bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining molecular and functional imaging in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Conteduca Vincenza , Scarpi Emanuela , Wetterskog Daniel , Caroli Paola , Romanel Alessandro , Lolli Cristian , Jayaram Anuradha , Gurioli Giorgia , Brighi Nicole , Poti Giulia , Wingate Anna , Schepisi Giuseppe , Matteucci Federica , Paganelli Giovanni , Demichelis Francesca , Attard Gerhardt , De Giorgi Ugo
Published: March 2021

141

Background: Recently, plasma tumour DNA (ptDNA) has been identified as a potential early noninvasive biomarker of treatment response in mCRPC patients ( Conteduca, Br J Cancer 2020). In this study, we sought to determine whether pre-treatment ptDNA could accurately reflect metabolic tumor burden in mCRPC and if it could be in combination with functional imaging could provide better prognostication. Methods: Between October 2011 and June 2016, 102 plasma samples from mCRPC patients treated with abiraterone or enzalutamide were collected. Targeted next-generation sequencing was performed to determine baseline ptDNA fraction. Maximum standardized uptake value (SUVmax), total lesion activity (TLA), and metabolic tumour volume (MTV) were calculated on 18F-fluorocholine positron emission tomography/computed tomography. A Weibull multiple regression model was adopted to evaluate the combined impact of clinical, molecular and imaging features on overall survival (OS) and to obtain a prognostic score. Each variable was allotted a “partial score” that depended on the size of the regression coefficient. Total scores ranged between 0 and 5.85 and assigned patients to 3 different risk groups according to 18-months survival probability: group I, >70%; group II 30%-70%; and group III, <30%. We estimated OS probabilities by the exponential model and by the Kaplan-Meier method. Results: We observed a significant association between ptDNA levels dichotomized as below or above median plasma tumor fraction (low ptDNA≤0.188 versus high ptDNA>0.188) and median SUVmax (p<0.0001), MTV (p=0.0005) and TLA (p<0.0001). Patients were randomly divided into a training set (n=68) and a validation set (n=34). In the training cohort, we performed a multivariable analysis showing that visceral metastasis, serum LDH, MTV and ptDNA were independent predictors of OS [HR=2.64, 95%CI 1.32-5.26, p=0.006; HR=3.69, 95%CI 1.98-6.87, p<0.0001; HR=1.91, 95%CI 1.13-3.21, p=0.015; and HR=2.64, 95%CI 1.32-5.26, p=0.003, respectively]. In the training set, median OS was significantly different among the 3 risk groups (risk group I, 29.2 months [95% CI, 18.3 to 37.0 months]; risk group II, 15.9 months [95% CI, 10.6 to 24.0 months]; and risk group III, 8.7 months [95% CI, 6.3 to 15.4 months]; p<0.0001). Similar results were observed in the validation set groups (risk group I, 23.4 months [95% CI, 8.1 to 38.5 months]; risk group II, 13.3 months [95% CI, 3.7 to 18.0 months]; and risk group III, 7.3 months [95% CI, 2.6 to 11.8 months]; p=0.001). Conclusions: Integrating plasma DNA analysis with functional imaging may improve prognostic risk stratification and treatment selection in mCRPC patients. A larger prospective evaluation is now warranted.
Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.
Authors: Sabol Rachel , Ledet Elisa Marie , Jaeger Ellen , Moses Marcus W. , Lewis Brian E. , Layton Jodi Lyn , Barata Pedro C. , Sartor A. Oliver
Published: March 2021

143

Background: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history records are incomplete in published studies. Methods: Prospective and complete family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes (Invitae testing) from 2016-2020. Comprehensive FH were obtained in all PCa patients in this database and analysis of prevalent FH was assessed at the time of sample collection. Age, race, metastastes at any time, and Gleason score were also ascertained. MUTYH heterozygotes were not considered pathogenic. Results: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. Men with Gleason scores 8-10 at time of diagnosis were more likely to have PV/LPV ( P= 0.004). One or more first degree relatives (FDR) with any cancer with was not predictive for germline PV/LPVs for men with PCa ( P= 0.96). Analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast cancer ( P = 0.028) or ovarian cancer ( P = 0.015) was predictive for PV/LPVs. Though one or more FDR with prostate cancer did not predict a PV/LPV in the overall panel, further analysis indicate that a history of a FDR with PCa was predictive for PV/LPV in a DNA damage repair (DDR) gene ( P= 0.044). Conclusions: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. A FDR with PCa was predictive for PV/LPV in DDR genes. These data emphasize the contribution of FH to germline genetic testing results in a cohort with complete ascertainment of cancer in first degree relatives.
Prognostic role of docetaxel-induced reduction of free testosterone serum levels in metastatic prostate cancer patients.
Authors: Kappler Paula , Brunotte Stefan , Ivanyi Philipp , Morgan Michael A. , Reuter Christoph W.
Published: March 2021

