bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival outcomes of metastatic renal cell carcinoma (RCC) patients with pancreatic metastases (PM): Pooled analysis from a large clinical trials database.
Authors: Shaya Justin , Lin Xun , Cabal Angelo , Panian Justine , Weise Nicole , McKay Rana R.
Published: May 2020

e17072

Background: Pancreatic metastases are a rare site of metastasis for RCC. It has been suggested that patients with metastases to the pancreas have a more indolent disease course, however long term survival outcomes with systemic therapy are not well defined. Methods: We conducted a pooled analysis of metastatic RCC patients treated in phase II/III clinical trials. The primary objective was to evaluate overall survival in patients with PM compared to those without PM. Secondary objectives included progression-free survival (PFS) and objective response rate. Outcome measures were evaluated in the overall cohort and stratified by line and type of therapy and IMDC risk group. Statistical analyses were performed using Cox regression and Kaplan-Meier analysis. Results: We identified 4736 patients treated with either vascular endothelial growth factor (VEGF) targeted (n=3511), mammalian target of rapamycin (mTOR) targeted (n=665), or cytokine therapy (n=560), of which 5.0% (n=235) had PM at initiation of therapy. Median OS (mOS) in patients with PM was significantly prolonged compared to those without PM (Table). In a multivariate Cox regression model, this improvement in mOS remained statistically significant when adjusting for concurrent metastases to the lung, bone, or liver, line and type of therapy, and IMDC risk group. In further subgroup analysis, among patients with PM, superior mOS was noted in patients with favorable or intermediate IMDC risk, treatment naive patients, and treatment with VEGF inhibitors or cytokine therapy (Table). For the overall cohort, PFS was 10.9 vs 6.9 months for patients with and without PM (HR 0.72, 95% CI: 0.60, 0.86). Objective responses were higher in patients with PM vs those without PM (37% vs 24%, p<0.01). Conclusions: The presence of PM in advanced RCC is an independent positive predictor for survival. This effect is pronounced in patients treated with VEGF inhibitors and IMDC favorable and intermediate risk disease. Unraveling the molecular determinates of pancreatic tropism in RCC will be important for personalizing therapy for patients. [Table: see text]
The role of cytoreductive nephrectomy in metastatic renal cell carcinoma.
Authors: Alnimer Yanal Mufeed , Qasrawi Ayman , Katato Khalil
Published: May 2020

