bluuebunny/crossref_metadata_2025 huggingface dataset:
5-Year result of single-institute cohort study in single-fraction HDR monotherapy for localised prostate cancer.
Authors: Ahmed Imtiaz , Tun Khin Sandar , Shibuthomas Sharon , Cain Alex , Mahar Sadia , Yoganayagam Nicola , Cyriac Abby , Choudhury Mahbuba , Dawam Daben
Published: March 2023

362

Background: The aim if this single institute UK-based study was to look at 3-year and 5-year bRFS and toxicity profiles. Methods: It is a prospective data study with a total number of 174 patients who were treated with single-fraction HDR monotherapy between July 2014 and February 2017. Biochemical recurrence is defined using Phoenix criteria. Results: The median age was 67.5 years with the median presenting PSA of 8. Majority of patients were lower risk group with 55% for combined low and favourable intermediate risks. 81 patients had Gleason score 6(3+3) and 77 patients had GS 7(3+4). Total hormone duration was 8 months and median duration of hormone prior to HDR monotherapy was 4 months. Overall bRFS at 3 years was 96% and 5 years was 88%. 5-year bRFS as per risk stratification was 100% in low risk, 92% in favourable intermediate risk, 83% in unfavourable intermediate risk and 79% in high-risk groups. This study had better 5-year overall bRFS compared to published data in single fraction HDR monotherapy (88% vs 73.5%, p value 0.001) (Morton et al., 2020). Despite inferior 5-year overall bRFS in compared to 2-fractionated HDR monotherapy (88% vs 95%) (p value 0.001), no difference in 5-year bRFS noted in low and favourable intermediate risk groups (100% vs 100% and 92% vs 93% respectively) (Morton et al., 2020). Two-thirds (71%) of biochemically recurred patients found to have local recurrence disease. The median time of biochemical recurrence was 47 months. Higher risk groups had higher 5-year biochemical recurrence risk. Acute and late toxicity profiles were minimum with acute G2 GU toxicity (2%) and GI toxicity (1%); late G2 GU toxicity (2%) and GI toxicity (0%) with no G3, G4 GU or GI toxicities. Conclusions: This prospective study had shown better overall 5-year bRFS especially in low and favourable intermediate risk groups with minimal toxicities. Therefore, single-fraction HDR monotherapy could be considered for elderly or patients with significant co-morbidities who are more suitable for single treatment rather than 2 fractions in these risk groups. Further randomised multicentre studies in these risk groups are suggested.
A phase II study of rucaparib monotherapy in nonmetastatic, hormone-sensitive prostate cancer (nmHSPC) with “BCRAness” genotype (ROAR).
Authors: Sahu Kamal Kant Kant , Li Haoran , Mathew Thomas Vinay , Benson Mallory , Hawaks Josiah , Brown Julian , Thorne Kelli , Sherwin Kathy , Cheney Jackson , Boucher Kenneth M. , Gupta Sumati , Kohli Manish , Swami Umang , Agarwal Neeraj , Maughan Benjamin L.
Published: March 2023

364

Background: Prostate cancer (PCa) patients (pts) with DNA repair defects (aka “BRCAness”) generally have more aggressive disease and a worse overall prognosis compared to men without BRCAness (PMID: 33781305). Biochemical recurrence (BCR) develops in almost one-third of men with PCa after treatment with local therapy. We hypothesized that treatment with rucaparib monotherapy in men with systemic treatment naïve high-risk nmHSPC would result in acceptable disease control, allow a delay of androgen deprivation therapy (ADT) and the onset of metastasis. Methods: This is a single-arm, open-label, phase II trial; eligibility criteria: (1) Histologically proven prostate adenocarcinoma, presence of one of the following alterations in (by soft tissue or liquid biopsy): BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, NBN, PALB2, RAD51C, RAD51D, RAD51, RAD51B, (2) No radiographic evidence of metastatic disease by conventional scans (3) PSA doubling time of ≤10 months. The primary endpoint: PSA progression-free survival (PSA-PFS). Secondary endpoints: safety, the proportion of pts with a PSA 50% response (PSA50), and an undetectable PSA. Results: Seven pts were enrolled in the study with the following pathogenic alterations: ATM (n=3), BRCA2 (n=2), BRCA1 (n=1), BRIP1 (n=1), RAD51(n=1), and received treatment with rucaparib at 600 mg twice daily. A 4-week treatment duration comprised one cycle. The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI: 0 - 85.11 months). 2/7 patients achieved PSA50; both had nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 pt each). No dose-limiting toxicities or severe AEs were seen. The study was prematurely terminated in June 2022 after the accrual of 7 pts because next-generation scans (e.g., PSMA-PET) became the standard of care for pts with BCR. Conclusions: Rucaparib demonstrated acceptable toxicity and preliminary efficacy in pts with PCa with BCR. Gene alteration-specific efficacy will be presented in the meeting. Limitations: Small cohort, no comparison arm. Hence results should be interpreted cautiously but generally consistent with larger prospective trials of PARP inhibitors. Clinical trial information: NCT03533946 . [Table: see text]
Germline DNA damage response (DDR) mutations in an East Asian (EA) cohort with prostate cancer (PCa).
Authors: Lua Joanne Y.H. , Chan Johan W.K. , Ong Enya H.W. , Chow Melody , Tay Kae-Jack , Tuan Jeffrey K.L. , Wang Michael L.C. , Lee Lui Shiong , Kanesvaran Ravindran , Khor Li Yan , Chua Melvin L.K. Lee Kiang
Published: March 2023