144

Background: We have recently demonstrated that a salvage therapy with carboplatin plus weekly docetaxel is effective in docetaxel-refractory prostate cancer (PC) and interferes with testosterone biosynthesis (Reuter et al.; Oncol Res & Treat. 2018, 41 (suppl.1): p.10). In this study, the impact of docetaxel monotherapy on free and total testosterone serum levels (fT, TT) and the prognostic role of fT and TT were analyzed in mPC patients. Methods: 62 consecutive mPC patients were treated with at least two cycles of docetaxel (75 mg/m2 q3w; 50 mg/m2 q2w, or 35 mg/m2 q1w) until disease progression, occurrence of intolerable adverse effects or completion of the planned cycle number. Efficacy measures were done following PCWG2 recommendations. FT and TT were measured before and during chemotherapy. Results: At the current analysis (August 31, 2020), the median follow-up time was 21.2 months. Response of prostate-specific antigen (PSAR; ≥50% PSA reduction) was observed in 42/62 (67.7%) and 12/36 (33.3%) patients with measurable disease exhibited a partial remission (PR). Median progression-free survival (PFS) for all patients was 8.1 months (CI 95% 3.6, 12.5) and median overall survival (OS) was 25.7 months (CI 95% 19.4, 32.1). The most common reversible grade 3/4 toxicity was leukopenia/neutropenia (29/33.9%). Median fT and TT serum levels were reduced below the detection limit during docetaxel treatment (fT: from 0.34 pg/mL to < 0.01 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified PSAR > 50%, fT reduction of 100% and number of organs involved as independent prognostic risk factors for PFS. Furthermore, fT reduction of 100% and FT nadir values < 0.01 pg/mL were independent prognostic risk factors for OS (p < 0.05). Conclusions: These data demonstrate that fT is an important prognostic factor for PFS and OS in mPC patients.
Role of free testosterone serum levels during salvage chemotherapy with carboplatin plus weekly docetaxel in patients with docetaxel-refractory, metastatic castration-resistant prostate cancer (mCRPC).
Authors: Brunotte Stefan , Ivanyi Philipp , Kappler Paula , Morgan Michael A. , Reuter Christoph W.
Published: March 2021

145

Background: Carboplatin plus docetaxel (CD) may be effective in mDRPC. Platinum(II)-complexes interfere with steroid biosynthesis and thus lower testosterone levels . In this study, the impact of CD on free and total testosterone (fT, TT) serum levels and the prognostic role of fT and TT were analyzed in mDRPC patients. Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least 2 cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel (35 mg/m2) iv for one hour on days 1, 8, (15) plus prednisone 2x5 mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Results: Of the 118 pts. treated since February 2005, 95.8% had bone, 47.5% lymph node, 28.0% liver and 20.3% lung metastases. Median follow-up time was 14.4 months at the time of the current analysis. The objective response rate (ORR) was 46.4% in the 69 pts. with measureable disease (58.5%). Response of prostate-specific antigen (PSAR ≥ 50%) was observed in 56 (47.9%) patients. Median progression free survival (PFS) was 7.6 months (CI 95% 6.0, 9.1) and median overall survival (OS) was 15.7 months (CI 95% 12.2, 19.2). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (36.4/28.8%). Median FT serum levels were 0.35 pg/mL before and < 0.18 pg/mL during CD treatment (nadir levels, p < 0.001; detection limit < 0.18 pg/mL). In multivariate analyses, LDH > 2xULN, PSAR≥50% and FT nadir levels below the detection limit ( < 0.18 pg/mL) during CD treatment were associated with longer PFS (p < 0.05). Conclusions: These data suggest that CD may be an important salvage treatment option for mDRPC patients by inhibition of the testosterone biosynthesis.
Baseline pathogenic mutations in non-AR/non-TP53 genes and prediction of response to high-dose testosterone.
Authors: Jaeger Ellen , Caputo Sydney , Ledet Elisa Marie , Moses Marcus W. , Layton Jodi Lyn , Lewis Brian E. , Barata Pedro C. , Sartor A. Oliver
Published: March 2021

146

Background: The fact that high dose of testosterone (HDT) elicits positive responses in a subset of prostate cancer patients (pts) is surprising and puzzling. Genomics data differentiating responders (Rs) from non-responders (NRs) is sparse. Pts with mutations in DNA repair pathway genes may be particularly sensitive to HDT (see BA Teply et al. Eur Urol 71:499, 2017). Herein we perform exploratory analyses to better understand the role of pathogenic mutations (muts) in ctDNA as a predictive biomarker for patients treated with HDT. Methods: ctDNA essays were performed with the Guardant360 methodology pre-HDT. Point mutations were classified by cancervar (http://cancervar.wglab.org). Truncating mutations (frameshift and nonsense) were manually curated to assess for pathogenicity. All patients had CRPC and were pre-treated with abiraterone and/or enzalutamide. HDT was typically administered as 400 mg testosterone cypionate q 3-4 weeks. Rs were compared to NRs. All Rs had >3 more cycles of HDT and a >50% PSA decline (N = 17). Non-responders had <3 cycles and no PSA decline (N = 23). Only muts with an allelic fraction of >0.5% were analyzed given dubious importance of mutations with lower allelic fractions. Results: AR muts (4/17 vs 6/23 in Rs and NRs) and TP53 muts (10/17 vs 11/23 in Rs and NRs) were similar ( P= 0.85 and 0.49, respectively) but the number of pts with non-AR/non-TP53 muts was distinct (3/17 for Rs, and 12/23 for NRs; P= 0.026). The average number of non-AR/non-TP53 muts (Rs = 0.23 and NRs = 0.83) was higher in the NRs (P = 0.046). When analyzing DNA repair alterations, no differences were noted in those with BRCA1/BRCA2/ATM mutations in the Rs and NRs (1/17 vs 6/23 respectively; P= 0.09). Conclusions: AR and TP53 pathogenic mutations are common in both Rs and NRs but other pathogenic mutations are more common in non-responders. We hypothesize that genetic pathways outside of the AR/TP53 axis drive resistance to HDT. Additional studies are warranted to assess whether or not these pathways drive resistance to HDT. Limitations are acknowledged with regard to the Guardant assay gene selection for CRPC pts.
Prognostic association between common laboratory tests and overall survival in men with de novo metastatic castration-sensitive prostate cancer: A population-based study.
Authors: Malone Shawn , Wallis Christopher J.D. , Morgan Scott Carlyle , Hamilton Robert James , Cagiannos Ilias , Basappa Naveen S. , Ferrario Cristiano , Gotto Geoffrey , Fernandes Ricardo , Noonan Krista , Niazi Tamim , Hotte Sebastien J. , Saad Fred , Chan Katherine , Hew Huong , Park-Wyllie Laura , Shayegan Bobby
Published: March 2021