e17080

Background: The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (MRCC) is unclear. Two randomized clinical trials (RCT) in the cytokine era demonstrated a survival benefit of CN in MRCC. However, the efficacy of this approach is unknown after the introduction of tyrosine kinase inhibitor (TKI) therapy and immunotherapy (IC) in the frontline setting of MRCC. Methods: We studied the the impact of CN in MRCC on overall survival (OS) using the Surveillance, Epidemiology, and End Results (SEER)-18 registries. The R software was used for statistical analysis. Results: A total of 5488 patients with MRCC between 2010-2016 were identified. The median age was 62 years, 70% were males and 55% underwent partial or total nephrectomy. After a median follow-up time of 36 months, median OS was 12 months. Histology was clear cell (CC) in 79% the cases and 21% were non-clear cell (NCC). On univariate Cox regression, patients with CC histology who underwent CN had a 0.35 [95% confidence interval (CI), 0.33-0.38] lower risk of death compared to those who did not. After adjustment for age, gender, number of sites involved by metastasis (bone, liver, lung and/or brain), grade and administration of chemotherapy, patients who got CN had a 0.33 (CI, 0.29-0.36) lower risk of death compared to those who did not. The following factors were associated with higher risk of death in multivariable Cox proportional hazard ratio (HR) model: number of metastatic sites, HR = 1.50 (CI, 1.43-1.58); grade III vs. II, HR = 1.39 (CI, 1.22-1.59); grade IV vs. II, HR = 2.08 (CI, 1.80-2.39); female gender, HR = 1.16 (CI, 1.07-1.26), those who didn’t receive chemotherapy (or unknown status) with a HR of 1.39 (CI, 1.28-1.50) and increasing age with a hazard ratio of 1.009 (CI 1.005-1.013) for each year increase. With NCC, the following factors were associated with higher mortality: number of metastatic sites, HR = 1.34(CI, 1.24-1.46), older age, HR = 1.01(CI, 1.003-1.014) for each year increase, grade III vs. II,HR = 1.97(CI,1.41-2.77);IV vs. II,HR = 1.98 (CI, 1.41-2.77); and those who didn’t receive chemotherapy with HR = 1.52 (CI, 1.32-1.74). On the other hand, those who had CN had lower mortality, HR = 0.46 (CI, 0.38-0.55). Conclusions: In this large cohort, there was a survival benefit of CN in MRCC. However, our study is limited by the lack of treatment details and possible selection bias for the patients who got CN. TARIBO is an ongoing RCT that aims to identify the benefit from CN in MRCC in the TKI and IC era. Until the trial is concluded, CN should be considered for eligible patients with MRCC, regardless of histology.
The change of serum C-reactive protein levels during molecular-targeted treatments could predict the response to anti-PD-1 treatment in metastatic renal cell carcinoma patients.
Authors: Takamatsu Kimiharu , Mizuno Ryuichi , Hayakawa Nozomi , Tanaka Nobuyuki , Kosaka Takeo , Kikuchi Eiji , Oya Mototsugu
Published: May 2020

e17085

Background: Immuno-oncology (IO) checkpoint inhibitors, such as programmed death-1/programmed death-ligand1 (PD-1/PD-L1) inhibitors have been standard of care in the metastatic renal cell carcinoma (mRCC) systemic treatment. However, predictive biomarkers for IO checkpoint inhibitors which is clinically usable have been still unclear. The aim of this study was to evaluate the clinical significance of the change of serum C-reactive protein (CRP) levels during molecular-targeted treatments (VEGFR-TKI and mTOR-I) prior to nivolumab as the predictive marker for the response of nivolumab in patients with refractory mRCC. Methods: A total of 73 mRCC patients (favorable 25(34%), Intermediate 38(52%) and poor 10(14%) risk group by IMDC criteria) treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. The elevation of serum CRP during molecular-targeted therapies before nivolumab induction was defined as the CRP-elevation group. The clinical impact of CRP-elevation as well as other clinical and pathological prognostic factors on progression-free survival (PFS) and overall survival (OS) from nivolumab were assessed. Results: The median follow-up period after nivolumab initiation was 13.2 months (range 3.0-60.8). Forty-nine patients (67%) were categorized into the CRP-elevation group. A clear impact of the CRP-elevation on the response of nivolumab was observed: the median PFS of the CRP-elevation group was 11.9 months, and that of the CRP-non elevation was not-reached (p = 0.038). On multivariate analysis, the CRP-elevation before nivolumab was the independent prognostic factor to predict PFS in nivolumab treatment (HR: 2.68, 95% CI: 1.01-7.11, p = 0.047). CRP-elevation group had a tendency of shorter OS than CRP-non elevation group (p = 0.071). Conclusions: The change of serum CRP levels during molecular-targeted therapies could be the predictive factor for the efficacy of nivolumab in mRCC patients.
Trends in the use of administrative databases in urologic oncology: 2000-2019.
Authors: Leopold Zev , Dave Priya , Menon Adarsh , Patel Hiren V. , Srivastava Arnav , Jang Thomas L , Singer Eric A.
Published: May 2020