373

Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. Additionally, germline mutations in DDR genes are linked to PCa susceptibility. Here, we report the germline DDR mutation frequencies in an EA PCa cohort, and their associations with clinicopathological indices and outcomes. Methods: We utilized a prospectively recruited cohort of 891 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline mutation profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Following joint genotyping, common variants of ≥1% were filtered, and only variants defined as pathogenic (P)/likely pathogenic (LP) in ClinVar or predicted to be P by CADD or REVEL were retained. We used a 32 DDR gene-set for tests of association with clinicopathological indices, biochemical relapse-free rate (bRFR), and distant metastasis-free survival (DMFS). Results: Median follow up was 54 (33-83) mo; median age at diagnosis was 70 (64-74) y. 741 (84%) men had localized PCa, 65 (7%) had N+M0, and 80 (9%) had M1 disease. Among those with localized PCa, 417 (56%) were stratified as NCCN high/very high. 5-year DMFS was 100%, 96%, 86%, and 74% for NCCN low, intermediate, high/very high, and N+M0 PCa, respectively. 31 (3.5%) men in our cohort harbored a P/LP variant in at least one of the 32 DDR genes; P/LP variants were most frequently observed for BRCA2 (N=11[1.2%]), ATM (N=6[0.7%]), and RAD50 (N=5[0.6%]). P/LP variants were more frequent in men with N+M0/M1 compared with those with localized PCa (29% vs 16%, P=0.05), and in men with GS 9-10 vs 6-8 tumors (43% vs 20%, P=0.002). Presence of P/LP DDR variants were significantly associated with bRFR (HR 2.44 [95% CI:1.0-6.1], P=0.049) in M0 patients treated with RT+/-hormonal therapy on univariable and multivariable analyses. Conclusions: Herein, we observed lower frequencies of germline DDR P/LP mutations in our EA PCa cohort than other published Chinese cohorts (Wei, et al. 2018; Wei, et al. 2020). Nonetheless, there was a strong trend for increased incidence of DDR mutations with more advanced PCa. Men with DDR mutations were more likely to fail treatment than men without. [Table: see text]
Comparative transcriptomic analysis of DNA-damage response and androgen receptor pathway activity between biopsy and radical prostatectomy specimens before and after pre-operative real-time MRI-guided stereotactic body radiotherapy.
Authors: Nagar Himanshu , Dillard Alicia , Hakansson Alexander K. , Liu Yang , Davicioni Elai , Wolfe Sydney , Hu Jim C. , Scherr Douglas , Khani Francesca , Marciscano Ariel E. E. , Barbieri Christopher
Published: March 2023

375

Background: Pre-Prostatectomy MRI-Guided Stereotactic Body Radiotherapy for High-Risk Prostate Cancer Trial (PREPARE SBRT; NCT03663218) is an ongoing clinical trial testing the safety of preoperative MRI-guided SBRT for men with clinically localized high-risk prostate cancer. We sought to compare transcriptomic profiles of biopsy (Bx) specimens to acutely irradiated radical prostatectomy (RP) specimens. Methods: Biopsy and post-irradiated RP specimens from 10 subjects were examined. The median interval between the end of RT and the date of RP was 5 days. Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before irradiation and RP samples post-irradiation using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for effects in tissue preservation from the procedure different of Bx vs RP. Linear regression model with the interaction effect of cohort (SBRT vs control) by procedure (Bx vs RP) to select signatures impacted by radiation treatment. Results: Transcriptomic signatures associated with Androgen Receptor (AR) activity were significantly downregulated (p=0.002) in irradiated RP specimens compared with pre-treatment biopsies. Analysis of DNA damage repair (DDR) pathways demonstrated that nucleotide excision repair (NER) and non-homologous end joining (NHEJ) signatures were increased (p=0.002 and p=0.02, respectively) after pre-operative RT whereas homologous recombination (p=0.06) and mismatch repair (p=0.08) were not significantly different between pre-treatment and irradiated tissues. Several metabolic-associated pathways were impacted by pre-operative RT including increased glycogen metabolism (p=0.008) and a NADH-NADPH conversion (p=0.001) signature indicative of RT-induced oxidative damage. Consistent upregulation of transcriptomic features associated with increased angiogenesis (p=0.0012) and stromal remodeling (p=0.0008) was observed in irradiated samples. Conclusions: Paired transcriptomic analysis following pre-operative RT demonstrated differential upregulation of specific DDR pathways including NHEJ and NER and metabolic alterations related to oxidative stress and glycogen metabolism. AR activity signatures were decreased in response to pre-operative RT.
Metformin for biochemical recurrence of prostate cancer: Immune data from a phase 2 study.
Authors: Bilusic Marijo , Toney NIcole J , Donahue Renee Nicole , Karzai Fatima , Madan Ravi Amrit , Schlom Jeffrey , Gulley James L. , Rai Priyamvada , Due Cassie , Gregory Philip , Mateo-Victoriano Beatriz , Plimack Elizabeth R. , Geynisman Daniel M.
Published: March 2023

