bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective randomized trial of gene expression classifier utility following radical prostatectomy (G-MINOR).
Authors: Morgan Todd Matthew , Okoth Linda A. , Spratt Daniel Eidelberg , Dunn Rodney , Feng Felix Y , Johnson Anna M. , Lane Brian R. , Linsell Susan , Ghani Khurshid R. , Montie James E. , Mehra Rohit , Daignault-Newton Stephanie , Huang Huei-Chung , Todorovic Tamara , Davicioni Elai , Burks Frank , Rodriguez Paul , Sarle Richard , Miller David Christopher , Cher Michael L. ,   Michigan Urological Surgery Improvement Collaborative
Published: March 2021

15

Background: Decipher is a tissue-based genomic classifier (GC) developed and validated in the post-radical prostatectomy (RP) setting as a predictor of metastasis. We conducted the first prospective randomized controlled trial assessing the use of a prostate cancer GC, with a primary objective to determine the impact of test results on adjuvant treatment decisions. Methods: The Genomics in Michigan ImpactiNg Observation or Radiation (G-MINOR) randomized trial enrolled participants across 12 centers between January 2017-August 2018. Eligible patients had undergone RP within 9 months of enrollment, had pT3-4 disease and/or positive surgical margins, and a PSA < 0.1ng/mL. Patients were assigned to either the GC or Usual Care (UC) group using cluster-crossover block randomization. Patients and providers in both arms received a CAPRA-S recurrence risk score. Decipher scores were obtained on RP tissue of all patients, but patients and providers in the UC arm were blinded to the results. The primary endpoint was the impact of impact of GC test result on adjuvant treatment decisions compared to clinical factors alone within 18 months of RP. Results: 356 patients were randomized and 340 had at least 18 months of follow-up. Of these, all but 2 control (UC) patients had sufficient tissue to pass quality control for GC testing. Randomization resulted in 175 (51.5%) GC and 165 (48.5%) UC patients. There were no significant differences in clinical variables or Decipher scores between arms. At 18 months post-RP, 19 (10.9%) patients in the GC group and 12 (7.3%) patients in the UC group had received adjuvant treatment. In the primary analysis, availability of the GC score in the GC arm was significantly associated with adjuvant treatment in GC high-risk patients after controlling for CAPRA-S risk (OR 7.6, 95%CI 1.95-29.6, p = 0.009). In the GC arm, both GC score (OR 8.8, 95%CI 1.9-39.7, p = 0.005) and CAPRA-S score (OR 3.8, 95%CI 1.09-12.9, p = 0.04) were independently associated with adjuvant treatment in a multivariable logistic regression model. Conclusions: In the first ever randomized trial testing the impact of a prostate cancer genomic classifier on treatment decisions, the use of a GC post-RP impacted post-operative treatment in a manner concordant with classifier risk. Further follow-up will be necessary to assess the impact of GC testing on oncologic outcomes. Clinical trial information: NCT02783950. [Table: see text]
Identification of prognostic and predictive biomarkers of overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel, prednisone (DP) +/- bevacizumab (B) in CALGB 90401 (Alliance).
Authors: Halabi Susan , Yang Qian , Starr Mark D. , Brady John C. , Armstrong Andrew J. , George Daniel J. , Kelly William Kevin , Beltran Himisha , Morris Michael J. , Nixon Andrew B.
Published: March 2021

154

Background: CALGB 90401 was a phase III trial of 1050 pts with mCRPC comparing DP+B versus DP alone. While this trial did not show an improvement in OS in the overall population, there were improved PSA response, objective responses and delays in progression suggesting that subsets of men may derive benefit from this combination The purpose of this analysis was to identify and validate plasma angiokines (PAs) that are prognostic or predictive of OS and PFS benefit from bevacizumab in men with mCRPC. Methods: Baseline EDTA plasma samples from 679 consenting pts were analyzed using an optimized multiplex ELISA platform for 25 PAs related to tumor growth, angiogenesis, and inflammation. The data were randomly split into training (n = 462) and testing (n = 217) sets. The proportional hazards model was utilized to test for the prognostic and predictive importance of the PAs in predicting OS and PFS, with and without adjustment for clinical risk score. Analyses were adjusted for multiplicity using false discovery rate (FDR). Results: For the prognostic analysis, 14 PAs (angiopoeitin-2, BMP9, Chromogranin A, HER3, HGF, ICAM-1, IL6, OPN, PIGF, TIMP, TSP2, VEGFA, VEGFR1, and VEGF-R3) were prognostic of OS and 8 PAs (angiopoietin-2, HER3, ICAM-1, IL6, OPN, TIMP, VEGFA and VEGF-R3) were prognostic of PFS in the training set (FDR < 0.05). None of the PAs were statistically significant for OS or PFS when adjusting by the clinical risk score, suggesting that angiokine levels associate with clinical prognostic factors. OPN was predictive of OS in the training set but no other PAs were found to be predictive of PFS improvement with DP+B. Using the testing set, we were unable to validate that OPN is predictive of OS/PFS or any of the PAs are predictive biomarkers of the OS or PFS benefits of DP+B over DP alone in men with mCRPC. Conclusions: While PAs are prognostic for OS and PFS in univariate analysis, we were unable to validate the results in the testing set. Furthermore, we did not identify any PAs that are predictive of benefit from the addition of bevacizumab to docetaxel/prednisone with ADT in this setting. Nevertheless, these remain worthy of further evaluation as potential therapeutic targets.
Plasma cell-free DNA profiling of PI3K/Akt pathway aberrations in two multi-institutional independent metastatic castration-resistant prostate cancer (mCRPC) cohorts.
Authors: Kwan Edmond Michael , Dai Chao , Fettke Heidi , Hauser Christine , Bukczynska Patricia , Ng Nicole , Foroughi Siavash , Graham Lisa-Jane K. , Mahon Kate Lynette , Tan Winston , Wang Amy , Zhao Zhixin , Zheng Tiantian , Zhou Kemin , Yu Jian-Jun , Du Peter , Horvath Lisa , Jia Shidong , Kohli Manish , Azad Arun
Published: March 2021

