Differentiation fate of a stem-like CD4 T cell controls immunity to cancer.

The T cell response to cancer controls disease progression and response to immunotherapy1-3. Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here we identified a population of PD1+TCF1+ CD4 T cells with stem-like properties that are capable of self-renewal and differentiation into canonical CD4 effector cells. Primarily residing in tumour-draining lymph nodes (TDLNs), these tumour-specific CD4 T cells are restricted by T regulatory (Treg) cells to a stem-like fate that predominantly generated induced Treg (iTreg) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon Treg depletion, stem-like CD4 T cells differentiated into T helper 1 (TH1) cells, and via IFNγ production induced robust effector differentiation from TCF1+ CD8 T cells in TDLNs, a state we defined as 'active'. Notably, enforcing TBET expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of Treg cells, endogenous stem-like CD4 T cells actively generated TH1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, TH1 differentiation in patients with kidney cancer predicted successful immunotherapy responses and improved progression-free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies.

Postprostatectomy Radiotherapy Timing and Long-Term Health-Related Quality of Life.

Importance: The association between radiotherapy (RT) timing after radical prostatectomy and long-term patient-reported health-related quality of life (HRQOL) in men with prostate cancer is unknown. Objective: To measure long-term HRQOL in men with prostate cancer up to 15 years after prostatectomy with or without RT and examine whether early vs late postprostatectomy RT is associated with differences in sexual, urinary, and bowel HRQOL. Design, Setting, and Participants: A prospective, multicenter, longitudinal cohort analysis using HRQOL data from the PROST-QA (2003-2006) and RP2 consortium (2010-2013) studies was conducted. Men with localized prostate cancer undergoing radical prostatectomy were included. Data were analyzed between May 8, 2023, and March 1, 2024. The study was conducted in 12 high-volume academic medical centers in the US. Exposures: Men were stratified based on receipt and timing of postprostatectomy RT: prostatectomy only, early RT (<12 months), and late RT (≥12 months). Main Outcomes and Measures: Longitudinal sexual, incontinence, urinary irritation, bowel, and hormonal/vitality HRQOL were measured via the Expanded Prostate Cancer Index Composite at baseline; months 2, 6, and 12; and annually thereafter. Treatment groups were compared using multivariable linear mixed-effects models of change in longitudinal domain scores. Pad use for incontinence was measured longitudinally among men receiving postprostatectomy RT. Results: A total of 1203 men were included in the study: prostatectomy only (n = 1082), early RT (n = 57), and late RT (n = 64). Median age for the entire cohort was 60.5 (range, 38.8-79.7) years, and 1075 men (92.0%) were White. Median follow-up was 85.6 (IQR, 35.8-117.2) months. Compared with men receiving prostatectomy alone, those receiving postprostatectomy RT had significantly greater decreases in sexual, incontinence, and urinary irritation HRQOL. However, timing of postprostatectomy RT, specifically early vs late, was not associated with a long-term decrease in any HRQOL domain. There was evidence of improved recovery of sexual, continence, and urinary irritation scores among men receiving early RT compared with those receiving late RT after prostatectomy. Before the start of postprostatectomy RT, 39.3% of men in the early RT cohort and 73.4% of men in the late RT cohort were pad-free. By the sixth visit post-RT, 67.4% in the early RT cohort and 47.6% in the late RT cohort were pad-free. Conclusions and Relevance: In this multicenter, prospective analysis, postprostatectomy RT appeared to be negatively associated with long-term HRQOL across all domains. However, receipt of early vs late postprostatectomy RT may result in similar long-term HRQOL outcomes.

Upgrading of Grade Group 1 Prostate Cancer at Prostatectomy: Germline Risk Factors in a Prospective Cohort.