377

Background: Metformin impacts immune response in several ways. It protects CD8 TILs from apoptotic death, downregulates CD39 and CD73, reduces MDSC activity and suppresses the transcription of PD1 thus enhancing CD8+ T cell antitumor activity (Ma et al, 2000, Nature). There is limited data on the immunologic impact of metformin treatment in hormone sensitive prostate cancer. Methods: We conducted an open label, randomized, phase II trial of bicalutamide with or without metformin of patients with high risk, biochemically recurrent prostate cancer (NCT02614859). Patients were randomized 1:2 to observation for an initial 8 weeks or metformin 1000 mg twice daily. Bicalutamide 50 mg/day was added after 8 weeks to both arms. The study discontinued accrual after interim analysis indicated no difference in PSA at 32 weeks between the two arms; however, metformin monotherapy for 8 weeks induced modest PSA declines observed in 40% of patients. Here we report immune responses in a subgroup of patients (N=12), including systemic cytokine levels and 158 circulating immune cell subsets after 8 weeks of metformin monotherapy. Results: Twelve patients treated at the NCI were analyzed. After 8 weeks, the metformin arm showed increased pDCs and lower Tregs compared to baseline. Significant differences in the percent change of immune parameters after 8 weeks of metformin monotherapy compared to 8 weeks of observation are summarized. Conclusions: Metformin has been shown to reduce markers of immune exhaustion in hormone sensitive prostate cancer which is supported by a greater reduction of PD-1+ and Tim3+ NK cells. Additional immune changes included increases in activated subpopulations of natural killer (NK) cells, which have been reported as a potential predictive biomarker of prolonged treatment response to hormone therapy in prostate cancer (Pasero et al, Oncotarget, 2015). Clinical trial information: NCT02614859 . [Table: see text]
Limited relevance of the “very low risk” prostate cancer classification in the modern era: Results from a large institutional active surveillance cohort.
Authors: Shee Kevin , Cowan Janet E. , Washington Samuel L. , Nguyen Hao G , Shinohara Katsuto , Carroll Peter , Cooperberg Matthew R.
Published: March 2023

381

Background: Although the American Urological Association recently dropped the “very low risk” (VLR) category for prostate cancer (PCa), the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum based on number of positive biopsy cores, tumor extent in each core, and PSA density. This subdivision may be outdated in the modern era in which targeted prostate biopsies are common practice. We identified the proportion of VLR patients at our institution to determine whether an alternative classification may be more appropriate for risk-stratification in the modern era. Methods: Participants were diagnosed from 2000-2019 with cT1-2N0/xM0/x PCa, PSA <20ng/ml, biopsy Gleason grade group (GG) 1-2, and initially managed with AS. VLR PCa was defined as <3 positive cores, ≤50% cancer per core, and PSA density <0.15. UCSF-CAPRA score was calculated for each patient. The primary outcome was major upgrade (≥GG3) on subsequent biopsy. Multivariable Cox proportional hazards regression models were used to calculate associations between CAPRA score and risk of major upgrade, adjusting for age, genomic testing, and prostate MRI finding. Results: Of 1554 patients initially managed with AS, 364 (23%) met NCCN VLR criteria. 49 (3%), 781 (50%), 505 (33%), and 219 (14%) patients had CAPRA scores of 0, 1, 2, and 3, respectively. Proportion of patients deemed VLR decreased over time; among 84 patients initially managed with AS during or after 2018, only one patient (1%) met VLR criteria in 2018, while the stratification by CAPRA demonstrated that 21 (25%), 25 (30%), and 38 (45%) patients had CAPRA scores of 1, 2, and 3, respectively, over the same period. CAPRA score was significantly associated with major upgrade on biopsy on multivariable Cox proportional hazards regression modeling independent of age, genomic testing, and MRI finding (HR 1.46, 95%CI 1.22-1.74, p<0.01). Conclusions: The relevance of VLR PCa in the modern targeted biopsy era has diminished, with no cases meeting VLR criteria in a large AS cohort after 2018. CAPRA score is an option for a more contemporary risk stratification tool for men on AS.
The difference in serum testosterone recovery between Gn-RH Antagonist and LH-RH agonist among patients with prostate cancer treated with radiation therapy.
Authors: Takei Akinori , Sakamoto Shinichi , Niino Jun , Takeuchi Nobuyoshi , Kanesaka Manato , Sazuka Tomokazu , Imamura Yusuke , Akakura Koichiro , Ichikawa Tomohiko
Published: March 2023

382

Background: Only limited data exist related to the serum testosterone (TST) recovery after discontinuation of Gn-RH antagonist (Degarelix acetate). In the present study, we investigated the difference in serum testosterone (TST) recovery between LH-RH agonist and Gn-RH antagonist among prostate cancer (Pca) patients received radiation therapy in combination with androgen deprivation therapy (ADT). Methods: We analyzed the association between TST levels after the end of endocrine therapy and clinical factors in 130 patients who underwent ADT for prostate cancer at Chiba University hospital between May 2003 and May 2020. The proportional hazards model and Kaplan-Meier methods were used for the statistical analysis. Results: The median patient age and PSA were 72 years, and 16.8ng/mL, respectively. The median initial TST and nadir TST were 457 ng/dL, and 20ng/dL, respectively. The median duration of ADT was 857 days. As factors affect the speed of recovery to the castration level (TST 50 ng/dL), univariate analysis showed that Gn-RH antagonist presented the significantly shorter TST recovery compared to those of LH-RH agonist (HR 1.9, p=0.0078), together with the duration of hormone therapy (857 days) and Nadir TST level (20 ng/dL), GS8 and PSA (16.8ng/mL). Multivariate analysis showed that Nadir TST level was an independent predictor (HR 2.0, p=0.0093). As factors affect the speed of recovery to the physiological level (TST 200 ng/dL), univariate analysis showed that Gn-RH antagonist presented the significantly shorter TST recovery compared to those of LH-RH agonist (HR 2.1, p=0.0064). Multivariate analysis showed that duration was the only independent predictor (HR0.34, p=0.0029). Kaplan-Meier curve demonstrated shorter time for the TST recovery in Gn-RH antagonist compared to the LH-RH agonist for the castration level (p=0.0064) and the physiological level (p=0.0052). Conclusions: TST recoveries were significantly shorter in Pca patients treated with Gn-RH antagonist than LH-RH agonist. Nadir TST value, duration, and a type of LH-RH drug may comprehensively suggest us the dynamics of TST recovery after ADT. [Table: see text]
Disparities in prostate cancer survival outcomes in Appalachian Kentucky.
Authors: Pandey Deepali , Chen Quan , Huang Bin , Myint Zin , Wang Peng
Published: March 2023