159

Background: Tumour tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the phosphatidylinositol-3-kinase (PI3K)/Akt-signaling pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays for robustly identifying PI3K/Akt pathway aberrations including CNVs are urgently required. Methods: In this multi-institutional prospective biomarker study, we used the Predicine cfDNA assay, optimised for CNV detection, to perform targeted sequencing in 231 mCRPC patients in two independent cohorts (Australian, n = 78; US, n = 153). Kaplan-Meier survival estimates and multivariable Cox regression analysis were used to assess associations between genomic aberrations and progression-free survival (PFS) and overall survival (OS). Results: PTEN loss and PIK3CA gain were detected in 37% (85/231) and 17% (39/231) of patients, respectively. Poorer outcomes were observed in patients with PI3K/Akt pathway aberrations, including those with dual PTEN loss and PIK3CA gain (HR 2.3, 95% CI 1.2-4.4). Similarly, cumulative CNV burden in the PI3K/Akt and AR pathways (0 vs 1 vs ≥2 CNVs in Australian cohort: median OS 33.5 vs 17.2 vs 9.7 months, p< 0.001; 0 vs 1 vs ≥2 CNVs in US cohort: median OS 35.5 vs 14.3 vs 9.2 months, p< 0.001) was associated with significantly worse clinical outcomes. Notably, 21% (31/146) of PTEN-neutral patients harbored other alterations in the PI3K/Akt pathway. Conclusions: Our cfDNA assay readily detected PI3K/Akt pathway CNVs, with the prevalence of PTEN loss comparable to prior tissue sequencing studies. CNVs in the PI3K/Akt pathway were associated with deleterious clinical outcomes, especially when concurrent with AR gain. Additional PI3K/Akt pathway aberrations were found in approximately one-fifth of PTEN-neutral mCRPC. Collectively, our data demonstrate the potential utility of profiling cfDNA to facilitate and optimize patient selection for treatment with Akt inhibitors in mCRPC. [Table: see text]
HHV-8 positive clinically advanced castrate-resistant prostate cancer (mCRPC): A potentially distinct molecular subset.
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Spiess Philippe E. , Danziger Natalie , Lin Douglas I. , Huang Richard , Mata Douglas A , Decker Brennan James , Gjoerup Ole , Sokol Ethan , Tukachinsky Hanna , Venstrom Jeffrey Michael , Ross Jeffrey S.
Published: March 2021

163

Background: Herpesvirus HHV-8 has been detected in normal prostate tissue and has been linked to the acquisition of androgen-independent growth of prostate cancer cells in vitro, early development of anti-androgen therapy resistance, and more aggressive disease in a subset of patients with mCRPC. We used comprehensive genomic profiling (CGP) to test the hypothesis that HHV-8 associated mCRPC is a distinct molecular subset of mCRPC featuring altered AR signaling compared to HHV-8 negative mCRPC. Methods: Using a hybrid capture-based FDA-approved CGP assay, a series of 4,918 mCRPC were sequenced to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). HHV-8 status was determined by CGP-based identification of unique viral reads. Results: Overall, 128 (2.6%) of the mCRPC cases harbored HHV-8 sequences (Table). The patient age distribution was similar in the HHV-8+ and HHV-8− groups. GAs in AR, predominantly amplifications, and RAD21 were slightly reduced in HHV-8+ mCRPC cases (P = .01 for both). The frequencies of GAs in genes associated with mCRPC including PTEN, BRCA2, ATM, CDK12, and the TMPRSS2: ERG fusion were similar in the two groups. HHV-8+ patients were less likely to be of European ancestry (P = 0.001). Putative biomarkers associated with immunotherapy response (MSI status, TMB, and PD-L1 expression) were also similar in the two groups. Conclusions: HHV-8+ mCRPC is a rare sub-type of mCRPC with lower frequency of AR GAs compared to HHV-8− mCRPC cases, suggesting a potential role of HHV-8 in inducing androgen-independent prostate cancer growth. Additional alterations associated with potentially enhanced PARP inhibitor response seen in HHV-8+ mCRPC (e.g., RAD21) suggest that early performance of CGP may inform precision treatment strategies to be tested in clinical trials. [Table: see text]
Genomic landscape of CDK12 mutated metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Spiess Philippe E. , Danziger Natalie , Huang Richard , Mata Douglas A , Decker Brennan James , Sokol Ethan , Montesion Meagan , Tukachinsky Hanna , Venstrom Jeffrey Michael , Ross Jeffrey S.
Published: March 2021

