provide mentorship to URiM students interested in urology, in an effort to address the continued low numbers of Black and LatinX urologists in the workforce. METHODS: The 2-day virtual mentorship program was launched in June 2020 and held annually thereafter. Demographic information was collected, and surveys were distributed at 1week and 3months after the events. Surveys assessed participants' perception of the utility and effectiveness of the sessions. Thematic analysis was performed on qualitative data. Fourth-year med students were followed longitudinally to determine urology match results. RESULTS: Over the last 3years, MUA hosted 208 students from 104 medical schools. Participants self-identified as 42.3% (n = 88) identified as African American/Black, 14.9% (n = 31) Hispanic/LatinX, 12.98% (n = 27) white, 18.75% (n = 39) as Asian/Indian 7.7% (n = 16) as Middle Eastern/North African, and 0.48% Native Hawaiian/Pacific Islander (n = 1). Overall, fourth-year MUA participants matched at a higher rate than the national average (80.2% vs 71.4%; P = .0486). Narrative feedback revealed five themes: (1) the importance of community support within urology, (2) the utility of vulnerability and storytelling, (3) the importance of representation of diverse backgrounds, (4) the desire for in-person mentorship opportunities, and (5) the need for transparency in application logistics. CONCLUSION: Mentorship programs such as MUA allow URiM students to have greater exposure to the field of urology and to networking opportunities.

Recent Advances in Blood-Based Liquid Biopsy Approaches in Prostate Cancer.

ABSTRACT: The advent of high-throughput technologies has enabled the analysis of minute amounts of tumor-derived material purified from body fluids, termed "liquid biopsies." Prostate cancer (PCa) management, like in many other cancer types, has benefited from liquid biopsies at several stages of the disease. Although initially describing circulating tumor cells in blood, the term "liquid biopsy" has come to more prominently include cell-free, circulating tumor DNA, as well as RNA, proteins, and other molecules. They provide tumor molecular information representing the entire, often-heterogeneous disease, relatively noninvasively and longitudinally. Blood has been the main liquid biopsy specimen in PCa, and urine has also proven beneficial. Technological advances have allowed clinical implementation of some liquid biopsies in PCa, in disease monitoring and precision oncology. This narrative review introduces the main types of blood-based PCa liquid biopsies focusing on advances in the past 5 years. Clinical adoption of liquid biopsies to detect and monitor the evolving PCa tumor biology promises to deepen our understanding of the disease and improve patient outcomes.

Early Detection of Prostate Cancer: AUA/SUO Guideline Part II: Considerations for a Prostate Biopsy.

PURPOSE: The summary presented herein covers recommendations on the early detection of prostate cancer and provides a framework to facilitate clinical decision-making in the implementation of prostate cancer screening, biopsy, and follow-up. This is Part II of a two-part series focusing on initial and repeat biopsies, and biopsy technique. Please refer to Part I for discussion of initial prostate cancer screening recommendations. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. The systematic review was based on searches in Ovid MEDLINE and Embase and Cochrane Database of Systematic Reviews (January 1, 2000-November 21, 2022). Searches were supplemented by reviewing reference lists of relevant articles. RESULTS: The Early Detection of Prostate Cancer Panel developed evidence- and consensus-based guideline statements to provide guidance in prostate cancer screening, initial and repeat biopsies, and biopsy technique. CONCLUSIONS: The evaluation of prostate cancer risk should be focused on the detection of clinically significant prostate cancer (Grade Group 2 or higher [GG2+]). The use of laboratory biomarkers, prostate MRI, and biopsy techniques described herein may improve detection and safety when a prostate biopsy is deemed necessary following prostate cancer screening.

Early Detection of Prostate Cancer: AUA/SUO Guideline Part I: Prostate Cancer Screening.

PURPOSE: The summary presented herein covers recommendations on the early detection of prostate cancer and provides a framework to facilitate clinical decision-making in the implementation of prostate cancer screening, biopsy, and follow-up. This is Part I of a two-part series that focuses on prostate cancer screening. Please refer to Part II for discussion of initial and repeat biopsies as well as biopsy technique. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. The systematic review was based on searches in Ovid MEDLINE and Embase and Cochrane Database of Systematic Reviews (January 1, 2000-November 21, 2022). Searches were supplemented by reviewing reference lists of relevant articles. RESULTS: The Early Detection of Prostate Cancer Panel developed evidence- and consensus-based guideline statements to provide guidance in prostate cancer screening, initial and repeat biopsy, and biopsy technique. CONCLUSIONS: Prostate-specific antigen (PSA)-based prostate cancer screening in combination with shared decision-making (SDM) is recommended. Current data regarding risk from population-based cohorts provide a basis for longer screening intervals and tailored screening, and the use of available online risk calculators is encouraged.