39

Background: Prostate cancer (PC) is the most common male cancer in the United States and the second leading cause of cancer-related death. Our group previously reported that men from Appalachian Kentucky had worse survival outcomes compared to non-Appalachian Kentucky and general population. This survival difference could be mainly due to socio-economic disparities. However, several new treatments have been approved for metastatic PC (mPC) in the last decade and these current standard of care (SOC) therapies have significantly improved survival outcomes in mPC. Therefore, we aim to investigate whether the recent change in SOC treatments have improved overall survival (OS) in patients with Appalachian (App) Kentucky vs. Non-Appalachian (Non-App) Kentucky from 2004–2019. Methods: All male patients who were > 20 years old with primary diagnoses of prostate adenocarcinoma, listed in Kentucky cancer Registry (KCR), diagnosed between 2004 and 2019, were included in the study. Basic demographics and survival outcomes were compared for all stages of PC and between App and Non-App Kentucky. We also compared the survival difference between two time periods 2004- 2011 vs. 2012-2019. Kaplan Meir and multivariate Cox Regression were performed to compare patients’ overall survival (OS). Results: A total of 36,695 patients were included in this retrospective analysis, of which 74.3% were Non-App and 15.7% were App. Caucasians predominated in both groups (N-App 85% vs. App 97%). The majority of Kentucky patients were aged between 50-74 years (79%). App Kentucky was noted to have more poorly differentiated histology (44.4% vs 40.1%), high Gleason score (26.4% vs 20%), more distant disease at the time of diagnosis (8.3 vs 6.7%), and higher percentage of patients with smoking history (40.1% vs 34.9%) compared to Non-App, respectively. A higher proportion of Non-App Kentucky had private insurance (35%) at the time of cancer diagnosis compared to more patients enrolled in Medicare (56.6%) or Medicaid (4.7%) in App. There was a survival difference between App and Non-App Kentucky by univariate analysis (p<0.001). In multivariate Cox regression showed that Non-App patients had better OS (p<0.001; HR=0.92, 95%CI 0.87-0.96). Patients diagnosed in the years 2012- 2019 had better survival compared to patients in 2004 – 2011 group (p=0.01; HR=0.94, 95%CI 0.9-0.99). Other factors that contributed to better survival include younger age, lived in the metro area, had private insurance, being a nonsmoker, being lower stage, and receiving treatment. We got similar result for stage IV patients, but the App variable was not significant in the COX regression (p=0.2). Conclusions: Our study shows that Appalachian has worse outcomes compared than Non-Appalachian Kentucky based on population-based analysis from 2004-2019. Additional research is needed to understand the health care disparities in App Kentucky.
Inherited risk for prostate cancer (PCa): Following the natural history of men with high-risk genetics using multiparametric MRI (mpMRI).
Authors: Couvillon Anna , Turkbey Baris , Choyke Peter L. , Lee-Wisdom Katherine , McKinney Yolanda , Sidlow Robert , Mullane Michael P. , Giri Veda N. , Morgan Todd Matthew , Cheng Heather H. , Merino Maria J. , Figg William Douglas , Pinto Peter A. , Dahut William L. , Karzai Fatima
Published: March 2023

390

Background: PCa has inherited risk factors including high genetic risk variants such as BRCA1/2, HOXB13, and DNA mismatch repair genes. mpMRI has been shown to be effective for detection and staging of localized PCa. This study follows participants (prts), born biologically male, without a diagnosis of PCa with known germline pathogenic or likely pathogenic variants (PV) in BRCA1/2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C/D, BRIP1, or FANCA-FANCM (NCT03805919). Methods: Up to 500 eligible prts 30-75 years old (yo) with a documented germline PV will enroll. Prts undergo biennial clinical exam and mpMRI, and annual PSA monitoring and are followed at 12-month intervals to determine PSA, prostate cancer diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes clinical or imaging findings. Biopsy specimens undergo molecular analyses. Results: To date, 175 prts have been enrolled: 169 (97%) White, 3 Hispanic (2%), 1 African American (1%), 1 Asian (1%), and 1 biethnic (1%). Median age is 47 yo. The most common monoallelic PV are: 48.6% BRCA2, 25.1% BRCA1, 6.3% CHEK2 and 5.7% MSH2. PVs in ATM, PALB2, HOXB13, PMS2, MLH1, MSH6, BRIP1, EPCAM and RAD51D are ≤4%. One subject carries three distinct PVs ( BRCA2, CHEK2, BRIP1). Indication for biopsy was found in 26.3% of prts with 22/46 (47.8%) with a PIRADS 4 lesion, 6/46 (13.0%) PIRADS 3 lesion, 12/46 (26.1%) elevated PSA (median=2.8 ng/mL) or 6/46 (13.0%) due to clinical discretion. Adenocarcinoma was diagnosed on 13/39 (33.3%) biopsies with median age at diagnosis=59 yo. 9/13 (69%) prts had a PSA <3 ng/ml at diagnosis. Nine prts were diagnosed with ISUP Grade Group (GG) 1, 3 with GG2, and 1 with GG3. Eight prts opted for active surveillance (AS), 2 for radiation therapy (RT), and 3 for prostatectomy (RP). Two prts on AS converted to definitive treatment (one RP and one RT) due to progression in GG on the year 1 AS biopsy. Conclusions: mpMRI screening in men with germline PV can be used for diagnosis and monitoring of PCa and facilitates detection below conventional PSA thresholds in a high genetic risk setting. Access to genetic testing and other variables need to be addressed in underrepresented minorities. Correlative studies, including cfDNA and PBMCs, are ongoing. Clinical trial information: NCT03805919 . [Table: see text]
Associations between plant-based diets and risk of disease progression in men with prostate cancer.
Authors: Liu Vivian N , Van Blarigan Erin L. , Zhang Li , Graff Rebecca E. , Langlais Crystal , Cowan Janet E. , Carroll Peter , Chan June M. , Kenfield Stacey A.
Published: March 2023