165

Background: Identifying prostate cancer patients likely to benefit from immune checkpoint inhibitors (ICPI) remains an unmet need. Specific loss-of-function genomic alterations (GA) in CDK12 are associated with focal tandem duplications linked to fusion-induced production of neoantigens and are a promising candidate biomarker for ICPI. Using comprehensive genomic profiling (CGP) we compared the GA landscape of CDK12 altered (CDK12mut+) and unaltered (CDK12mut-) tumors. Methods: 4,918 mCRPC tumors were sequenced using a hybrid capture-based FDA-approved CGP assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining -49% and high staining ≥50% expression. Results: Overall, 315 (6.4%) of the mCRPC cases were CDK12mut+ (Table). CDKmut+ cases had significantly fewer GA in TMPRSS2: ERG (P < .0001), TP53 (P < .0001), PTEN (P < .0001), ATM (P = .001), PIK3CA (P = .003), RB1 (P = .02), BRCA2 (P < .0001) and APC (P = .002). CDK12mut+ cases featured higher frequencies only in CCND1 (P < .0001), BRAF (P = .007) and ERBB2 (P < .001) as well as in cell cycle regulatory genes including MDM2/4 (P < .0001), CDK4 (P < .0001) and CDK6 (P = .002). CDK12mut+ cases featured more frequent MSI-H status (P = .007), significantly higher median TMB (P < .001) and more frequent low positive (1-49% staining) PD-L1 expression (P = .02). High (≥50%) PD-L1 expression was rarely identified in either cohort. Conclusions: CDK12mut+ mCRPC demonstrates a unique genomic profile with significant differences compared with CDK12mut- mCRPC. Lower frequencies of GA associated with homologous recombination defect and mTOR pathway may impact the use of platinum agents, as well as PARPi and PIK3CA/Akt/mTOR inhibitors. Opportunities for targeted therapies for BRAF and ERBB2 driven mCRPC may be enriched in the CDK12mut+ tumors and raise the possibility of combination therapy strategies although the numbers of patients are small and validation is needed. The slightly higher MSI High status, median TMB and PD-L1 staining may be associated with additional benefit from ICPI and warrants further prospective investigation. [Table: see text]
Analysis of germline alterations and testing patterns in Hispanic men with prostate cancer.
Authors: Shaya Justin , Madlensky Lisa , Millard Frederick E. , Randall James Michael , Stewart Tyler Francis , Ajmera Archana , Cherry Reena , Rose Brent S. , Parsons John Kellogg , McKay Rana R.
Published: March 2021

Background: Little is known about the prevalence of germline alterations in Hispanic men with prostate cancer (PC). Here, we examine the rates of germline alterations in Hispanic men with PC, compare these rates to non-Hispanic white men, and examine factors associated with clinicians offering testing. Methods: Single center, retrospective analysis of patients (pts) with PC who self-identify as Hispanic and meet the NCCN criteria for germline testing. Pts who consented for testing underwent a commercial multigene germline assay. Among those tested, the proportion of pathogenic alterations and variants of uncertain significance (VUS) were computed in 20 genes associated with germline alterations in PC. This was compared to non-Hispanic white (NHW) pts who also underwent germline testing. Multivariate logistic regression was performed to assess clinical and demographic factors associated with clinicians offering germline testing and/or genetics referral. Results: We identified 136 Hispanic men with PC eligible for germline testing between 2018-2020. 26.1% (n=34) of pts underwent germline testing and among those tested, 14.7% (n=5/34) had a pathogenic alteration detected. Median age of the cohort was 70 years and 46.3% (n=63) had metastatic disease. Spanish was the primary language for 50% (n=68) and 14.0% (n=19) of pts had at least 1 first-degree relative with PC. Alterations were detected in ATM (n=2), CHEK2 (n=1), MSH2 (n=1), MSH6 (n=1). When stratified by disease status, the rate of pathogenic alterations was 7.7% (n=1/13) in localized and 19.0% (n=4/21) in metastatic disease. When compared to NHW pts who underwent testing (n=139), the rate of pathogenic alterations was not significantly different (14.7% in Hispanic vs 12.2% in NWH, p=0.77). The rate of VUS in Hispanic pts was significantly higher than NHW pts (20.6% in Hispanic vs 7.2% in NWH, p=0.047). In a multivariate model examining the factors associated with receipt of testing in Hispanic men (Table), the presence of metastatic disease and a family history of PC were positively associated with testing. Spanish as a primary language was negatively associated with testing. Age was not a significant predictor. Conclusions: Among Hispanic men who underwent germline testing, there was a similar rate of pathogenic germline alterations compared to NHW men. Among Hispanic men, primary Spanish speakers appear to have lower rates of germline testing. Bilingual strategies are needed to improve rates of testing to ensure equity in germline testing for all patients. [Table: see text]
Bilateral disease and risk of prostate cancer progression in an active surveillance cohort.
Authors: Khondakar Nabila , O'Connor Luke P. , Williams Cheyenne , Daneshvar Michael , Egan Jillian , Yerram Nitin , Webster Brad , Merino Maria , Choyke Peter L. , Wood Bradford , Turkbey Baris , Pinto Peter A.
Published: March 2021