BACKGROUND: Localized prostate tumors show significant spatial heterogeneity, with regions of high-grade disease adjacent to lower grade disease. Consequently, prostate cancer biopsies are prone to sampling bias, potentially leading to underestimation of tumor grade. To study the clinical, epidemiologic, and molecular hallmarks of this phenomenon, we conducted a prospective study of grade upgrading: differences in detected prostate cancer grade between biopsy and surgery. METHODS: We established a prospective, multi-institutional cohort of men with grade group 1 (GG1) prostate cancer on biopsy who underwent radical prostatectomy. Upgrading was defined as detection of GG2+ in the resected tumor. Germline DNA from 192 subjects was subjected to whole-genome sequencing to quantify ancestry, pathogenic variants in DNA damage response genes, and polygenic risk. RESULTS: Of 285 men, 67% upgraded at surgery. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. No assessed genetic risk factor was predictive of upgrading, including polygenic risk scores for prostate cancer diagnosis. CONCLUSIONS: In a cohort of patients with low-grade prostate cancer, a majority upgraded at radical prostatectomy. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores portended the presence of higher-grade disease, while germline genetics was not informative in this setting. Patients with low-risk prostate cancer, but elevated PSA density or percent cancer in positive biopsy cores, may benefit from repeat biopsy, additional imaging or other approaches to complement active surveillance. IMPACT: Further risk stratification of patients with low-risk prostate cancer may provide useful context for active surveillance decision-making.

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.

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis.

Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.

Effect of Brachytherapy With External Beam Radiation Therapy Versus Brachytherapy Alone for Intermediate-Risk Prostate Cancer: NRG Oncology RTOG 0232 Randomized Clinical Trial.

PURPOSE: To determine whether addition of external beam radiation therapy (EBRT) to brachytherapy (BT) (COMBO) compared with BT alone would improve 5-year freedom from progression (FFP) in intermediate-risk prostate cancer. METHODS: Men with prostate cancer stage cT1c-T2bN0M0, Gleason Score (GS) 2-6 and prostate-specific antigen (PSA) 10-20 or GS 7, and PSA < 10 were eligible. The COMBO arm was EBRT (45 Gy in 25 fractions) to prostate and seminal vesicles followed by BT prostate boost (110 Gy if 125-Iodine, 100 Gy if 103-Pd). BT arm was delivered to prostate only (145 Gy if 125-Iodine, 125 Gy if 103-Pd). The primary end point was FFP: PSA failure (American Society for Therapeutic Radiology and Oncology [ASTRO] or Phoenix definitions), local failure, distant failure, or death. RESULTS: Five hundred eighty-eight men were randomly assigned; 579 were eligible: 287 and 292 in COMBO and BT arms, respectively. The median age was 67 years; 89.1% had PSA < 10 ng/mL, 89.1% had GS 7, and 66.7% had T1 disease. There were no differences in FFP. The 5-year FFP-ASTRO was 85.6% (95% CI, 81.4 to 89.7) with COMBO compared with 82.7% (95% CI, 78.3 to 87.1) with BT (odds ratio [OR], 0.80; 95% CI, 0.51 to 1.26; Greenwood T P = .18). The 5-year FFP-Phoenix was 88.0% (95% CI, 84.2 to 91.9) with COMBO compared with 85.5% (95% CI, 81.3 to 89.6) with BT (OR, 0.80; 95% CI, 0.49 to 1.30; Greenwood T P = .19). There were no differences in the rates of genitourinary (GU) or GI acute toxicities. The 5-year cumulative incidence for late GU/GI grade 2+ toxicity is 42.8% (95% CI, 37.0 to 48.6) for COMBO compared with 25.8% (95% CI, 20.9 to 31.0) for BT (P < .0001). The 5-year cumulative incidence for late GU/GI grade 3+ toxicity is 8.2% (95% CI, 5.4 to 11.8) compared with 3.8% (95% CI, 2.0 to 6.5; P = .006). CONCLUSION: Compared with BT, COMBO did not improve FFP for prostate cancer but caused greater toxicity. BT alone can be considered as a standard treatment for men with intermediate-risk prostate cancer.

Interval estimation for operating characteristic of continuous biomarkers with controlled sensitivity or specificity.

The receiver operating characteristic (ROC) curve provides a comprehensive performance assessment of a continuous biomarker over the full threshold spectrum. Nevertheless, a medical test often dictates to operate at a certain high level of sensitivity or specificity. A diagnostic accuracy metric directly targeting the clinical utility is specificity at the controlled sensitivity level, or vice versa. While the empirical point estimation is readily adopted in practice, the nonparametric interval estimation is challenged by the fact that the variance involves density functions due to estimated threshold. In addition, even with a fixed threshold, many standard confidence intervals including the Wald interval for binomial proportion could have erratic behaviors. In this article, we are motivated by the superior performance of the score interval for binomial proportion and propose a novel extension for the biomarker problem. Meanwhile, we develop exact bootstrap and establish consistency of the bootstrap variance estimator. Both single-biomarker evaluation and two-biomarker comparison are investigated. Extensive simulation studies were conducted, demonstrating competitive performance of our proposals. An illustration with aggressive prostate cancer diagnosis is provided.

