bluuebunny/crossref_metadata_2025_split 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]