207

Background: Active surveillance (AS) is considered the standard of care for managing patients with low-risk prostate cancer. Identifying risk factors for disease progression on AS can improve risk stratification. As previously described, the presence of bilateral disease may affect disease progression. Current systematic biopsy techniques inadequately predict presence of bilateral disease. We hypothesize that combined mpMRI-guided fusion biopsy and systematic biopsy will improve detection of bilateral disease. Methods: Our institutional database of patients referred for AS from 2007-2020 was queried. All AS patients received combined 12-core systematic biopsy and mpMRI-Fusion biopsy (Cbx), and those with Gleason Grade group 1 (GG1) on confirmatory Cbx were included. Cox regression analysis identified baseline characteristics associated with AS progression, defined as progression to GG ≥ 2. The distributions of GG and National Comprehensive Cancer Network (NCCN) risk categories were also compared. Results: 103 patients with prostate cancer and at least one follow-up biopsy at our institution were included in the analysis. 30% (31/103) had bilateral disease and 70% (72/103) had unilateral disease. On univariable and multivariable analysis, both PSAD (univariable HR = 1.6; 95% CI: 1.1-2.2; multivariable HR = 1.7; CI: 1.2-2.5) and presence of bilateral disease (univariable HR = 2.2; 95% CI: 1.3-4.0; multivariable HR = 2.2; 95% CI: 1.2-4.0) at time of confirmatory biopsy were significantly associated with AS progression. On Kaplan-Meier analysis, median time from Cbx to AS progression ≥ GG2 for the whole cohort was 52 months (95% CI: 44 - 68). The median time to progression for patients with unilateral and bilateral disease was 68 months and 52 months, respectively (log-rank test, p = 0.0055). Bilateral disease was marginally associated with receiving an NCCN score of high or very high on upgraded biopsy (RR: 3.16, 95% CI: 1.004-9.932). NCCN score at time of confirmatory biopsy was not associated with progression. However, NCCNs scores and GG at time of progression were higher among patients with bilateral disease (p = 0.015 and p = 0.024). Ultimately, use of combined biopsy resulted in 16.1% more bilateral cancers detected when compared to systematic biopsy. Conclusions: Detection of bilateral disease using combined biopsy was significantly associated with disease progression in patients on AS. Notably, combined biopsy resulted in greater detection of bilateral disease than systematic biopsy alone. Identifying presence of bilateral disease using combined biopsy could ultimately contribute to management decisions in patients on AS.
Management of localized prostate cancer during the Covid-19 pandemic at a multidisciplinary cancer center in New York City, New York.
Authors: Wood Andrew , Shpeen Benjamin , Lee Jeffrey , Snyder Rose , Xu Yiqing , Kotamarti Srinath , Teper Ervin , Lubin Marc , Silver David , Becker Kevin Douglas , Meghal Trishala , Schulman Ariel
Published: March 2021

213

Background: In March 2020, the coronavirus disease (COVID-19) spread across New York City. All non-emergent medical care was delayed, and healthcare resources were redirected to COVID-19 patients. Physicians managing prostate cancer faced unprecedented decisions to balance risks of the pandemic against risks of cancer progression. Here we review management of localized prostate cancer at an Urban Cancer Center in New York City during the height of the pandemic. Methods: We examined men with newly diagnosed, localized prostate cancer seen in initial consultation by Urology or Radiation Oncology between January 1 and June 30, 2020 (COVID-19 cohort). We reviewed cancer management, as well as the impact of the pandemic on treatment choice and patterns of care. Chi square and t-test analyses were performed to compare the COVID-19 cohort to a similar cohort managed before the pandemic from July 1, 2019 to December 31, 2019 (pre-COVID-19 cohort). Results: We identified 75 men in the COVID-19 cohort. NCCN risk profile: 20% low risk, 53.4% intermediate, and 26.7% high. During the height of the pandemic, there was 7 week pause in both new radiation therapy (RT) and radical prostatectomy. 11 patients continued previous RT, 1 of which developed a symptomatic covid infection and required a 2 week pause in treatment. During the operating room restart, 11 patients underwent radical prostatectomy including 8 with unfavorable-intermediate or high-risk disease. No surgical patients acquired COVID-19. Compared to the pre-COVID-19 cohort, the COVID-19 cohort had longer time from initial visit to treatment (92.1 days vs 71.0 days, p = 0.045) and a larger percentage of patients who were seen but did not return for management (25.3% vs 14%, p = 0.044). Conclusions: Our cancer center had a coordinated, 7-week cessation in primary RT and surgery for prostate cancer during the height of the COVID-19 pandemic. There were no severe COVID-19 infections among patients finishing RT, or the first cohort of men having surgery during the restart of treatments, suggesting that localized prostate cancer treatments can be safely delivered in the event of a second wave. We identified a substantial number of men who were seen, but did not return for management, highlighting a cohort who need to be reintegrated into the healthcare system. [Table: see text]
Impact of active surveillance for prostate cancer on the risk of depression and anxiety: Patient-reported outcomes (PROs) from the Vican Prospective Cohort.
Authors: Pignot Geraldine , Touzani Rajae , Marino Patricia , Walz Jochen , Rybikowski Stanislas , Maubon Thomas , Salem Naji , Mancini Julien , Gravis Gwenaelle , Bendiane Marc Karim , Bouhnik Anne Deborah
Published: March 2021

220

Background: Active surveillance (AS) is an option for low-risk localized prostate cancer and its use is on the rise due to the good long-term oncologic results. However, its impact on the quality of live of patients, particularly in terms of anxiety and emotional responses related to cancer is poorly evaluated. Methods: The french VICAN cohort is a representative sample of 4174 patients treated for cancer and survivors after 5 years. Patient-reported Outcomes (PROs) were collected prospectively by self-questionnaires on quality of live (SF-12) and treatments side effects. Among the 447 patients with prostate cancer, patients managed by active surveillance (AS), radiotherapy (RT), or radical prostatectomy (RP), for localized T1-T2 N0 M0 cancer with a Gleason score < 8 were selected. Data regarding depressive symptoms and percieved anxiety were analysed comparatively. Results: A total of 301 patients were included, among whom 68 (22.6%) managed by AS, 170 (56.5%) treated by RP and 63 (20.9%) treated with RT. Patients treated with AS had a lower clinical stage (p = 0.04) compared with patients in RP and RT groups. Regarding the impact on the quality of live, there was no significant difference in terms of depressive symptoms (no depressive symptoms reported for 82.4% of patients in the AS group vs 88.8% in RP and 74.6% in RT, p = 0.468) or percieved anxiety (no anxiety reported in 63.3% of cases in the AS group vs 71.2% in RP and 66.6% in RT, p = 0.214). Conclusions: Patients managed by AS for localized prostate cancer do not report more depressive symptoms or anxiety than patients treated with curative treatment (RP or RT). This confirms the importance of offering this therapeutic option if the histopathological criteria allow it and if the patient is compliant.
The BARCODE1 pilot study targeting men with increased genetic risk of developing prostate cancer: Examining the feasibility of a community-based screening program using polygenic risk score to target screening.
Authors: McHugh Jana Kathlyn , Benafif Sarah , ni Raghallaigh Holly , Bancroft Elizabeth , Kote-Jarai Zsofia , Eeles Ros A. ,   Barcode1 Study Team
Published: March 2021