e17111

Background: Administrative databases (AD) provide investigators with nationally representative study populations to answer research questions using large sample sizes. Their use has significantly grown over the past 20 years, particularly in urologic oncology. We aimed to quantify the trends and incidence of AD use in published manuscripts in urologic oncology. We examined six commonly used databases: National Cancer Database (NCDB), Surveillance, Epidemiology and End Results Database (SEER), SEER-Medicare (SEER-M), Nationwide Inpatient Sample, National Surgical Quality Improvement Program, and Premier Healthcare Database. Methods: A literature review powered by PubMed and DistillerSR from 2000 to 2019 aggregated manuscripts that used the aforementioned databases to study a genitourinary malignancy. Included publications were categorized by database used, corresponding author department affiliation, organ, journal, year, and contribution - defined as temporal treatment trends, outcomes and survival, comparative effectiveness research, and cost-effectiveness. Results: There were 2265 publications across 307 journals that met the inclusion criteria. Between 2000 and 2019 the compound annual growth rate of these publications was 18.7%. SEER contributed most heavily over the study period, with a 14.6% growth rate. NCDB use grew 75.6% annually starting in 2012. Prostate cancer comprised the majority of publications (51.3%), followed by kidney (23.1%) and bladder (22.5%) cancer. Journals publishing these manuscripts had a median impact factor of 2.78 (range 0.36 - 223.68) in 2018. Urologists published 52.5% of AD manuscripts over the study period, with epidemiologists and radiation oncologists publishing 18.2% and 10.6%, respectively. Conclusions: Our results show substantial growth in the use of ADs for the study of genitourinary oncology. The increased use is likely multi-factorial and may be driven by increasing competition to secure funding, ability to answer questions previously limited by sample size, and improved quality of databases. Given the broad use of ADs, investigators and specialty societies should advocate for continued improvement in the data captured by them.
Integrated-omics of MRI-visible and -invisible prostate cancer identifies molecular correlations with clinical outcome.
Authors: Kim Eric , Miheecheva Natalia , Ramachandran Akshaya , Lyu Yang , Galkin Ilia , Svekolkin Viktor , Postovalova Ekaterina , Bagaev Alexander , Nomie Krystle , Ogloblina Anna , Frenkel Felix , Ataullakhanov Ravshan , Hsieh James J , Pachynski Russell Kent
Published: May 2020

e17506

Background: The inclusion of multiparametric MRI (mpMRI) to prostate cancer (PCa) diagnostics has increased the detection rate and has improved the prediction rate of clinically significant PCa. Yet, mpMRI has a false negative rate of 12.6%, missing 6-13% of clinically significant PCa. The mechanisms underlying MRI visibility are poorly understood; therefore, to probe the molecular and cellular underpinnings of PCa MRI visibility, we profiled tissue from Gleason score and clinically matched patients with MRI-visible and MRI-invisible PCa who underwent radical prostatectomy. Methods: MRI-invisible (n = 7) and MRI-visible (n = 8) PCa tumors were evaluated with multiplex immunofluorescence (MxIF; 14 markers) and were subjected to gene expression profiling using the HTG EdgeSeq Oncology Biomarker Panel (2,549 genes). Gene expression analysis was also performed using The Cancer Genome Atlas (TCGA), including normal prostate (n = 52) and PCa (n = 387) tissue. Analyses were performed using the BostonGene automated pipeline. Results: MpMRI-visible PCa tumors (62.5%) displayed compact epithelial tumor architecture compared with mpMRI-invisible PCa tumors (28.5%). mpMRI-visible PCa had higher malignant cell density (p = 0.04) and increased neighboring malignant cells (p = 0.07), correlating with MRI-visible PCa complex tumor architecture (r = 0.49 for neighboring malignant cells vs tumor cell density). Tumor stromal organization differences were determined by measuring Wasserstein distances between distributions, and mpMRI-invisible PCa stroma appeared more similar to normal tissue. The visible group exhibited lower expression of stroma-enriched genes such as filamin C (FLNC) (FDR < 0.1) and cellular adhesion-related genes (FDR < 0.4), with gene expression signatures markedly different compared to normal prostate tissue. Higher malignant cell density, neighboring malignant cells, and Wasserstein distances, and low FLNC expression – all mpMRI visibility characteristics – were associated with patient relapse (p = 0.02). Low stroma signature expression in the TCGA cohort correlated with inferior PCa PFS (p = 0.005). Conclusions: This is the first integrated multi-omics analysis of clinically matched mpMRI-visible and -invisible PCa. mpMRI-invisible tumors exhibited molecular, cellular, and structural characteristics more akin to normal prostate tissue, which may render them undetectable by imaging. A stroma-associated gene signature, a mpMRI-invisible tumor feature, correlated with better PCa clinical outcomes.
A genomic blood test (NETest) identifies neuroendocrine transformation of prostate cancer.
Authors: Rahbar Kambiz , Kidd Mark S. , Drozdov Ignat A. , Malczewska Anna , Bodei Lisa , Rajwa Pawel , Boegemann Martin , Bernemann Christof , Kitz Alexandra , Modlin Irvin Mark
Published: May 2020