149

Background: Despite significant advancements in the treatment of metastatic prostate cancer, a validated prognostic tool for patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) is still lacking. Using population-based data from Ontario, Canada, we sought to examine the prognostic association between common laboratory tests and survival for patients with mCSPC. Methods: A population-based cohort of men aged 66 years and older diagnosed with de novo metastatic prostate cancer between 2014-2019 were included. We assessed the association between laboratory tests at the time of cancer diagnosis and overall survival (OS). Utilizing a complete case analysis, we used Cox proportional hazards models to assess the association between these laboratory tests and OS while adjusting for patient and disease characteristics. Results: A total of 3,556 men with de novo mCSPC were included. On multivariable analysis, there were significant associations between OS and neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, albumin, hemoglobin, PSA decrease and PSA nadir <0.1 ng/mL (please see table). Conclusions: Commonly available laboratory tests provide important prognostic information for patients with newly diagnosed mCSPC given demonstrated associations to overall survival. Apart from PSA kinetics, none of these baseline tests were performed in more than 57% of patients indicating underutilization of these low-cost prognostic biomarkers. [Table: see text]
The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone-sensitive prostate cancer.
Authors: Shaya Justin , Lee Aaron , Cabal Angelo , Panian Justine , Randall James Michael , Millard Frederick E. , Stewart Tyler Francis , Rose Brent S. , Parsons John Kellogg , McKay Rana R.
Published: March 2021

150

Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes. [Table: see text]
Landscape of genomic alterations of circulating tumor DNA in advanced genitourinary cancer patients: SCRUM-Japan MONSTAR SCREEN Project.
Authors: Matsubara Nobuaki , Kato Taigo , Fujisawa Takao , Shiota Masaki , Eto Masatoshi , Osawa Takahiro , Abe Takashige , Shinohara Nobuo , Yasumizu Yota , Tanaka Nobuyuki , Oya Mototsugu , Nishimoto Koshiro , Horasawa Satoshi , Kuramoto Naomi , Nakamura Yoshiaki , Taniguchi Hiroya , Yoshino Takayuki , Nonomura Norio
Published: March 2021

152

Background: Circulating tumor DNA in plasma (ctDNA) is an emerging resource for detecting genomic alterations in various cancers. However, the characteristics and clinical utility of ctDNA are not fully elucidated, especially in patients with genitourinary (GU) cancers. Methods: In April 2019, SCRUM-Japan started the MONSTAR-SCREEN project, which evaluates the ctDNA from patients with various advanced solid tumors. We collected plasma and tumor samples from patients with advanced prostate cancer (PC), urothelial carcinoma (UC), and renal cell carcinoma (RCC). Plasma ctDNA and tissue genomic DNA were analyzed using NGS-based cell-free DNA assay, a modified version of FoundationOne Liquid (F1L) including blood tumor mutational burden (TMB) analysis, and tissue-based panel, FoundationOne CDx (F1CDx), respectively. Success rate of ctDNA was defined as the percentage of patients whose sample quality control status was “pass” or “qualified”. Level of ctDNA was defined as the maximum allele fraction (AF) for all known somatic alterations detected. Results: As of June 18, 2020, ctDNA analysis results were available for 470 of 540 patients with advanced solid tumors. Among them, we analyzed 70 advanced GU cancers (35 PC, 17 UC, and 18 RCC) and 400 non-GU cancers. The success rate of ctDNA was significantly lower in GU cancers than in non-GU cancers (81.4% vs. 91.5%, P = 0.016). The levels of ctDNA in PC and UC were similar to those in non-GU cancers. RCC had the second lowest ctDNA level (median 0.13%) after that in malignant melanoma. The median TMB, as estimated by ctDNA, was 4.40, 0.88 and 0.44 mutations/Mb in UC, PC and RCC, respectively. The most frequently altered genes were TP53 (34%), AR (11%), BRCA2 (11%), ATM (8.6%), and CDK12 (8.6%) in PC, TP53 (59%), TERT (41%), and CHEK2 (18%) in UC, and TP53 (22%), ATM (11%), and MTOR (11%) in RCC. The mutation rate in genes related to DNA damage response (DDR) pathways was significantly higher in GU cancers compared to that in non-GU cancers (30.0% vs. 18.0%, P = 0.033). However, other pathways were less frequently altered in GU cancers versus non-GU cancers, including Wnt (5.7% vs. 16.8%, P = 0.017), PI3K (8.6% vs. 19.0%, P = 0.039) and RAS/MAPK (8.6% vs. 29.5%, P < 0.001). Conclusions: Our results reveal the genomic landscape of ctDNA in several advanced solid tumors, and highlight the differences between tumor types. Comprehensive analysis of ctDNA using the F1L assay reveled alterations in DDR-associated genes were significantly more frequent in GU cancers than in non-GU cancers. Clinical trial information: UMIN000036749.
Differential levels of serum PSA related to volume of benign, Gleason pattern 3 and pattern 4 prostate tissue.
Authors: Andolfi Ciro , Vickers Andrew , Cooperberg Matthew R. , Carroll Peter , Cowan Janet E. , Paner Gladell P , Eggener Scott E.
Published: March 2021