227

Background: A significant proportion of Prostate cancer (PrCa) risk is attributable to heritable risk factors of which only a minority are high risk Mendelian traits. A greater proportion of PrCa is due to the combined effect of multiple low risk variants. There have been approximately 170 single nucleotide polymorphisms (SNPs) identified that are associated with PrCa risk in Europeans. Although each of these confer a low to moderate risk of PrCa, the cumulative risk (polygenic risk score, PRS) of increasing numbers of these risk alleles may confer a substantial relative risk. In PrCa genetic profiling, using PRS, could be used to target population screening to those at highest risk. BARCODE1 is the first study to prospectively review the use of a genetic profile in PrCa screening in the general population in the UK. Methods: Our study invited healthy males aged 55-69 to participate through their Primary Care physicians. Collection kits were mailed to retrieve saliva samples. Genotyping was carried out after DNA extraction using a study specific assay and the PRS was calculated for each participant using the sum of weighted alleles for 130 risk loci. Prostate MRI and Biopsy were then offered to men in the top 10% of the genetic risk profile. Results: 1434 men were invited by letter to participate. The uptake was 26%, of whom 87% of men were eligible for inclusion. Following DNA extraction, genotyping, and quality control checks, data were available for 297 men. 25 participants had PRS in the top 10% and were invited for screening; 19 underwent a prostate MRI, and 18 went on to have a systematic (+/- targeted prostate biopsy. There were 7 diagnoses of PrCa (38.9%). The cancers detected were low-risk and are being managed with Active Surveillance (AS). Results of the first year of follow up will be presented and an update of the main study which aims to recruit 5000 men. Conclusions: The BARCODE1 pilot has shown the feasibility of this population-based study, with an overall uptake of 26% and a cancer incidence of nearly 40%. We have identified approximately 70 Primary care providers who have contributed to the transition to the full BARCODE1 study, which will aim to recruit 5,000 men. The BARCODE1 study results will be important in defining the role of PRS genetic profiling in targeted PrCa population screening. Clinical trial information: IRAS257684.
Risk of urinary morbidity associated with photoselective vaporization of the prostate (PVP) in prostate cancer patients undergoing a combined radiotherapy regimen consisting of dynamic adaptive radiotherapy (DART) and brachytherapy boost.
Authors: Dattoli Michael J. , Kaminski Joseph M , Lawrence Gregory , Kaplon Daniel
Published: March 2021

231

Background: Recent studies have shown PVPs to be associated with diminished perioperative and postoperative complications compared to transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH). This is the first study to evaluate the timing of PVP intervention and post-treatment morbidity related to a combined regimen of DART and Pd-103 brachytherapy for treatment of prostate cancer. Methods: Between 12/05 and 04/20, 51 consecutive patients underwent Greenlight Laser (GLL) or Olympus Plasma Button (OPB) PVP after DART (median dose: 45 Gy) and before Pd-103 brachytherapy (median dose: 90 Gy). 27 patients received GLL PVP and 24 patients received OPB PVP. Peripheral seed loading designs were utilized to achieve optimal urethral sparing. The time from DART to PVP ranged from 1 to 81 days (median: 18 days). For 12 patients, the interval between DART and PVP was ≤7 days. The time from PVP to seed implant ranged from 0 to 55 days (median: 18 days). For 13 patients, the interval between PVP and implant was ≤7 days. American Urological Association (AUA) symptom scores were compiled prior to PVP and on the last post-brachytherapy follow-up. Post-implant follow-up ranged from 6 months to 15 years (median: 6.4 years). Results: No patient experienced post-implant urinary retention or incontinence. Morbidity was limited to RTOG grade 1-2 symptoms, with the exception of one patient who experienced protracted dysuria, which was identified to be secondary to a pre-existing prostate anomaly (steep urethral curvature). Only that patient required dilation for urethral stricture. AUA scores improved or remained the same in 43 of 51 patients. Only 1 patient of the remaining 8 experienced an increase in AUA > 8 points. Conclusions: In our experience, there have been remarkably few adverse urinary sequelae following Pd-103 implantation in patients with prior PVP and DART. In contrast to TURPs, PVPs are safe even with short intervals between DART and brachytherapy. Based upon these results, pre-implant PVP is preferred, rather than PVPs or TURPs in the post-implant setting.
Investigation of a 22-gene genomic classifier (GC) for risk stratification and molecular subtyping in an Asian prostate cancer (PCa) cohort.
Authors: Yee Wei Loong Sherman , Woo Wai Yee , Sim Adelene , Low Kar Perng , Meng Alice , Tan Janice Ser Huey , Tuan Jeffrey , Tan Terence WK , Wang Michael Lian Chek , Tay Kae-Jack , Cheng Christopher , Yeong Joe Poh Sheng , Liu Yang , Lee Lui Shiong , Kanesvaran Ravindran , Tan Michael Chien Sheng , Davicioni Elai , Khor Li Yan , Chua Melvin Lee Kiang
Published: March 2021