392

Background: Plant-based diets have been linked to multiple health benefits. For prostate cancer (PC), individual plant foods (e.g., tomatoes with lycopene) appear to reduce PC incidence and mortality. However, less is known about plant-based dietary patterns and PC survivorship. Methods: We examined 2038 men diagnosed with T1-T3a PC who were enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) and had completed a food frequency questionnaire (FFQ) a median of 31.5 months post-diagnosis. “Overall” and “healthy plant-based” dietary indices (PDI and hPDI, respectively,) were calculated from the FFQ. Multivariable Cox proportional hazards models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between plant-based diets and risk of PC progression (recurrence, secondary treatment, bone metastases, or PC death) as the primary outcome, and PC recurrence as a secondary outcome. We also examined whether age, stage, grade, and walking pace modified associations. Results: We observed 204 progression events (169 due to biochemical recurrence) over a median follow up of 7.4 years after the FFQ. Men in the highest quintile of PDI had a 52% lower risk of progression (HR 0.48, 95% CI 0.36-0.65, p-trend<0.001) and a 53% lower risk of recurrence (HR 0.47, 95% CI 0.32-0.68, p-trend<0.001) compared to men in the lowest quintile. Although the hPDI was not associated with PC progression or recurrence overall (p-trend >0.05), men in the higher quintiles had statistically significant reductions in risk of recurrence. Among men >65 years, greater consumption of a healthful plant-based diet was associated with lower risk of PC recurrence (HR 0.41, 95% CI 0.24-0.7, p-trend=0.03). In addition, among those with a brisk/fast walking pace (>3 h/wk), men in the highest PDI quintile had a 56% (HR 0.33, 95% CI 0.26, 0.73) lower risk of PC progression, and a 59% (HR 0.41, 95% CI 0.25, 0.68) decrease in risk of PC recurrence. Grade and stage did not modify associations between either index and PC progression or recurrence. Conclusions: This study indicates that plant-based dietary patterns are associated with lower risk of PC progression and recurrence, particularly among older men and those who reported a higher intensity walking pace. PC survivors may be recommended diet and exercise counseling to improve clinical outcomes after PC diagnosis.
The landscape of prostate cancer research in Canada.
Authors: Fraser Mike , Mohammad Atiqa
Published: March 2023

394

Background: Prostate cancer (PCa) is the most prevalent malignancy in Canadian men; in 2023, an estimated 24,700 men will be diagnosed while ~4,700 will die of their disease. Lifetime risk of developing PCa is approximately 1-in-8 and approximately 3% of all deaths of Canadian men are caused by the disease. While Canada has a robust, modern health research landscape, with major academic centres located in all provinces and territories, the investment in academic PCa research – and the impact of that investment – has not been systematically quantified. An improved understanding of this landscape is necessary to ensure research funding remains efficient, impactful, and equitable. As such, we evaluated the size, scope, and impact of the investment in academic PCa research in Canada. Methods: We extracted funding records from the Canadian Research Information System (CRIS), the United States Congressionally Directed Medical Research Program database and the United States National Institutes of Health RePORT database for the National Cancer Institute, using keywords ‘prostate’ OR ‘prostatic’ AND ‘cancer’ OR ‘carcinoma’ for 1999-2021. US-sourced records were included when the principal investigator (PI) was based at a Canadian institution at the time the award was granted. Records were validated using data from the Canadian Cancer Research Alliance (CCRA). Intramural and industry-derived funding was unavailable and thus excluded from the analysis. Results: We identified 1,748 unique funding events (FEs) from 33 sources. These FEs involved 1,561 investigators and had an inflation-adjusted value of $682,113,116. The top three funders of PCa research were the Canadian Institutes of Health Research, Movember Canada, and the Canadian Cancer Society. Basic and translational research received ~83% of all funding while psychosocial, health economics, and epidemiology research received only ~7.2%. Strikingly, we found that 30.5% of all funding was held by 1% of investigators. We identified 6,671 dyads ( ie. pairs of collaborating investigators); 85% collaborated only once, while 15% collaborated at least twice (range: 2-19). Female investigators participated in significantly fewer collaborations than males (P: 3.28 x 10-3) and were less likely than expected to serve as PI (P: 8.87 x 10-8). FEs with ≥ one female PI had a significantly lower value than those with only male PIs (P: 1.34 x 10-6) and FEs with only female PIs had a significantly value than those with only male PIs (P: 7.32 x 10-4). Conclusions: While Canadian PCa research has been highly funded over the past 25 years, there remain substantial funding disparities across scientific disciplines, geographic regions, and, in particular, gender. There is also substantial ‘wealth inequality’; a small minority of investigators receive most of the funding. We are currently assessing stakeholder attitudes toward these disparities, to help inform the next phase of PCa research funding in Canada.
Implementing 18F-DCFPyL PET in clinical practice: Prescribing patterns and utilization at a large academic center.
Authors: Hsu Miles , Shan Xinhe , Takvorian Samuel U , Pantel Austin , Narayan Vivek , Shevach Jeffrey , Vapiwala Neha , Vaughn David J. , Haas Naomi B.
Published: March 2023