Intra-practice Urologist-level Variation in Targeted Fusion Biopsy Outcomes.

OBJECTIVE: To examine the extent to which the urologist performing biopsy contributes to variation in prostate cancer detection during fusion-guided prostate biopsy. METHODS: All men in the Michigan Urological Surgery Improvement Collaborative (MUSIC) clinical registry who underwent fusion biopsy at Michigan Medicine from August 2017 to March 2019 were included. The primary outcomes were clinically significant cancer detection rate (defined as Gleason Grade ≥2) in targeted cores and clinically significant cancer detection on targeted cores stratified by PI-RADS score. Bivariate and multivariable logistic regression analyses were performed. RESULTS: A total of 1133 fusion biopsies performed by 5 providers were included. When adjusting for patient age, PSA, race, family history, prostate volume, clinical stage, and PI-RADS score, there was no significant difference in targeted clinically significant cancer detection rates across providers (range = 38.5%-46.9%, adjusted P-value = .575). Clinically significant cancer detection rates ranged from 11.1% to 16.7% in PI-RADS 3 (unadjusted P = .838), from 24.6% to 43.4% in PI-RADS 4 (adjusted P = .003), and from 69.4% to 78.8% in PI-RADS 5 (adjusted P = .766) lesions. CONCLUSION: There was a statistically significant difference in clinically significant prostate cancer detection in PI-RADS 4 lesions across providers. These findings suggest that even among experienced providers, variation at the urologist level may contribute to differences in clinically significant cancer detection rates within PI-RADS 4 lesions. However, the relative impact of biopsy technique, radiologist interpretation, and MR acquisition protocol requires further study.

Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma.

CONTEXT: Dramatic gains in our understanding of the molecular biology of clear cell renal cell carcinoma (ccRCC) have created a foundation for clinical translation to improve patient care. OBJECTIVE: To review and contextualize clinically impactful data surrounding genomic biomarkers in ccRCC. EVIDENCE ACQUISITION: A systematic literature search was conducted focusing on genomic-based biomarkers with an emphasis on studies assessing clinical outcomes. EVIDENCE SYNTHESIS: The advancement of tumor sequencing techniques has led to a rapid increase in the knowledge of the molecular underpinnings of ccRCC and with that the discovery of multiple candidate genomic biomarkers. These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1; copy number variations; transcriptomic multigene signatures; and specific immune cell populations. Many of these biomarkers have been assessed for their association with survival and a smaller number as potential predictors of a response to systemic therapy. In this scoping review, we discuss many of these biomarkers in detail. Further studies are needed to continue to refine and validate these molecular tools for risk stratification, with the ultimate goal of improving clinical decision-making and patient outcomes. CONCLUSIONS: While no tissue or blood-based biomarkers for ccRCC have been incorporated into routine clinical practice to date, the field continues to expand rapidly. There remains a critical need to develop and validate these tools in order to improve the care for patients with kidney cancer. PATIENT SUMMARY: Genomic biomarkers have the potential to better predict outcome and select the most appropriate treatment for patients with kidney cancer; however, further research is needed before any of these currently developed biomarkers are adopted into clinical practice.

NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

MyProstateScore in men considering repeat biopsy: validation of a simple testing approach.