249

Background: A 22-gene GC has been proposed to refine risk stratification of localized PCa by conventional NCCN criteria, and this may potentially influence treatment recommendations. Nonetheless, majority of studies looking at the utility of GC were conducted in White and non-White men from Western cohorts. We therefore investigated the association of GC with NCCN risk groups (RG) in an Asian PCa cohort. Additionally, we examined for inter-racial differences in molecular subtyping between Asian and White/non-White PCa. Methods: GC (Decipher Biosciences Inc., CA) was performed on diagnostic biopsies of men who were treated with radiotherapy +/- hormonal therapy at a single institution (N = 75). ISUP Gleason’s grade (GG) and tumor cellularity were reviewed by an expert GU pathologist. RNA was extracted from 2 x 2.0-mm tumor cores using Qiagen AllPrep DNA/RNA FFPE Kit (Qiagen, Germany) and gene expression was performed on Affymetrix Human Exon 1.0 ST Array (ThermoFischer, CA). PAM50 molecular subtyping was derived using the DecipherGRID database. Results: We profiled 80 tumors from 75 patients, comprising of 18 (24.0%), 9 (12.0%), 21 (28.0%), and 19 (25.3%) NCCN low-/favorable intermediate-, unfavorable intermediate-, high- and very high-RG, respectively; of note, 8 (10.7%) patients had regional/metastatic disease at diagnosis. Using the GC, 27 (33.8%), 14 (17.5%) and 39 (48.8%) were classified as low- (<0.45), intermediate- (0.45-0.6) and high-RG, respectively (>0.6). When stratified using a three-tier clinico-genomic (CG) classification system (Spratt et al. 2017), 6 of 21 (28.6%) NCCN-defined high-risk and 4 of 19 (21.1%) very high-risk patients were downgraded to CG-defined intermediate-/low-risk, while 2 of 27 (7.4%) NCCN low-/intermediate-risk patients were in fact upgraded to CG high-risk. Next, we interrogated the PAM50 basal-luminal signature in our cohort. Interestingly, when matched to White (N = 5762) and non-White (N = 155) for NCCN RG, ISUP GG and age, we observed a high proportion of basal subtype (62.7%) in Asians, which contrasted the prevalence observed in White (16.7%) and non-White (15.9%) North American patients (Chi-sq P <0.001). Conclusions: Here, we demonstrated the utility of the 22-gene GC for refining the NCCN risk stratification in a largest Asian PCa dataset to-date. An unexpectedly high proportion of PAM50 basal-subtype was observed, suggesting race-specific differences of the tumor transcriptome.
Immunohistochemical evaluation of glutaminase expression in prostate adenocarcinoma and correlation with clinicopathologic parameters.
Authors: Myint Zin , Hensley Patrick J. , James Andrew Callaway , Wang Peng , Strup Stephen , Yan Donglin , St Clair William H. , DiPaola Robert S. , Allison Derek B.
Published: March 2021

251

Background: Glutaminolysis plays a significant role in the metabolic reprogramming of cancer cell growth and proliferation. Glutaminase (GLS1), the rate-limiting enzyme of the glutamine pathway, is frequently dysregulated in cancer. High GLS1 expression is reported in colorectal and breast cancers and has been found to correlate with the tumor stage and disease progression. Furthermore, a new orally bioavailable glutaminase inhibitor (CB-839) is in early phase clinical trials in select tumors. The purpose of this study is to investigate the status of GLS1 expression in prostate cancer (PCa) and to correlate expression levels with clinicopathologic parameters. Methods: Radical prostatectomy samples from 154 patients with prostate adenocarcinoma were retrospectively reviewed and used to evaluate GLS1 expression by immunohistochemistry (IHC). The IHC expression score was calculated by multiplying the intensity of the stain by the proportion of cells staining; cases were then segmented into negative, low, or high expression groups. In addition, 41 samples of benign prostate tissue were used as a control. Associations between GLS1 levels and clinicopathologic parameters were analyzed by Pearson’s chi-squared and Log-rank tests. Results: GLS1 expression in the benign controls were negative, low, and high in 59%, 41%, 0% of cases, respectively, compared to 53%, 21.5%, 25.5%, respectively, in PCa (p < 0.003). Most PCa patients were age < 60 (55.8%), white (78.6%), stage T2 (52.9%), node negative (80.5%), Grade Group 3 (44%), and non-smokers (63.6%). There was no difference between GLS1 expression and age, race, Gleason score, stage, node status, and smoking status by univariate analysis. The median biochemical-progression free survival for negative, low, and high expression was 10, 9, and 10 years, respectively (p = 0.7). Conclusions: In our study, PCa samples were more likely to have GLS1 expression compared to benign controls. Although GLS1 expression did not appear to be a prognostic marker, our cohort was enriched for cases with localized disease and low-to-intermediate grade PCa. As a result, future studies are warranted to evaluate the expression levels in high grade and advanced PCa cases to determine a role for prognostic and or therapeutic implication to justify future preclinical studies with CB-839.
The effect of maximum tumor diameter on disease control in intermediate and high-risk prostate cancer patients treated with brachytherapy boost.
Authors: Parsons Matthew , Hutten Ryan , Khouri Ashley , Tward Alexander , Morrell Glen , Peterson John Stuart , Cannon Donald Maurice , Lloyd Shane , Johnson Skyler B
Published: March 2021