164

Background: PSA is an essential component of prostate cancer screening, management, and oncologic risk. We evaluated how serum levels of PSA vary by volume of benign tissue, Gleason pattern 3 (GP3), and Gleason pattern 4 (GP4). Methods: Consecutive men undergoing radical prostatectomy at two academic institutions for pT2N0, Gleason grade group 1-4, and undetectable postoperative PSA were reviewed. For each man, estimated volume (cc) of benign, GP3, and GP4 were extracted from the prostatectomy specimen. The primary analysis evaluated the association between pre-operative PSA and volume of each type of prostate tissue using multivariable linear regression with adjustment for age. An assessment of predictiveness (R2) for PSA level was performed with each predictor and associated non-linear terms were removed from the model. Results: Estimated contribution to serum PSA for institutions A and B was 0.04-0.05 ng/ml/cc for benign, 0.08-0.11 ng/ml/cc for GP3, and 0.62-0.83 ng/ml/cc for GP4 (Table). We did not see a difference between PSA levels per cc of GP3 vs. benign tissue (p=0.4). R2decreased only slightly when removing age (0.006-0.010), benign tissue (0.049-0.051) or GP3 (0.011-0.023) from the model. When GP4 was removed, R2 decreased 0.063-0.310. R2 was far higher for GP4 than for Grade Group alone and was equal or superior to Grade Group plus total prostate volume. Conclusions: In early stage Grade Group 1-4 prostate cancer, one cc of Gleason pattern 4 was associated with 6 to 20-fold more serum PSA than one cc of Gleason pattern 3 or benign tissue. No difference in PSA per cc was observed between Gleason pattern 3 and benign tissue which has clinical implications for screening and active surveillance. [Table: see text]
Genomic characterization and molecular taxonomy of sarcomatoid variant prostate cancer.
Authors: Duong Mary , Barrett Alex , Schaeffer Jeff , Taxter Tim , Gross Mitchell E.
Published: March 2021

168

Background: Sarcomatoid carcinoma is a rare and aggressive histologic variant pattern of prostate cancer with morphologic features associated with both mesenchymal and epithelial tissue elements. While sarcomatoid cancer can be found concurrently with adenocarcinoma in untreated specimens, it is most often encountered in post-treatment biopsies. Limited data is available to categorize genomic alterations in sarcomatoid prostate cancer or to genetically define any potential relationship between sarcomtaoid and adenocarcinoma patterns from the same patient. Methods: Clinical characteristics, histology, and genomic alterations for 5 cases of sarcomatoid prostate cancer and 2193 cases with adenocarcinoma are presented. All cases were analyzed for genomic alterations against a custom panel via Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth and whole transcriptome RNA sequencing) for germline and/or somatic mutations. The xT assay detects single nucleotide variants, specific insertion/deletions, amplifications and gene fusions, as well as TMB and MSI status. Results: Patterns of genomic alterations in sarcomatoid cancer are tabulated and compared with adenocarcinoma. Of note, BRCA2 alterations were found in 2 of 5 sarcomatoid cases including 1 example of BRCA2 loss and 1 variant of undetermined significance (p.K2316R). Sequential analysis of samples from the subject with BRCA2 loss demonstrates genomic alterations that are shared across multiple samples despite different histologic patterns and following 14 months of treatment with GnRH antagonist and abiraterone (Table). Conclusions: Sarcomatoid prostate cancer shares many genomic alterations with that found in adenocarcinoma. Genomic characterization of this variant form of prostate cancer may reveal clinically actionable genetic changes. [Table: see text]
PSA velocity to predict clinical progression in African American and non-Hispanic White patients with low-risk prostate cancer undergoing active surveillance.
Authors: Javier-Desloges Juan , Nelson Tyler , Courtney Patrick Travis , Deka Rishi , Nalawade Vinit , Mell Loren K. , Murphy James Don , Parsons J Kellogg , Rose Brent S.
Published: March 2021