e17511

Background: Neuroendocrine-like differentiation (NELD) and an aggressive phenotype are key features of castration-resistant prostate cancer (CRPC). Current blood-based biomarkers cannot detect these treatment-refractory variants. Our aim was to evaluate the NETest, a blood-based 51-marker gene neuroendocrine detection tool, as a CRPC-diagnostic versus prostate cancer (PCA). Methods: In silico evaluation: NETest gene identification in the TCGA-PRAD ( n= 500 PCA) and CRPC RNAseq datasets (cBIOPortal: dbGap-phs000909.v.p1, tissue samples: n= 47, including 15 CRPC). Blood gene expression: PCA: n= 50, CRPC: n= 40, hormone-sensitive PCA: n= 75 and benign prostatic hyperplasia (BPH: n= 41). NETest assay: Normalized gene expression, algorithmically assessed and scored: 0-100. Cut-off 20. PSA: ECLIA diagnostic assay: cut-off 4ng/L, > 10ng/ml = actionable value. Statistics: ANOVA, AUROC analyses and sensitivity/specificity metrics. Data is mean±SEM. Results: RNAseq: Two (4%) of the 51 NETest genes were identified in TCGA-PCA. In contrast, all 51 NETest genes (100%) were identified in CRPC tumors. Thirty-three (65%) were detected as upregulated (1.09-1425-fold vs. normal tissue). Blood-PCR: 49/51 (96%) NETest genes detected in CRPC blood. NELD-gene expression was significantly upregulated ( > 2-fold, p< 0.01) in CRPC vs. PCA ( TPH1, PNMA2, SSTR etc). NETest scores were elevated in CRPC (79±2.8) (ANOVA, p< 0.0001) vs. PCA (22±2) and BPH (23±3). The AUC differentiating CRPC from PCA was 0.93 ( p< 0.0001). NETest was elevated in 94% of CRPC vs. 13% PCA and 15% BPH (both p< 0.001). The diagnostic sensitivities and specificities were 94% and 87%, respectively. PSA: PSA was elevated in CRPC (220±372ng/ml). This was different to PCA (14±20ng/ml, p< 0.0001) and BPH (10.3±5.7ng/ml, p< 0.003). The AUC for CRPC vs. PCA/BPH was 0.70 ( p= 0.10). PSA > 10ng/ml occurred in 70% of CRPC, 60% of PCA ( p= NS) and 39% of BPH ( p< 0.05). The AUC for NETest (0.93) was significantly better than PSA (z-statistic: 4.63, p< 0.0001). Conclusions: The NETest is a liquid biopsy that detects neuroendocrine neoplasia genes in the blood and accurately identifies NELD in castration-resistant prostate cancer. We anticipate that the NETest could be used to provide real-time information relevant to the evolving neuroendocrine status of a PCA during therapy.
Effect of PSA on equal treatment of high-risk patients.
Authors: Ferenczi Basil , Frankel Jason , Jung Nathan , Porter Christopher , Flores John Paul
Published: May 2020