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Background: Larger maximum tumor diameter (MTD) has been associated with worse prostate cancer outcomes for those undergoing surgery as well as salvage radiation. MTD is also an important consideration for patients weighing active surveillance. However, the impact of MTD in intermediate and high-risk prostate cancer treated with external beam radiotherapy (EBRT) and brachytherapy boost is unknown. We set out to evaluate MTD of the dominant nodule on MRI as a prognostic factor in patients treated with EBRT and brachytherapy boost for localized prostate cancer. Methods: Patients with prostate cancer treated with EBRT and brachytherapy boost were identified from an institutional database. In patients with a pretreatment MRI, data on MTD were retrospectively collected. Clinical data including age, ADT use, pretreatment PSA, International Society of Urologic Pathology (ISUP) group, clinical T-stage, and presence of adverse pathology on imaging (either seminal vesicle invasion or extraprostatic extension) were also collected. Multivariable and univariable cox proportional hazards models for biochemical failure (BF) and distant metastasis (DM) were produced in patients with MTD grouped by receiver operating characteristic (ROC) cutpoint. Cumulative hazard functions for BF and DM were compared with log-rank test and stratified by ISUP group. Results: Of 191 patients treated with EBRT and brachytherapy boost, 113 had pretreatment MRI and available MTD measurement. Median follow up was 40 months (interquartile range 23-66 months) and median MTD was 17 mm (interquartile range 13-22mm). Increasing MTD was associated with higher T stage and increased ADT use. ROC cutpoint optimization identified MTD of 24mm to be the optimal cut-point for both BF and DM. On univariate log-rank analysis, patients with MTD > 24mm had higher 5-year BF (31% vs 4%, p = 0.004) and DM (21% vs 4%, p = 0.002) than those with MTD≤24. Stepwise multivariable cox model for BF (P = 0.130, HR 1.08, 95% CI 0.98-1.21) and DM (P = 0.115, HR 1.09, 95% CI 0.98-1.23), MTD did not demonstrate statistical significance when controlling for clinical t-stage, adverse pathologic features on imaging, ISUP group, and ADT use. However, in patients with ISUP group 4-5 disease, MTD > 24 was independently associated with increased risk of DM (P = 0.032, HR 1.18, 95% CI 1.01-1.37). Conclusions: This is the first study to evaluate MTD on MRI as a prognostic factor in the setting of brachytherapy boost. These results demonstrate that for patients treated with EBRT and brachytherapy boost, MTD is independently associated with risk for metastasis in patients with ISUP grade 4 and 5 disease. Although these results require further validation, this suggests a possible role for MTD as a factor in risk assessment models and clinical decision-making.
Single-cell analysis of cellular state heterogeneity in human localized prostate cancer.
Authors: Song Hanbing , Weinstein Hannah N.W. , Allegakoen Paul , Wadsworth Marc , Xie Jamie , Yang Heiko , Feng Felix Y , Carroll Peter R. , Wang Bruce , Cooperberg Matthew R. , Shalek Alex , Huang Franklin W.
Published: March 2021

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Background: Prostate cancer is the second most common malignancy in men worldwide. The development of cancer from prostate tissue involves complex interactions of tumor cells with surrounding epithelial and stromal cells and can occur multifocally, suggesting that prostate epithelial cells may undergo cellular state transitions towards carcinogenesis. Previous studies on localized prostate cancer molecular changes have focused on unsorted bulk tissue samples, leaving a gap in our understanding of the cellular heterogeneity in the tumor microenvironment. Single-cell analyses of tumor specimens have the potential to reveal, at unprecedented resolution, cellular composition, as well as instructive intercellular interactions. Methods: To characterize the localized prostate cancer tumor microenvironment, we performed single-cell RNA-sequencing (scRNA-seq) on prostate biopsies, radical prostatectomy specimens, and matched patient-derived organoids from localized prostate cancer patients. Results: Within prostate epithelial cells, we identified a population of club cells that may act as progenitor cells. Furthermore, we uncovered luminal-like epithelial cellular states augmented in androgen signaling across basal and club cell populations. By classifying tumor cells based on ERG expression status, we found that ERG- tumor cells, in contrast to ERG+ cells, share transcriptomic heterogeneity with surrounding luminal epithelial cells and are associated with common stromal and immune microenvironment responses. These results suggest that specific immune niches may arise based on TMPRSS2-ERG fusion status. Finally, we generated prostate epithelial organoids derived from matched localized prostate cancer patients and characterized their transcriptomic profiles by scRNA-seq. These patient-derived organoids recapitulated tumor-associated epithelial cell states but also harbored distinct cell types and states from their parent tissues. Conclusions: Our data from localized prostate cancer specimens and organoids provide diagnostically relevant insights and will help advance our understanding of the cancer cellular states associated with prostate carcinogenesis.
Stage at presentation and oncologic outcomes for agent orange exposed and non-exposed United States veterans diagnosed with prostate cancer.
Authors: Tward Alexander , Tward Jonathan David
Published: March 2021