196

Background: The utility of prostate-specific antigen velocity (PSAV) to predict clinical progression in patients with localized prostate cancer (PC) on active surveillance remains unclear, and in African American (AA) patients on active surveillance remains undefined. Methods: We performed a cohort analysis using the national US Veterans Affairs Informatics and Computing Infrastructure (VINCI). We identified 5296 patients diagnosed with localized prostate cancer (PC) from 2001 to 2015 managed with active surveillance. Follow-up extended through March 31, 2020. We defined low-risk PC as ISUP grade group 1 (GG1) clinical tumor stage ≤ 2A, and PSA level ≤ 10 ng/dl; and active surveillance as no definitive treatment within the first year after diagnosis with at least one additional staging biopsy after diagnostic biopsy. The primary outcome was grade progression on repeat biopsy/prostatectomy defined as GG2 or GG3. The secondary outcome was incident metastases. Cumulative incidence functions and multivariable Cox proportional hazards models were used to test associations between PSAV and outcomes. Results: The final cohort included 3919 Non-Hispanic White patients (NHW) (74%) and 1377 AA (26%) patients. GG2 progression on repeat biopsy occurred in 2062 (38.9%) patients, with a cumulative incidence (CI) of 43.2 % and GG3 progression occurred in 728 (13.7%) patients, with a CI of 18% at seven years. Fifty-four (0.8%) patients developed metastases, with a CI of 1.4% at ten years. In unadjusted analyses, compared to NHW patients, AA patients were significantly more likely to progress to GG2 (52.8% vs 39.8%, p<0.001), and GG3 (22.2% vs 16.8%, p=0.01). On MV analysis, PSAV was a significant predictor of GG2 (HR 1.32 [1.26-1.39]), GG3 (1.5 [1.40-1.62]), and metastases (1.38 [1.10-1.74]). A significant interaction term between race and PSAV indicated the need for different PSAV thresholds for AA and NHW men. Based on maximally selected rank statistics, optimal thresholds for separating outcomes were different in AA vs NHW men. (0.44 vs. 1.18). Conclusions: In this analysis of PSAV in low-risk prostate cancer patients on AS—to our knowledge, the largest to date for AA patients—we observed that PSAV is a robust predictor of upgrading on restaging biopsy as well as metastasis. Compared to NHW patients, AA patients were more likely to progress at lower values of PSAV and therefore merit close follow-up on active surveillance protocols.
An FDA pooled analysis: Characteristics and outcomes of patients with nonmetastatic castration-resistant prostate cancer, based on prior history of prostatectomy and/or radiation therapy.
Authors: Fallah Jaleh , Zhang Lijun , Weinstock Chana , Suzman Daniel L. , Tang Shenghui , Goldberg Kirsten B. , Kluetz Paul Gustav , Beaver Julia A. , Pazdur Richard , Ibrahim Amna , Amiri-Kordestani Laleh
Published: March 2021

197

Background: Patients (pts) enrolled in trials of androgen receptor inhibitors (ARI) in the non-metastatic castration resistant prostate cancer (nmCRPC) setting may or may not have received definitive treatment with prostatectomy and/or radiation therapy (Surg/RT). We investigated the characteristics and outcomes of pts with nmCRPC based on prior history of Surg/RT. Methods: Data were pooled from all trials of ARI in nmCRPC submitted to the FDA as of October 2020. Pts baseline characteristics were summarized by prior history of Surg/RT. The Kaplan-Meier method was used to estimate median metastatic-free survival (MFS) and overall survival (OS) of each treatment arm by prior history of Surg/RT status. Hazard Ratios (HR) with corresponding 95% confidence intervals (CI) were estimated using a Cox proportional hazards model stratified by trial and adjusted for baseline characteristics. Results: Three trials met the inclusion criteria. Of 4117 pts enrolled, 2251 (55%) had prior surg/RT. The median age at the time of enrollment was 72 and 76 years in pts with and without prior Surg/RT, respectively. The median time from initial diagnosis of prostate cancer to enrollment on the trials of ARI was 9.1 and 5.7 years in pts with and without prior Surg/RT, respectively. PSA doubling time and number of prior hormonal therapies were similar between the two groups with and without prior Surg/RT. History of prior Surg/RT varied by geographic region: 76% (N = 611/807) in North America, 50% (N = 1110/2229) in Europe, 39% (N = 220/570) in Asia/Pacific, 52% (135/262) in South America, and 73% (171/233) in Australia/New Zealand. ECOG performance status (PS) at the time of enrollment was 0 and 1 in 80% and 20% of the pts with prior Surg/RT, respectively. In pts without prior Surg/RT, ECOG PS was 0 in 65% and 1 in 35% of pts. Gleason score was ≥8 in 36% and 47% of pts with and without prior Surg/RT, respectively. MFS and OS results in pts with and without prior Surg/RT are in the table. Conclusions: In this retrospective analysis, MFS and OS was improved in pts who received ARIs compared to placebo, regardless of prior history of Surg/RT. Any relative differences based on prior history of Surg/RT can only be considered hypothesis generating. [Table: see text]
Utilization and survival outcomes between definitive versus conservative treatments among elderly men with high-risk prostate cancer.
Authors: Patel Sagar Anil , Gay Hiram Alberto , Michalski Jeff M. , Baumann Brian Christopher , Brenneman Randall , Hershatter Bruce Warren , Jani Ashesh B. , Fischer-Valuck Benjamin Walker
Published: March 2021