Covariate-specific evaluation of continuous biomarker.

Diagnostic tests usually need to operate at a high sensitivity or specificity level in practice. Accordingly, specificity at the controlled sensitivity, or vice versa, is a clinically sensible performance metric for evaluating continuous biomarkers. Meanwhile, the performance of a biomarker may vary across sub-populations as defined by covariates, and covariate-specific evaluation can be informative. In this article, we develop a novel modeling and estimation method for covariate-specific specificity at a controlled sensitivity level. Unlike existing methods which typically adopt elaborate models of covariate effects over the entire biomarker distribution, our approach models covariate effects locally at a specific sensitivity level of interest. We also extend our proposed model to handle the whole continuum of sensitivities via dynamic regression and derive covariate-specific ROC curves. We provide the variance estimation through bootstrapping. The asymptotic properties are established. We conduct extensive simulation studies to evaluate the performance of our proposed methods in comparison with existing methods, and further illustrate the applications in two clinical studies for aggressive prostate cancer.

Covariate adjustment in continuous biomarker assessment.

Continuous biomarkers are common for disease screening and diagnosis. To reach a dichotomous clinical decision, a threshold would be imposed to distinguish subjects with disease from nondiseased individuals. Among various performance metrics, specificity at a controlled sensitivity level (or vice versa) is often desirable because it directly targets the clinical utility of the intended clinical test. Meanwhile, covariates, such as age, race, as well as sample collection conditions, could impact the biomarker distribution and may also confound the association between biomarker and disease status. Therefore, covariate adjustment is important in such biomarker evaluation. Most existing covariate adjustment methods do not specifically target the desired sensitivity/specificity level, but rather do so for the entire biomarker distribution. As such, they might be more prone to model misspecification. In this paper, we suggest a parsimonious quantile regression model for the diseased population, only locally at the controlled sensitivity level, and assess specificity with covariate-specific control of the sensitivity. Variance estimates are obtained from a sample-based approach and bootstrap. Furthermore, our proposed local model extends readily to a global one for covariate adjustment for the receiver operating characteristic (ROC) curve over the sensitivity continuum. We demonstrate computational efficiency of this proposed method and restore the inherent monotonicity in the estimated covariate-adjusted ROC curve. The asymptotic properties of the proposed estimators are established. Simulation studies show favorable performance of the proposal. Finally, we illustrate our method in biomarker evaluation for aggressive prostate cancer.

LINEAR BIOMARKER COMBINATION FOR CONSTRAINED CLASSIFICATION.

Multiple biomarkers are often combined to improve disease diagnosis. The uniformly optimal combination, i.e., with respect to all reasonable performance metrics, unfortunately requires excessive distributional modeling, to which the estimation can be sensitive. An alternative strategy is rather to pursue local optimality with respect to a specific performance metric. Nevertheless, existing methods may not target clinical utility of the intended medical test, which usually needs to operate above a certain sensitivity or specificity level, or do not have their statistical properties well studied and understood. In this article, we develop and investigate a linear combination method to maximize the clinical utility empirically for such a constrained classification. The combination coefficient is shown to have cube root asymptotics. The convergence rate and limiting distribution of the predictive performance are subsequently established, exhibiting robustness of the method in comparison with others. An algorithm with sound statistical justification is devised for efficient and high-quality computation. Simulations corroborate the theoretical results, and demonstrate good statistical and computational performance. Illustration with a clinical study on aggressive prostate cancer detection is provided.

Impact of Prostate Health Index Results for Prediction of Biopsy Grade Reclassification During Active Surveillance.