42

Background: 18F-DCFPyL imaging was recently approved for initial staging in patients (pts) with prostate cancer and suspected metastasis and for those with biochemical recurrence (BCR). 18F-DCFPyL recently became available at our NCI-Designated Comprehensive Cancer Center comprising 6 teaching hospitals and 2 outpatient facilities. As real-world data on 18F-DCFPyL usage in the US are lacking, our objective was to describe prescription patterns and utilization for 18F-DCFPyL. Methods: We identified 18F-DCFPyL scans performed at our center from 1/1/2022-5/10/2022 and abstracted corresponding clinical data through electronic medical record (EMR) review. Demographic, laboratory, pathological and clinical data and provider-level usage were characterized by review of the EMR and, if necessary and feasible, provider interview. Results: There were 164 18F-DCFPyL scans performed across the study period for 164 unique pts (median age 70 years, 73.8% White, 20.1% Black). Ordering providers belonged to Medical Oncology (54.3%), Radiation Oncology (42.7%), Urology (2.4%), and Nuclear Medicine (1%). The majority of scans were ordered for isolated PSA rise (n=93, 56.7%) and initial staging (n=26, 15.9%), in concordance with FDA-approved indications. Nevertheless, many scans were ordered for alternate indications. Restaging of pts with known refractory or metastatic disease (11.0%), PSA persistence after definitive therapy (8.5%), and PSA rises below the threshold of BCR (4.9%) were common alternate rationales for imaging. A minority of scans had a secondary indication such as RT field planning, distinguishing between two primary cancers, PSA persistence in high-risk disease, possible radioisotope therapy, and, most frequently, clarification of lesions seen on conventional imaging (n = 7). 22 pts were on androgen-deprivation (ADT, n=17) or anti-androgens (AR, n=11) when receiving PSMA imaging, with 5 pts on both; the median testosterone at time of imaging was <20 ng/dL. Indeterminate lesions, defined as tracer avid with uncertain malignant status, were most often found in lymph nodes (n = 22) and focal rib lesions (n = 17), of which 12 were solitary, 3 were multifocal and 2 were superimposed on fractures. Conclusions: Shortly after adoption at a large cancer center, 18F-DCFPyL has been prescribed in various clinical settings outside of FDA approvals. Around 1/8 were performed with pts on ADT/AR, with testosterone at castrate levels. Findings of uncertain malignant etiology included solitary (7%) and multifocal (2%) rib lesions. These data reveal substantial variability in usage and areas of uncertainty in the interpretation of 18F-DCFPyL imaging in real-world clinical settings, underlining the need for further studies on its potential usefulness in expanded indications.
Origin of extragonadal versus gonadal seminomas.
Authors: Tasneem Sara , Chen Jim Zhongning , Johns Andrew , Tu Shi-Ming , Estecio Marcos Roberto
Published: March 2023

423

Background: There is debate whether a primary seminoma of the anterior mediastinum originates from a stranded germ cell in the midline near the thymus as it migrates from the yolk sac to the gonad1 or from abnormal development of the thymic anlage during embryogenesis.2 We hypothesized that if extragonadal seminoma were to arise from an adult stem cell at an ectopic site rather than from an errant primordial germ cell (PGC), it would display a methylated imprint resembling that of thymic epithelial tumors, such as a thymoma, rather than that of a gonadal seminoma. Methods: We performed reduced representation bisulfite sequencing (RRBS) of FFPE DNA of testicular seminoma, anterior mediastinal seminoma, thymomas, atypical thymomas, and thymic carcinomas. Results: RRBS of testicular seminoma (n=1), anterior mediastinal seminoma (n=1), thymomas (n=2), atypical thymomas (n=2), and thymic carcinomas (n=2) showed that the methylated genetic imprint of an extragonadal seminoma clustered more closely to that of an atypical thymoma than that of testicular seminoma. Conclusions: Our preliminary RRBS results suggest that extragonadal seminoma may have a thymic rather than PGC origin. We plan to confirm these results by evaluating certain PGC-specific genetic biomarkers and epigenetic signatures in additional cases. References: 1. Dixon FJ, Moore RA. Testicular tumors: a clinicopathological study. Cancer 1953;6:427. 2. Schlumberger HG. Teratoma of the anterior mediastinum in the group of military age: a study of sixteen cases, and a review of theories of genesis. Arch Pathol 1946;41:398.
Refining the serum miR-371a-3p test for viable germ cell tumor detection: Identification and definition of an indeterminate range.
Authors: Bagrodia Aditya , Lafin John T. , Scarpini Cinzia , Konneh Bendu , Gerald Thomas , Nuno Michelle , Piao Jin , Savelyeva Anna , Jia Liwei , Murray Sarah , Cheng Yun , Margulis Vitaly , Woldu Solomon L. , Coleman Nicholas , Amatruda James F. , Frazier Lindsay Lindsay , Murray Matthew
Published: March 2023