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Background: Exposure of Vietnam War Veterans to the defoliant Agent Orange (AO) has been linked to increased tumor stage of Veterans diagnosed with prostate cancer. However, information on the effect of exposure to treatment outcomes is lacking. The goal of this study was to evaluate oncologic outcomes in Veterans based on AO exposure history, accounting for known prognostic covariates not previously studied. Methods: United States military Veterans diagnosed with prostate adenocarcinoma born between the years 1930-1956 were identified from a large professionally curated institutional database. Evaluable patients had to have known AO exposure status, age, NCCN risk group, Charlson comorbidity score, smoking status, and whether initial therapy was surgical, radiation, or systemic. Risk of death, metastasis, and progression stratified by the type of initial therapy received was analyzed using Cox regression. Results: There were 70 AO exposed and 561 non-exposed Veterans identified, with a median follow-up of 10.0 years. AO exposure Veterans (AOeV) were significantly younger (64.0 versus 65.7 years, p=0.013) at diagnosis and presented at more advanced stages (e.g. Stage 4: 14.3% versus 2.5%) than non-exposed Veterans (non-AOeV). There was no difference for overall survival (HR=0.86, p=0.576, metastasis-free survival (HR=1.5, p=0.212), or progression-free survival (HR=0.67, p 0.060) between AOeV versus non-AOeV in analyses stratified by treatment received accounting for other prognostic covariates. Cigarette smoking was associated with a 2- 3-fold increased risk of death over those who quit or never smoked. Conclusions: Although AOeV do present at younger age and higher clinical stages than non-AOeV, the oncologic outcomes after accounting for treatments received and other prognostic covariates are similar. The implication is that AOeV are more likely to be recommended multimodality or systemic therapies at presentation.
Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma (pRCC): Results from the randomized phase II SWOG 1500 study.
Authors: Pal Sumanta K. , Tangen Catherine , Thompson Ian Murchie , Haas Naomi B. , George Daniel J. , Heng Daniel Yick Chin , Shuch Brian M. , Stein Mark N. , Tretiakova Maria S. , Humphrey Peter , Adeniran Adebowale , Narayan Vivek , Bjarnason Georg A. , Vaishampayan Ulka N. , Alva Ajjai Shivaram , Zhang Tian , Cole Scott Wesley , Plets Melissa , Wright John , Lara Primo "Lucky" N.
Published: March 2021

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Background: MET signaling is a key molecular driver in pRCC. Given that there is no optimal therapy for metastatic pRCC, we sought to compare an existing standard (sunitinib) to putative MET kinase inhibitors. Methods: Eligible patients had pathologically verified pRCC, Zubrod performance status 0-1, and measurable metastatic disease. Patients may have received up to 1 prior systemic therapy excluding VEGF-directed agents. Patients were randomized 1:1:1:1 to receive either sunitinib 50 mg po qd (4 wks on/2 wks off), cabozantinib 60 mg po qd, crizotinib 250 mg po bid, or savolitinib 600 mg po qd. Patients were stratified by prior therapy and pRCC subtype (I vs II vs not otherwise specified [NOS]) based on local review. The primary objective was to compare progression-free survival (PFS) for each experimental arm versus sunitinib. With 41 eligible patients per arm, we estimated 85% power to detect a 75% improvement in median PFS with a 1-sided alpha of 0.10 using intent-to-treat analysis. A pre-planned futility analysis was performed after 50% of PFS events occurred. Secondary endpoints included toxicity, response rate, and overall survival. Results: Between 4/2016 and 12/2019, 152 patients were enrolled; 5 were ineligible. Median age was 66 (range:29-89) and 76% were male; 92% had no prior therapy. By local pathologic review, 18%, 54% and 28% of patients were characterized as having type I, type II and NOS histology, respectively. In contrast, the frequency of type I, type II, and NOS by central review was 30%, 45% and 25%, respectively. Accrual to the savolitinib and crizotinib arms was halted early for futility (PFS hazard ratio > 1.0 for both); accrual continued to completion in the sunitinib and cabozantinib arms. Median PFS was significantly higher with cabozantinib relative to sunitinib (Table). Grade 3 or 4 adverse events occurred in 69%, 72%, 37% and 39% of patients receiving sunitinib, cabozantinib, crizotinib and savolitinib, respectively; one grade 5 adverse event was seen with cabozantinib. Overall survival and response data will be presented. Conclusions: In this multi-arm randomized trial, only cabozantinib resulted in a statistically significant and clinically meaningful prolongation of PFS in pRCC patients compared to sunitinib. These data support cabozantinib as a reference standard for eligible patients with metastatic pRCC. Clinical trial information: NCT02761057 . [Table: see text]
Patterns and predictors of oral anticancer agent utilization in diverse metastatic renal cell carcinoma patients.
Authors: Wheeler Stephanie B. , Spees Lisa , Jackson Bradford E , Baggett Christopher , Wilson Lauren E , Greiner Melissa A. , George Daniel J. , Scales Charles D. , Pritchard Jessica , Dinan Michaela Ann
Published: March 2021

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Background: Availability of targeted oral anti-cancer agents (OAA) has transformed care delivery for metastatic renal cell carcinoma (RCC) patients. Our objective was to identify patterns and predictors of OAA use within the 12 months after metastatic RCC was detected to understand the extent of real-world adoption of these treatment advances. Methods: We used a novel, North Carolina, registry-linked multi-payer claims data resource to examine patterns of use of sorafenib, sunitinib, pazopanib, everolimus, axitinib, cabozantinib, and levantinib in a cohort of metastatic RCC patients diagnosed over 10 years (2006-2015, with claims through 2016). Patients were required to have 12 months of pre- and post-metastatic-index-date continuous enrollment. Log-Poisson models estimated unadjusted and adjusted risk ratios (RRs) and 95% confidence limits (CLs) for associations between patient characteristics and OAA use. In sensitivity analyses, we used a competing risk framework to estimate adjusted risk differences (RD) in OAA use. Results: Our population-based study of 713 patients demonstrated relatively low (37%) OAA use at any time during the 12 months post-metastatic-index date among publicly and privately insured patients, with shifting patterns of use consistent with regulatory approvals over time. Lower OAA use was observed among patients who were older, frailer, and with greater comorbidity burden. Other patient-level characteristics, such as sex, race, rurality and type of insurance were not significant predictors of OAA use. Conclusions: These data underscore the importance of distinguishing clinically appropriate from potentially poor-quality care and warrant additional studies to understand in more depth the system, provider and patient level drivers of these patterns.