PURPOSE: We assessed whether Prostate Health Index results improve prediction of grade reclassification for men on active surveillance. METHODS AND MATERIALS: We identified men in Canary Prostate Active Surveillance Study with Grade Group 1 cancer. Outcome was grade reclassification to Grade Group 2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R1) vs clinical data+Prostate Health Index (R3). We considered an "or"-logic rule combining clinical score and Prostate Health Index (R4), and a "2-step" rule using clinical data followed by risk stratification based on Prostate Health Index (R2). Rules were applied to a validation set, where values of R2-R4 vs R1 for specificity and sensitivity were evaluated. RESULTS: We included 1,532 biopsies (n = 610 discovery; n = 922 validation) among 1,142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among the discovery set, at 95% sensitivity, R2 yielded highest specificity at 27% vs 17% for R1. In the validation set, R3 had best performance vs R1 with Δsensitivity = -4% and Δspecificity = +6%. There was slight improvement for R3 vs R1 for confirmatory biopsy (AUC 0.745 vs R1 0.724, ΔAUC 0.021, 95% CI 0.002-0.041) but not for subsequent biopsies (ΔAUC -0.012, 95% CI -0.031-0.006). R3 did not have better discrimination vs R1 among the biopsy cohort overall (ΔAUC 0.007, 95% CI -0.007-0.020). CONCLUSIONS: Among active surveillance patients, using Prostate Health Index with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

High throughput, label-free isolation of circulating tumor cell clusters in meshed microwells.

Extremely rare circulating tumor cell (CTC) clusters are both increasingly appreciated as highly metastatic precursors and virtually unexplored. Technologies are primarily designed to detect single CTCs and often fail to account for the fragility of clusters or to leverage cluster-specific markers for higher sensitivity. Meanwhile, the few technologies targeting CTC clusters lack scalability. Here, we introduce the Cluster-Wells, which combines the speed and practicality of membrane filtration with the sensitive and deterministic screening afforded by microfluidic chips. The >100,000 microwells in the Cluster-Wells physically arrest CTC clusters in unprocessed whole blood, gently isolating virtually all clusters at a throughput of >25 mL/h, and allow viable clusters to be retrieved from the device. Using the Cluster-Wells, we isolated CTC clusters ranging from 2 to 100+ cells from prostate and ovarian cancer patients and analyzed a subset using RNA sequencing. Routine isolation of CTC clusters will democratize research on their utility in managing cancer.

Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model.

Invariant natural killer T cells (iNKT cells) express a semi-invariant T cell receptor that recognizes certain glycolipids (including α-galactosylceramide, αGC) bound to CD1d, and can induce potent antitumor responses. Here, we assessed whether αGC could enhance the efficacy of a GM-CSF-producing tumor cell vaccine in the transgenic SV40 T antigen-driven TRAMP prostate cancer model. In healthy mice, we initially found that optimal T cell responses were obtained with αGC-pulsed TRAMP-C2 cells secreting GM-CSF and milk fat globule epidermal growth factor protein-8 (MFG-E8) with an RGD to RGE mutation (GM-CSF/RGE TRAMP-C2), combined with systemic low dose IL-12. In a therapeutic model, transgenic TRAMP mice were then castrated at ~ 20 weeks, followed by treatment with the combination vaccine. Untreated mice succumbed to tumor by ~ 40 weeks, but survival was markedly prolonged by vaccine treatment, with most mice surviving past 80 weeks. Prostates in the treated mice were heavily infiltrated with T cells and iNKT cells, which both secreted IFNγ in response to tumor cells. The vaccine was not effective if the αGC, IL-12, or GM-CSF secretion was eliminated. Finally, immunized mice were fully resistant to challenge with TRAMP-C2 cells. Together these findings support further development of therapeutic vaccines that exploit iNKT cell activation.

Collision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium.

PURPOSE: Our goal was to evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study. MATERIALS AND METHODS: We evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications. RESULTS: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep venous thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain. CONCLUSIONS: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.

Cancer-specific outcomes for prostate cancer patients who had prebiopsy prostate MRI.