425

Background: Existing conventional serum tumor markers (STMs) exhibit moderate performance for the detection of germ cell tumors (GCTs). Circulating miR-371a-3p has excellent performance in the detection of viable (non-teratoma) GCT pre-orchiectomy; however, its ability to detect occult disease is understudied. We refine the serum miR-371a-3p assay and expand upon our previous experience in this setting. Methods: We compared performance of raw (Cq) and normalized (∆Cq, RQ) values from prior assays (n=93), and validated interlaboratory concordance by aliquot swapping. Revised assay performance was determined in a cohort of 32 patients suspected of occult retroperitoneal disease. Assay superiority was determined by comparing resulting receiver-operator characteristic (ROC) curves using the Delong method. Pairwise t-tests were used to test for interlaboratory concordance. We defined an indeterminate range as the mean of the low Cq peak from controls ± 2 SDs. Results: Performance was comparable when thresholding based on raw Cq vs. normalized values. Calculated sensitivity and specificity were both greater than 0.9 in all cases and did not change appreciably across any of the metrics tested. Interlaboratory concordance of miR-371a-3p was high, but reference genes miR-30b-5p and cel-miR-39-3p were discordant. We identified for the 1st time an indeterminate range; Introduction of an indeterminate range of Cq 28-35 with a repeat run for any indeterminate improved assay accuracy from 0.84 to 0.92 in a group of patients suspected of occult GCT. Conclusions: We recommend that serum miR-371a-3p test protocols are updated to a) utilize threshold-based approaches using raw Cq values, b) continue to include an endogenous (e.g., miR-30b-5p) and exogenous non-human spike-in (e.g., cel-miR-39-3p) microRNA for quality control, and c) to re-run any sample with an indeterminate result.
Bilateral germ cell tumor of the testis (TGCT): Implications for a stem cell versus genetic origin of cancers.
Authors: Sanchez Darren , Chen Jim Zhongning , Ebare Kingsley , Joon Aron , Estecio Marcos Roberto , Zhang Miao , Adriazola Ana Cecilia , Shah Amishi Yogesh , Singh Sunny R , Ward John Francis , Pisters Louis L. , Tu Shi-Ming , Zacharias Niki Marie
Published: March 2023

428

Background: Bilateral TGCT offers a unique opportunity to elucidate a stem cell versus genetic origin of cancer (Coffey, 2008). Comparison of the epigenetics and genetics of disparate tumors in either synchronous or metachronous bilateral TGCT from the same patients is feasible and may be informative. Methods: We examined the clinical characteristics and natural history of 37 patients with bilateral TGCT. We performed reduced representation bisulfite sequencing (RRBS) of FFPE DNA and whole exon sequencing (WES) of 5 of those patients whose tumor samples were available for the study. Results: We identified 37 patients with bilateral TGCT, who underwent their first orchiectomy between January 1984 and April 2022 and the second between August 1997 and April 2022. Thirty-five (95%) of these patients are still alive. Seven patients had synchronous, while 30 had metachronous bilateral TGCT. There were 13 bilateral seminomas, 14 bilateral nonseminomas, and 10 bilateral seminoma and nonseminoma. For those patients with metachronous bilateral TGCT, the median time between the two TGCT was 59 months (range 6-400). WES revealed a mutation in 189 (<1%) out of about 20,000 genes in the 10 paired samples from 5 patients. A total of 2 genes were mutated in more than 1 sample: KIT (n=4), and KRAS (n=2). Although one patient with synchronous bilateral seminomas shared KIT mutation, another did not with KIT and KRAS mutations (Table). RRBS showed a similar methylation profile in the 2 metachronous nonseminomas, which did not share any genetic mutations in the WES study. Conclusions: The clinical course of our patients with synchronous and metachronous bilateral TGCT and the results of our RRBS and WES reaffirmed that a preponderance of TGCT was curable and alluded to whether its epigenetic vs genetic origins might be causative or contributory to its general curability vs potential lethality. Coffey J et al. Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: report of 220 tumors and review of literature. Genes Chromosomes Cancer 2008;47:34-42. [Table: see text]
Molecular features and actionable targets for testicular germ cell tumors in a real-world setting.
Authors: Morales-Grimany Rafael , Delgado Cesar , Baky Fady , Amini Armon , Gerald Thomas , Badia Rohit R , Taylor Jacob , Wang Luke , Javier-Desloges Juan , Margulis Vitaly , Woldu Solomon L. , Salmasi Amir , Millard Fred , McKay Rana R. , Bagrodia Aditya
Published: March 2023

430

Background: Molecular features of testicular germ cell tumors (GCT) in various clinical states (pre- vs post-chemotherapy, localized versus metastatic) may inform treatment options for patients with recurrence after definitive therapy. In his study, we describe molecular features and potential therapeutic targets in a cohort of patients with testicular GCT. Methods: We retrospectively examined clinicopathologic and next-generation sequencing (NGS) data from 27 patients with GCT. Tumors were sequenced using the Tempus|xT solid tumor assay, which includes DNA sequencing of 595-648 genes at 500x coverage and RNA sequencing for all human coding genes. Tumor mutational burden (TMB) was measured for all tumors and PD-L1 levels were assessed qualitatively by 22C3 pharmDx immunohistochemistry assay in 8 patients. All genetic variants detected were quantified and analyzed to identify potentially actionable targets. Results: We identified 13 (48%) stage I GCT, 11 (41%) stage II, and 3 (11%) stage III. There were 7 seminomas and 20 nonseminomas. 12 tumor specimen resections were obtained from orchiectomy, and 15 from retroperitoneal lymph node dissection (RPLND), of which, 8 were chemotherapy-naïve and 7 were post-chemotherapy. Chemo-naïve RPLND histology showed a combination of teratoma, seminoma, and mixed GCT, while post-chemo histology revealed 6 teratomas and 9 benign pathologies. The median TMB for the cohort was 0.75 mutations/megabase. Somatic mutations were identified in 55% of patients and most commonly within: KRAS (25.9%), KIT (11.1%), and PIK3CB (7.4%). PD-L1 expression was observed in 75% of the tumors measured (60% positivity at stage I and 100% positivity at stage III). Microsatellite stability was stable in 18 tumors tested. DNA alterations- [single base pair substitutions, insertions, and deletions]- in KRAS (GTPase) proto-oncogenes were detected in 7 tumors and tyrosine kinase receptor gene variants (KIT, P1K3CB) were found at similar frequencies across disease stages. Whole transcriptome NGS RNA expression assays were performed on 21 untreated specimens revealing overexpression of MTOR (33%), MAPK1(14%), and MET (8.0%). Actionable targets with FDA-approved therapies in other organ tissues were detected in 11 patients (40.7%). Incidental germline mutations, including MSH6, RB1, and MSH2, were identified in 9 patients though all were variants of unknown significance. Conclusions: In our study, a significant proportion of patients had potentially actionable molecular targets across the disease spectrum. The identified genetic alterations provide a genomic landscape for risk stratification, future therapies, and molecularly informed treatment paradigms for GCT patients.
Biomarkers of response to enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study.
Authors: Jindal Tanya , Kilari Deepak , Alhalabi Omar , Nizam Amanda , Khaki Ali Raza , Basu Arnab , Barata Pedro C. , Bilen Mehmet Asim , Shah Sumit , Zakharia Yousef , Milowsky Matthew I. , Bellmunt Joaquim , Emamekhoo Hamid , Davis Nancy B. , Grivas Petros , Gupta Shilpa , Hoimes Christopher J. , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S
Published: March 2023