204

Background: Prostate cancer (PCa) is the second leading cause of cancer death in men > 80 years old. However, studies have shown that older men are less likely to undergo curative treatment for localized PCa, possibly due to competing comorbidities or inability to accurately estimate life expectancy. Herein, we investigate utilization trends and survival outcomes amongst guideline-supported treatment options in elderly men with high-risk PCa in the United States. Methods: Men ≥ 80 years diagnosed with high-risk PCa (cT3-4 or Gleason 8-10 or PSA > 20) between 2004-2016 were analyzed from the National Cancer Database. Those missing risk-stratification or treatment data were excluded. Eligible patients were grouped based on their primary treatment modality: no treatment (observation), androgen deprivation therapy (ADT) alone, radiation therapy (RT) alone, RT + ADT, or radical prostatectomy (RP). Cochran-Armitage was used to evaluate treatment trends over time, and multivariable logistic regression was used to identify sociodemographic predictors of treatment. Overall survival (OS) between treatments was evaluated using Kaplan-Meier, log-rank, and multivariable Cox proportional hazards. Results: With a median follow up of 42 months, 19,920 men were eligible for analysis. The most utilized treatment modality was RT+ADT (37.2%), followed by ADT alone (29.4%), observation (23.9%), RT alone (7.8%), and RP (1.7%). There was a significant increase in use of RT+ADT and RT alone (p < 0.001) and decrease in use of ADT alone and observation ( p< 0.001); no change was seen in RP use. There was no OS difference between observation versus ADT alone (aHR 1.04, 95% CI 0.99-1.09, p = 0.11). Definitive local treatment was associated with improved OS compared to ADT alone (RT+ADT: aHR 0.48, 95% CI 0.46-0.50, p < 0.0001; RT alone: aHR 0.54, 95% CI 0.50-0.59, p < 0.0001; RP: aHR 0.50, 95% CI 0.42-0.59, p < 0.0001). Black men and uninsured status were independently associated with lower likelihood of undergoing definitive treatment (i.e. RT+ADT, RT, or RP). Conclusions: For men ≥ 80 years old with high-risk PCa in this large US registry, definitive local therapy using RT +/- ADT or RP was associated with a 50% reduction in overall mortality compared to observation or ADT alone. Less than half of men in this time period underwent a definitive treatment, and Black and uninsured men remained at particularly high risk of undertreatment.
Pinpointing uncharacterized prostate cancer in active surveillance patients through mpMRI biopsy.
Authors: Greenberg Jacob W. , Sanekommu Ganesh , Hughes William M. , Shelton Thomas M. , Koller Christopher R. , Natale Caleb , Miller Stephanie , Silberstein Jonathan L. , Krane L. Spencer
Published: March 2021

210

Background: The UroNav fusion biopsy system allows for the real time visualization of the prostate using multi-parametric MRI (mpMRI) data. This technology has become a valuable instrument for staging prostate cancer at the time of PSA elevation. However, data is still yet emerging over the use of this tool for patients currently being followed on an active surveillance (AS) protocol. In this study we sought to evaluate the efficacy of the UroNav system in patients on AS. Methods: Patients were enrolled into our prospective study, at a single center institution, approved by the Southeast Louisiana Veterans Health Care System (SLVHCS) IRB. Inclusion criteria for this study was men previously enrolled in an active surveillance protocol with a life expectancy ≥10 years. Statical analysis was performed using R 4.0.2 (Ann Arbor, MI). Results: A total of 103 patients were entered into this study for analysis. These patients had a median age of 67.1(62.8 - 70.8) and BMI of 28.6(25.5 - 32.3). The clinical profiles of these patients were median PSA of 6.36(4.65 - 8.89) with a velocity slope of (0.065 (-0.14 - 0.27), TRUS volume of 39.5(32.2 - 56.8), PSAD of 0.15(0.09 - 0.23), and a PI-RAD score of 4(3 – 5). A logistic regression was performed using upgrading on UroNav or Template bx as the outcome. Patients with an increased PSA were more likely to upgrade of Bx (OR = 1.2 (1.05 - 1.39)). Additionally, patients with decreasing MRI volumes were also more likely to upgrade on Bx (OR = 0.97 (0.94 - 0.98)). A total of 42 (40%) patients upgraded on either MRI or Template bx from their initial AS workup. MRI found 13 (12.6%) patients with an upgraded GG that displayed consistent or benign disease on template. Conversely, template also found 13 (12.6%) unique patients who upgraded but were found to have constant or benign disease on mpMRI. Conclusions: mpMRI guided biopsy is a useful tool that can further assist physicians in characterizing prostate cancer in patients being concurrently followed on an active surveillance protocol. MRI is able to find clinically significant cancer that would have otherwise been missed on traditional template biopsies. [Table: see text]
Racial diversity and reporting in FDA registration trials for genitourinary (GU) cancers from 2006-20.
Authors: Lythgoe Mark , Julve Maximilian , Krell Jonathan , Savage Philip , Grivas Petros , Khaki Ali Raza
Published: March 2021