PURPOSE: We characterized population-level cancer-specific outcomes for prostate cancer patients based on use of prebiopsy prostate MRI. METHODS: Using SEER-Medicare claims, we identified men diagnosed with localized prostate cancer from 2010-2015 and prostate-specific antigen (PSA) < 20 ng/mL. Primary exposure was prebiopsy prostate MRI prior to diagnosis (i.e., CPT 72197 linked to urology-specific diagnosis). Outcomes included diagnosis of Grade Group 2+ disease on biopsy and proportion treated with prostatectomy. We assessed those treated with prostatectomy and evaluated association with prebiopsy MRI and grade concordance between biopsy and prostatectomy. We estimated adjusted odds ratios with multivariable regression after accounting for other factors (e.g., age, year, PSA, race/ethnicity). RESULTS: We identified 48,574 patients, where 915 (1.9%) underwent prebiopsy MRI. Patients with prebiopsy MRI had more GG>2 cancer on biopsy (70.0% MRI vs. 62.8% no MRI) but lost significance after adjustment (OR 1.12, 95% CI 0.96-1.30). Patients with prebiopsy MRI were more likely to have prostatectomy (39.2% vs. 28.5%, adjusted OR 1.51, 95%CI 1.31-1.76). Downgrading from biopsy GG 3-5 to final GG 1-2 was less common after prebiopsy MRI (21.3% vs. 28.2% no MRI, P = 0.05) but not significant after adjustment (OR 0.74, 95% CI 0.51 - 1.08). Among 14,027 men with prostatectomy, accurate risk classification was not more likely with a prebiopsy MRI (48.0% no MRI vs. 49.6% prebiopsy MRI, P = 0.56). CONCLUSION: During initial adoption, men with prebiopsy prostate MRI had marginally increased detection of significant cancer on biopsy and were more likely to be treated with prostatectomy. For those treated with prostatectomy, use of prebiopsy MRI was not associated with a greater likelihood of accurate risk classification or grade concordance between biopsy and final pathology results.

Association of race with receipt of definitive therapy for high risk prostate cancer in older men.

OBJECTIVES: Black men are more likely to die of prostate cancer (PCa) than White men. Whether this difference is driven by biological versus sociodemographic and access to care differences is actively investigated. However, studies that have highlighted racial disparities in PCa outcomes have been poorly represented by elderly men, a notoriously undertreated group. Herein, we evaluated use of curative treatment between Black and White elderly men with aggressive PCa in a large US database. METHODS: Men ≥80 years diagnosed with National Comprehensive Cancer Network-defined high risk PCa between 2004 and 2016 were analyzed from the National Cancer Database. Multivariable logistic regression was used to model the effect of race and sociodemographic factors on receipt of definitive therapy (surgery or radiation +/- androgen deprivation therapy [ADT]) versus non-definitive therapy (ADT alone or observation) in inverse probability weighted groups matched for stage, prostate-specific antigen, and Gleason score. RESULTS: Between 2004 and 2016, utilization of definitive therapy with either surgery or radiation therapy increased in both White and Black men in the United States. However, we found that Black men compared with White men were significantly less likely to receive definitive therapy (OR 0.71, 95% CI 0.64-0.79, p < .001). Using multivariable modeling, effect size diminished after adjusting for sociodemographic variables. Notably, there is evidence of the racial disparity narrowing over time. CONCLUSIONS: These findings highlight striking but improving racial disparities in elderly men with high risk PCa in the US, an overall undertreated population.

Disparities in magnetic resonance imaging of the prostate for traditionally underserved patients with prostate cancer.

BACKGROUND: Prebiopsy magnetic resonance imaging (MRI) of the prostate improves detection of significant tumors, while decreasing detection of less-aggressive tumors. Therefore, its use has been increasing over time. In this study, the use of prebiopsy MRI among Medicare beneficiaries with prostate cancer was examined. It was hypothesized that patients of color and those in isolated areas would be less likely to undergo this approach for cancer detection. METHODS: Using cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) program linked to billing claims for fee-for-service Medicare beneficiaries, men with nonmetastatic prostate cancer were identified from 2010 through 2015 with prostate-specific antigen (PSA) <30 ng/mL. Outcome was prebiopsy MRI of the prostate performed within 6 months before diagnosis (ie, Current Procedural Terminology 72197). Exposures were patient race/ethnicity and rural/urban status. Multivariable regression estimated the odds of prebiopsy prostate MRI. Post hoc analyses examined associations with the registry-level proportion of non-Hispanic Black patients and MRI use, as well as disparities in MRI use in registries with data on more frequent use of prostate MRI. RESULTS: There were 50,719 men identified with prostate cancer (mean age, 72.1 years). Overall, 964 men (1.9% of cohort) had a prebiopsy MRI. Eighty percent of patients with prebiopsy MRI lived in California, New Jersey, or Connecticut. Non-Hispanic Black men (0.6% vs 2.1% non-Hispanic White; odds ratio [OR], 0.28; 95% CI, 0.19-0.40) and men in less urban areas (1.1% vs 2.2% large metro; OR, 0.65; 95% CI, 0.44-0.97) were less likely to have prebiopsy MRI of the prostate. CONCLUSIONS: Non-Hispanic Black patients with prostate cancer and those in less urban areas were less likely to have prebiopsy MRI of the prostate during its initial adoption as a tool for improving prostate cancer detection.