BACKGROUND: Men with persistent risk of Grade Group (GG) ≥ 2 cancer after a negative biopsy present a unique clinical challenge. The validated MyProstateScore test is clinically-available for pre-biopsy risk stratification. In biopsy-naïve patients, we recently validated a straightforward testing approach to rule-out GG ≥ 2 cancer with 98% negative predictive value (NPV) and 97% sensitivity. In the current study, we established a practical MPS-based testing approach in men with a previous negative biopsy being considered for repeat biopsy. METHODS: Patients provided post-digital rectal examination urine prior to repeat biopsy. MyProstateScore was calculated using the validated, locked model including urinary PCA3 and TMPRSS2:ERG scores with serum PSA. In a clinically-appropriate primary (i.e., training) cohort, we identified a lower (rule-out) threshold approximating 90% sensitivity and an upper (rule-in) threshold approximating 80% specificity for GG ≥ 2 cancer. These thresholds were applied to an external validation cohort, and performance measures and clinical outcomes associated with their use were calculated. RESULTS: MyProstateScore thresholds of 15 and 40 met pre-defined performance criteria in the primary cohort (422 patients; median PSA 6.4, IQR 4.3-9.1). In the 268-patient validation cohort, 25 men (9.3%) had GG ≥ 2 cancer on repeat biopsy. The rule-out threshold of 15 provided 100% NPV and sensitivity for GG ≥ 2 cancer and would have prevented 23% of unnecessary biopsies. Use of MyProstateScore >40 to rule-in biopsy would have prevented 67% of biopsies while maintaining 95% NPV. In the validation cohort, the prevalence of GG ≥ 2 cancer was 0% for MyProstateScore 0-15, 6.5% for MyProstateScore 15-40, and 19% for MyProstateScore >40. CONCLUSIONS: In patients who previously underwent a negative prostate biopsy, the MyProstateScore values of 15 and 40 yielded clinically-actionable rule-in and rule-out risk groups. Using this straightforward testing approach, MyProstateScore can meaningfully inform patients and physicians weighing the need for repeat biopsy.

A Phase I Trial of Neoadjuvant Stereotactic Body Radiotherapy Prior to Radical Prostatectomy for Locally Advanced Prostate Cancer.

PURPOSE: Men with locally advanced prostate cancer who undergo radical prostatectomy (RP) often develop recurrence and require postoperative radiotherapy. We aimed to determine the safety of neoadjuvant stereotactic body radiotherapy (SBRT) before RP in this population. METHODS AND PATIENTS: A single-institution phase 1 trial (NCT02946008) of men with high-risk or node-positive prostate cancer were enrolled between March and October 2017. The primary endpoint was to determine the maximum tolerated dose of SBRT based on a composite 30-day post-RP toxicity goal of ≤28% of patients experiencing a dose-limiting toxicity (DLT). Secondary outcomes included toxicity, efficacy, and multiple quality of life (QoL) inventories. SBRT (30-35 Gy/5 fractions) was delivered to the prostate and seminal vesicles, and 25 Gy/5 fractions to the pelvic lymph nodes. RP was performed for a median of 6 weeks post-SBRT. Hormone therapy was not allowed. RESULTS: Median follow-up was 40 months (range, 33-44). Twenty-five percent of the patients (n = 4) experienced a DLT within 30 days post-RP; however, the trial was stopped early (n = 16 of planned 38 patients) owing to the proportion and severity of the late adverse events. Post-RP grade 3 genitourinary and gastrointestinal toxicities occurred in 75% (n = 12) and 25% (n = 4) of patients, respectively. Two patients required cystectomy and urinary diversion ≥2 years post-RP. At 24 months post-RP, 75% (n = 12) of men used ≥1 pad/d and 0% had erections suitable for intercourse. Surgical margins were negative in all patients and 31% (n = 5) had complete or partial (pre-RP) MRI-response to SBRT. Three-year biochemical recurrence and distant metastasis were 45% (95% CI, 5%-68%) and 28% (95% CI, 0%-49%), respectively. CONCLUSIONS: Neoadjuvant SBRT followed by RP resulted in unacceptably high toxicity and severe QoL declines.

Genomic Sequencing Should Be Part of the Standard of Care for Most Urologic Cancers: For.

Genomic sequencing should be part of the standard of care for most urologic cancers.

Biomarkers for prostate cancer detection and risk stratification.

Although prostate cancer (PCa) is the most commonly diagnosed cancer in men, most patients do not die from the disease. Prostate specific antigen (PSA), the most widely used oncologic biomarker, has revolutionized screening and early detection, resulting in reduced proportion of patients presenting with advanced disease. However, given the inherent limitations of PSA, additional diagnostic and prognostic tools are needed to facilitate early detection and accurate risk stratification of disease. Serum, urine, and tissue-based biomarkers are increasingly being incorporated into the clinical care paradigm, but there is still a limited understanding of how to use them most effectively. In the current article, we review test characteristics and clinical performance data for both serum [4 K score, prostate health index (phi)] and urine [SelectMDx, ExoDx Prostate Intelliscore, MyProstateScore (MPS), and PCa antigen 3 (PCA3)] biomarkers to aid decisions regarding initial or repeat biopsies as well as tissue-based biomarkers (Confirm MDx, Decipher, Oncotype Dx, and Polaris) aimed at risk stratifying patients and identifying those patients most likely to benefit from treatment versus surveillance or monotherapy versus multi-modal therapy.