22

Background: GU cancers account for 1 in 5 of new cancer diagnoses in the USA. Significant racial disparities exist in terms of incidence, treatment and outcomes. Current FDA clinical trial guidance advises race reporting as a minimum of 5 categories (White/Caucasian, Black, Asian, American Indian or Alaskan Native [AIAN] and Native Hawaiian or Pacific Islander [NHPI]). Guidelines from the International Committee of Medical Journal Editors (ICMJE) recommend that authors should as a minimum, provide descriptive data for variables such as race and ethnicity. We analysed racial diversity in GU registration trials and compliance with FDA/ICMJE guidance in reporting. Methods: A retrospective review of new market authorisations in GU cancers from Jan 2006 to Oct 2020 was conducted utilizing the FDA website. Clinical trials cited on the licensing label for market authorization were recorded and corresponding registration trial publication identified. If race was unreported or partially reported (defined ≤3 groups), then the trial report on clinicaltrials.gov or FDA website was analysed. Total proportion of racial group participation and the proportion of registration trials with adequate reporting was determined. Results: We identified 42 new licensing indications, involving 33 unique drugs. Overall 30,316 patients participated in GU cancer registration trials; 21,068 (69.5%) White or Caucasian, 2516 (8.3%) Asian, 621(2%) Black or African American, 92 (0.3%) AIAN, 17 (0.1%) NHPI, 558 (1.8%) other or multiple races and 5463 (18%) unknown. Table shows breakdown by tumour group. Race reporting occurred in 23 (55%) registration trial publications, of which 5 provided only limited information (e.g. Caucasian only). For studies where no race information was reported, a further 10 (24%) had information within the trial report. In the 5 years prior to the introduction of FDA guidance in 2016 only 30% of registration studies met FDA/ICJME requirements. Since 2016 this has improved significantly to 60%. Conclusions: Despite the higher incidence of GU cancers in non-white populations, this study has revealed the relative over-representation of white participants in GU registration trials. The inclusion of black trial participants is in particular disproportionately low when compared to the burden of disease in this population group. Recruitment of black and other minority participants should be a research priority. [Table: see text]
Conditional progression-free survival in men on active surveillance for prostate cancer stratified by NCCN risk.
Authors: Gusev Andrew , Rumpf Florian , Salari Keyan , Twum-Ampofo Jeffrey , Wszolek Matthew F , Dahl Douglas M. , Blute Michael L. , Feldman Adam S.
Published: March 2021

222

Background: Active surveillance (AS) is an accepted management strategy for men with very low, low, and select cases of favorable intermediate National Comprehensive Cancer Network (NCCN) risk prostate cancer (PCa). However, how patients’ risk of disease progression evolves over time during AS has not been well defined. Conditional survival measures the probability a patient will continue to survive some number of years, given that they have already survived a certain number without progression. We evaluated our AS cohort to investigate overall and conditional progression free survival on AS, stratified by the NCCN risk groups. Methods: We reviewed our institutional database of 1254 men enrolled in AS for localized PCa from 1996-2016. Our AS protocol includes prostate specific antigen (PSA) and digital rectal exam (DRE) every 4-6 months for 3 years, then annually. Mandatory confirmatory 12 core biopsy is done at 12-18 months. Multiparametric magnetic resonance imagining (mpMRI) or additional systematic or MRI-fusion biopsies are done at the discretion of physician and patient. Overall freedom from pathologic grade progression on follow-up biopsy and treatment free survival were estimated using the Kaplan-Meier method. Survival curves were compared pairwise using the Log-rank test and adjusted for false discovery rates with the Benjamini-Hochberg procedure. Three-year conditional survival estimates were derived for both outcomes from the Kaplan-Meier estimator. Results: Of 1254 men, 521 (41.6%) met criteria for very low, 606 (48.4%) for low, and 125 (10.0%) for favorable intermediate NCCN risk at diagnosis. Median follow-up time was 6.5 years (IQR 4.1-9.4). Median pathologic grade progression free survival in years was significantly longer for very low risk (7.8, 95% CI 6.8-11.2) compared to low risk men (5.6, 95% CI 4.7-6.9), however neither was significantly different from favorable intermediate risk men (5.9). There was no significant difference in treatment free survival between the three risk groups. At diagnosis, the three-year risk for pathologic grade progression (24%, 95% CI 21-27%) and progression to treatment (22%, 95% CI 20-25%) were similar. However, with increasing time of event-free AS, the conditional probability of pathologic grade progression increased, while that of progression to treatment decreased. Conclusions: Our results demonstrate that despite a mild increase in pathologic progression free survival in very low risk men, there was no clear difference in overall treatment free survival between very low, low, and select favorable intermediate NCCN risk men. Further, with increased time spent on AS, despite elevated rates of pathologic progression, patient progression to treatment decreased. This trend may be indicative of changes in goals of care as men with PCa age and should be closely monitored during AS.
Hospital efficiency and quality of prostate cancer care.
Authors: Jayadevappa Ravishankar , Chhatre Sumedha , Malkowicz S. Bruce , Guzzo Thomas J. , Wein Alan J. , Schwartz Jerome Sanford
Published: March 2021