A panel of selected serum protein biomarkers for the detection of aggressive prostate cancer.

Background: Current PSA-based tests used to detect prostate cancer (PCa) lack sufficient specificity, leading to significant overdetection and overtreatment. Our previous studies showed that serum fucosylated PSA (Fuc-PSA) and soluble TEK receptor tyrosine kinase (Tie-2) had the ability to predict aggressive (AG) PCa. Additional biomarkers are needed to address this significant clinical problem. Methods: A comprehensive Pubmed search followed by multiplex immunoassays identified candidate biomarkers associated with AG PCa. Subsequently, multiplex and lectin-based immunoassays were applied to a case-control set of sera from subjects with AG PCa, low risk PCa, and non-PCa (biopsy negative). These candidate biomarkers were further evaluated for their ability as panels to complement the prostate health index (phi) in detecting AG PCa. Results: When combined through logistic regression, two panel of biomarkers achieved the best performance: 1) phi, Fuc-PSA, SDC1, and GDF-15 for the detection of AG from low risk PCa and 2) phi, Fuc-PSA, SDC1, and Tie-2 for the detection of AG from low risk PCa and non-PCa, with noticeable improvements in ROC analysis over phi alone (AUCs: 0.942 vs 0.872, and 0.934 vs 0.898, respectively). At a fixed sensitivity of 95%, the panels improved specificity with statistical significance in detecting AG from low risk PCa (76.0% vs 56%, p=0.029), and from low risk PCa and non-PCa (78.2% vs 65.5%, p=0.010). Conclusions: Multivariate panels of serum biomarkers identified in this study demonstrated clinically meaningful improvement over the performance of phi, and warrant further clinical validation, which may contribute to the management of PCa.

Decision regret, adverse outcomes, and treatment choice in men with localized prostate cancer: Results from a multi-site randomized trial.

INTRODUCTION: Men diagnosed with localized prostate cancer must navigate a highly preference-sensitive decision between treatment options with varying adverse outcome profiles. We evaluated whether use of a decision support tool previously shown to decrease decisional conflict also impacted the secondary outcome of post-treatment decision regret. METHODS: Participants were randomized to receive personalized decision support via the Personal Patient Profile-Prostate or usual care prior to a final treatment decision. Symptoms were measured just before randomization and 6 months later; decision regret was measured at 6 months along with records review to ascertain treatment choices. Regression modeling explored associations between baseline variables including race and D`Amico risk, study group, and 6-month variables regret, choice, and symptoms. RESULTS: At 6 months, 287 of 392 (73%) men returned questionnaires of which 257 (89%) had made a treatment choice. Of that group, 201 of 257 (78%) completely answered the regret scale. Regret was not significantly different between participants randomized to the P3P intervention compared to the control group (P = 0.360). In univariate analyses, we found that Black men, men with hormonal symptoms, and men with bowel symptoms reported significantly higher decision regret (all P < 0.01). Significant interactions were detected between race and study group (intervention vs. usual care) in the multivariable model; use of the Personal Patient Profile-Prostate was associated with significantly decreased decisional regret among Black men (P = 0.037). Interactions between regret, symptoms and treatment revealed that (1) men choosing definitive treatment and reporting no hormonal symptoms reported lower regret compared to all others; and (2) men choosing active surveillance and reporting bowel symptoms had higher regret compared to all others. CONCLUSION: The Personal Patient Profile-Prostate decision support tool may be most beneficial in minimizing decisional regret for Black men considering treatment options for newly-diagnosed prostate cancer. TRIAL REGISTRATION: NCT01844999.