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Background: EV, an antibody-drug conjugate (ADC) targeting Nectin-4, is used widely in treatment-refractory aUC, but limited data are available on biomarkers predictive of EV outcomes. We investigated potential biomarkers of response to EV in a pt cohort in the UNITE dataset. Methods: We included the retrospective UNITE study pts from 16 sites, with available next generation sequencing using institutional or commercial platforms, treated with EV alone outside clinical trials. Observed response (ORR) was determined by investigators for evaluable pts with scans after ≥1 dose of EV. Assessed molecular biomarkers included tumor mutation burden (TMB), PD-L1 status, somatic alterations (alts) in ≥ 10% of pts ( TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1, TSC1) and presence of ≥1 DNA damage response mutations ( ATM, BARD1, BRCA1, BRCA2, CDK12, CHEK2, PALB2, PPP2R2A, or RAD51B). ORRs were compared using Chi-squared test, while median progression-free and overall survival (mPFS, mOS) from EV start were compared with log-rank test and Cox proportional hazards in pts with and without biomarker presence. Results: A total of 170 pts had outcomes and NGS data available. Median age was 70, 133 (78%) were men, 144 (85%) Caucasian, 110 (65%) with pure urothelial histology, 118 (69%) with primary bladder tumor, and 116 (68%) had ≥ 2 lines of therapy before EV. For all pts, ORR 47%, mPFS 6 mos, mOS 12 mos. ORRs were higher in pts with ERBB2 (67% vs 44%; p = 0.05) and TSC1 (68% vs 25%; p=0.04) alts vs wild-type. Shorter mPFS was noted in pts with CDKN2A, CDKN2B, and MTAP alts, and longer mOS in pts with high TMB (table). Conclusions: This large, multi-site, retrospective cohort of pts with aUC identified several potential biomarkers associated with differential outcomes to EV. These findings, upon external validation, may help inform clinical decision making and potential therapy sequencing with available ADCs. Limitations include retrospective nature, pt selection, and confounding biases. [Table: see text]
Facility-level disparities in the delivery of guideline-based treatment across genitourinary cancers.
Authors: Szymaniak Julie A. , Zhang Li , Porten Sima P. , Meng Maxwell , Cooperberg Matthew R. , Carroll Peter , Washington Samuel L.
Published: March 2023

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Background: Disparities in guideline-based treatment (GBT) for genitourinary cancers are commonly presented individually, impeding comprehensive examinations of institutional drivers. While patient-level factors impacting disparities in treatment have been well documented, our understanding of how race-based disparities in treatment exist at the institution level remains relatively limited. In this study, we aim to characterize the prevalence of disparities in GBT for prostate (PCa), bladder (BCa), and kidney (KCa) cancer within the same facility to evaluate whether disparities cluster at the institutional level. Methods: Patients diagnosed with clinically localized (cT2-4aNX-1MX-0) bladder, (cT2b-4NX-0MX-0) prostate, or (cT2a-3cNX-1MX-0) kidney cancer between 2004-2017 within each National Cancer Database dataset were included. We collected clinicodemographics, treatment received, and facility data. GBT was defined according to NCCN Guidelines by TNM staging. We calculated rates of GBT by cancer type and race and compared rates between White, Black, Hispanic, and Asian patients using Chi-squared tests. Pairwise correlations in GBT rates between PCa, BCa, and KCa treated across and within facilities were estimated using Pearson correlation coefficients, where facilities with <10 cases of each cancer were excluded. Results: We identified 91904 BCa, 73,050 KCa, and 252,403 PCa cases. Overall, unadjusted GBT rates for BCa (41%, SD 18%) were significantly lower than for KCa (72%, SD 17%) and PCa (77%, SD 16%), all p<0.001. Correlation coefficients at academic medical centers were highest among the four facility types, though still low (r=0.31 prostate-bladder, 0.39 prostate-kidney, 0.39 bladder-kidney). BCa GBT was highest for White and Asian patients (50.5% and 48.6%, respectively) versus 42.2% for Black patients. KCa GBT rates were equivalent for White, Hispanic, and Asian patients (~76%) but lowest for Black patients (74.8%). In PCa, the highest GBT rate was 80.8% (White patients) and lowest was 76.5% (Black patients). After controlling for confounding variables and matching based on cohort size, intra-facility odds of receipt of GBT by Black patients (compared to White counterparts) correlated poorly across cancer types for all comparisons. This was true even when restricting analysis to higher-volume facilities (>200 patients), with r=0.1 for bladder-kidney, 0 for bladder-prostate, and 0.12 for kidney-prostate; p-value >0.05. Conclusions: Our findings show that, overall, there is little correlation between racial disparities in GBT across GU cancers treated in the same facility. As we push further for interventions to combat racial inequities in healthcare, we must continue to explore their prevalence within the context of a multi-disease and multi-level paradigm to identify systems-level factors that perpetuate their existence.