223

Background: There is no consistent evidence with respect to the role of hospital efficiency in improving quality of prostate cancer care. Study objective was to examine the association between hospital efficiency and quality of care in African American, Hispanic, and white Medicare beneficiaries with prostate cancer. Methods: Population-based cohort study using Surveillance, Epidemiological, and End Results-Medicare (SEER-Medicare) data from 2000–2016 for prostate cancer patients aged 66 or older. SEER-Medicare data was linked to American Hospital Association data. We computed hospital technical efficiency using data envelopment analysis. Outcomes were emergency room visits, complications, hospitalizations, cost, treatment and mortality (all-cause and prostate cancer-specific). We used competing risk analysis for survival, log-link GLM models for cost, and Poisson (zero inflated) models for count data. Propensity score and instrumental variable approaches were used to minimize potential biases. Results: We identified 87,117 eligible prostate cancer patients. Of these, 86% were white, 11% were African American, and 3% were Hispanic. Table shows the association between four quartiles of efficiency and outcomes. Higher hospital efficiency was consistently associated with decreased all-cause mortality, prostate cancer-specific mortality and emergency room visits. Association between hospital efficiency and mortality varied between racial and ethnic groups. Conclusions: Increasing hospital efficiency may reduce some of the disparity in prostate cancer outcomes. Our findings indicate important racial and ethnic differences that should be considered while planning hospital efficiency models to improve quality of prostate cancer care. Policies to redirect minority patients to hospital with higher efficiency may reduce racial and ethnic disparity in quality of care and outcomes. [Table: see text]
High-risk nonmetastatic prostate cancer in the elderly: Does adjuvant chemotherapy affect survival?
Authors: Akhtar Komal , Formica Margaret K , Madhira Bhaskara , Basnet Alina
Published: March 2021

229

Background: RTOG0521 and STAMPEDE showed improved Overall survival (OS) and progression free survival (PFS) respectively, of ACT (adjuvant chemotherapy) to ADT (androgen deprivation therapy) and RT (adjuvant radiotherapy) in HrPC (High Risk localized Prostate Cancer). The median age of males in these trials is in 60’s. We present an observational study reporting OS on addition of ACT to ADT and RT in male age > 65 with HrPC. Methods: A retrospective national cancer center database (NCDB) (2004-2015) analysis was done. Patients aged >65 years with non-metastatic HrPC who underwent ADT and RT with or without ACT were included. Group1 included RT+ ADT+ ACT, Group2 included RT+ ADT. OS was estimated using Kaplan Meier analysis, reported for sub groups based on age. An adjusted hazard ratio (aHR) was calculated utilizing a Cox proportional hazard regression model. Results: 1,380,357 patients with HrPC were identified. 11734 met our inclusion criteria; 128 in Group1 and 11606 in Group2. Median Age, Gleason and PSA were: Group1- 72, 9, 14.6, Group2- 74, 9 and 14. Patients who received ACT were more likely to be younger and treated in an academic setting. OS stratified by age is depicted in table. Among patients ≥ 75, OS was uniformly worse with ACT with non-significant p value (p=0.08). The aHR, group 1 vs group 2 is 1.22, 95% CI = 0.96-1.57, p=0.11, when adjusted for Age, Facility Type, Insurance, and Charlson-Deyo Score (CDS). Conclusions: Very elderly patients ≥75 years were not likely to get ACT. OS was not improved by addition of chemotherapy, at age ≥ 65yrs and more prominent at age ≥ 75. Limitations of observational database study are lack of randomizations, missing information, physician bias on choices of ACT, RT and ADT. [Table: see text]
Incidence and cost of radical prostatectomy for NCCN low-risk prostate cancer in Utah.
Authors: Gill David Michael , Baumgartner Jessica , Gygi Jesse , Foy Bridget , Crawford Bryan , Sandhu Zoya , Brant Jamie , Barney Brandon M. , Tward Jonathan David
Published: March 2021

232

Background: Guidelines Support active surveillance (AS) as the preferred treatment for men with NCCN low-risk prostate cancer (Gleason 3+3, prostate-specific antigen [PSA] <10 ng/ml, ≤T2a). Recent work from Mahal BA et al. (JAMA 2019) reports AS rates are increasing, but only 42.1% of men with low-risk prostate cancer underwent AS in 2015. Low-risk prostate cancer accounted for 30.1% of diagnoses. The majority of Utah residents treated for prostate cancer receive therapy at either The Huntsman Cancer Institute or Intermountain Healthcare facilities. We modeled the costs associated with the presumptive overtreatment of men with low-risk disease treated in 2017-2019. Methods: Data from The Huntsman Cancer Institute and Intermountain Healthcare cancer databases from 2017 to 2019 were retrospectively analyzed. Men with available pathologic, laboratory and clinical data who had undergone prostatectomy were stratified by having NCCN low, intermediate, and high-risk disease. Rates of radical prostatectomy by year and institution were analyzed. The cost of prostatectomy compared to AS was estimated to be $14,453 from recent work by Trogdon JG et al. (JAMA Oncol 2019). Results: Data was available for 1,155 Utahn men (Table). Of the 1155 surgeries performed, 69 (6%) were in low-risk patients. The total costs of care that might have been avoided over these three years are estimated to be $1 million. Conclusions: Approximately 6% of prostatectomies performed in Utah are in men with NCCN low-risk prostate cancer. While these rates are lower than the national average, we estimate approximately $1 million in medical costs and toxicities could be deferred had these patients opted for AS. Work is ongoing to characterize clinical toxicity of treatment in these men, and a multi-institutional collaborative education outreach program to reduce overtreatment is in development. [Table: see text]