"PROBE"ing the Role of Cytoreductive Nephrectomy in Advanced Renal Cancer.

The Southwest Oncology Group (SWOG)1931 trial, also known as PROBE (ClinicalTrials.gov Identifier: NCT04510597) is a phase III study evaluating the role of cytoreductive nephrectomy (CN) in metastatic renal cell cancer (RCC). Kidney cancer presenting with synchronous metastases has demonstrated shorter survival outcome compared to the patients relapsing with metastases after nephrectomy. Previously, CN has been associated with survival improvement when interferon-based systemic therapy was used. In the setting of antivascular therapy sunitinib, a prospective randomized clinical trial demonstrated no benefit of CN. Immune checkpoint-based combination therapy has now become the standard-of-care in the frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint-based systemic therapy. The sequence and optimal timing of nephrectomy is also not established. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in RCC within the context of immune checkpoint-based combination regimens. The study requires starting with systemic therapy; any one of the FDA approved immunotherapy-based regimens at the time the study was activated are permitted. The disease status and response are evaluated at 9-12 weeks of therapy and then consented patients are randomized 1:1 to receive CN or to continue systemic therapy. The patients who have rapid disease progression are considered ineligible for randomization as they need a switch in systemic therapy. Both groups should continue systemic therapy as long as they are tolerating the treatment and continuing to derive clinical benefit. Quality-of-life, tumor genomic testing, microbiome, radiomics and circulating tumor DNA assessments as predictive biomarkers are planned as study correlatives. The study hypothesis is that CN will improved OS in synchronous metastatic RCC when surgery is performed after starting systemic immune checkpoint-based combination therapy. A potential mechanism leading to improved survival is the broader antigen spread and higher neoantigen load enabled by the primary tumor enhancing the efficacy of the immune therapy. CN after initial systemic therapy would help select the patient subset most likely to benefit and will potentially enable eradication of immune resistant clones within the primary tumor.

Development of a Whole-urine, Multiplexed, Next-generation RNA-sequencing Assay for Early Detection of Aggressive Prostate Cancer.

BACKGROUND: Despite biomarker development advances, early detection of aggressive prostate cancer (PCa) remains challenging. We previously developed a clinical-grade urine test (Michigan Prostate Score [MiPS]) for individualized aggressive PCa risk prediction. MiPS combines serum prostate-specific antigen (PSA), the TMPRSS2:ERG (T2:ERG) gene fusion, and PCA3 lncRNA in whole urine after digital rectal examination (DRE). OBJECTIVE: To improve on MiPS with a novel next-generation sequencing (NGS) multibiomarker urine assay for early detection of aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: Preclinical development and validation of a post-DRE urine RNA NGS assay (Urine Prostate Seq [UPSeq]) assessing 84 PCa transcriptomic biomarkers, including T2:ERG, PCA3, additional PCa fusions/isoforms, mRNAs, lncRNAs, and expressed mutations. Our UPSeq model was trained on 73 patients and validated on a held-out set of 36 patients representing the spectrum of disease (benign to grade group [GG] 5 PCa). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The area under the receiver operating characteristic curve (AUC) of UPSeq was compared with PSA, MiPS, and other existing models/biomarkers for predicting GG ≥3 PCa. RESULTS AND LIMITATIONS: UPSeq demonstrated high analytical accuracy and concordance with MiPS, and was able to detect expressed germline HOXB13 and somatic SPOP mutations. In an extreme design cohort (n = 109; benign/GG 1 vs GG ≥3 PCa, stratified to exclude GG 2 cancer in order to capture signal difference between extreme ends of disease), UPSeq showed differential expression for T2:ERG.T1E4 (1.2 vs 78.8 median normalized reads, p < 0.00001) and PCA3 (1024 vs 2521, p = 0.02), additional T2:ERG splice isoforms, and other candidate biomarkers. Using machine learning, we developed a 15-transcript model on the training set (n = 73) that outperformed serum PSA and sequencing-derived MiPS in predicting GG ≥3 PCa in the held-out validation set (n = 36; AUC 0.82 vs 0.69 and 0.69, respectively). CONCLUSIONS: These results support the potential utility of our novel urine-based RNA NGS assay to supplement PSA for improved early detection of aggressive PCa. PATIENT SUMMARY: We have developed a new urine-based test for the detection of aggressive prostate cancer, which promises improvement upon current biomarker tests.