e17514

Background: National Comprehensive Cancer Network (NCCN) guidelines recommend definitive treatment for high risk prostate cancer (HRPCa). This study aims to assess treatment trends for men with HRPCa, focusing on men deemed high risk on the basis of an elevated PSA alone with otherwise low risk features. Our hypothesis is that this group is treated differently than other patients with high risk disease. Methods: The National Cancer Database (NCDB) prostate cancer (PCa) participant use file was queried for high risk patients ages 18-75 with biopsy proven PCa from 2010-2016. The NCDB represents approximately 55% of men treated for PCa in the United States. Patients were divided into two groups: the study group with PSA > 20 and otherwise low risk features, and a comparison group comprised of high-risk patients due to cT stage ≥T3a or Gleason Grade Group ≥4. Patients with nodal or metastatic disease were excluded. Rates of treatment by modality were compared over the years studied. Survival was modeled using Kaplan Meier analysis. Results: 91,565 patients met eligibility criteria with 12,156 in the study group and 79,409 in the comparison group (Table). In the study group, a significantly higher number of patients underwent surveillance (10.2%) versus the comparison group (0.3%)(p < 0.001). Furthermore, there was an upward trend in use of surveillance in the study group, with a surveillance rate of 18.9% in 2016. Amongst patients receiving radiation, only 26.1% received androgen deprivation therapy (ADT) in the study group versus 82.8% in the comparison group. Despite these findings, survival analysis demonstrated significantly higher 5-year overall survival in the study group (95.1%) vs the comparison group (87.8%) (HR = 0.41, p < 0.001). Conclusions: Men categorized as HRPCa by PSA alone with otherwise low risk features are treated less aggressively than other high-risk patients with significantly higher rates of surveillance and radiation without ADT. However, these men appear to have better survival outcomes than other high-risk patients at 5-year follow-up. [Table: see text]
Insights into Chinese prostate cancer germline gene mutation profile: HOXB13 G84E mutation is unsuitable for genetic testing.
Authors: Dong Baijun , Yang Bin , Li Yonghong , Chen Wei , Li Jing , Xu Zhenzhou , Wu Kaijie , Zhang Fengbo , Zhu Shimiao , Yi Lu , Hua Lixin , PAN Hao , Ma Hong , Sun Zhongquan , Cheng Huihua , Zhang Zhenting , Li Mingzhao , Chen Zhiwen , Wang Fangqin , Xue Wei
Published: May 2020

e17515

Background: Philadelphia Prostate Cancer Consensus Conference 2017 developed an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA. However, the consensus was mainly based on data from Caucasian populations. Genetic differences in the PC molecular landscape between Asian and Caucasian men have been established. Whether Caucasian-based genetic information can be used to guide clinical practice in Chinese population needs further evidence. Methods: 1123 patients with confirmed prostate cancer admitted from March 2018 to August 2019 from 18 Chinese centers were included in this retrospective study. We sequenced the association of 50 gene with prostate cancer risk, clinical treatment implications and predisposition, focusing on DNA repair gene and genetic susceptibility genes pathogenic mutations in Philadelphia Prostate Cancer Consensus Conference. Only protein-truncating alterations (nonsense/stop-gains, frameshift insertions and deletions, and donor and acceptor splice-site mutations) were coded as pathogenic or likely pathogenic protein-truncating alterations. Results: Among all cases, DNA repair gene pathogenic mutations were found in 133 men (11.84%), including BRCA2 (62 [5.5%]), ATM (15 [1.3%]), PALB2 (11 [0.97%]), GEN1 (7 [0.62%]), BRCA1 (6 [0.53%]), MLH3 (4 [0.35%]), MUTYH (4 [0.35%]), PMS1 (4 [0.35%]), RAD50 (4 [0.35%]), ATR (3 [0.27%]), CHEK2 (3 [0.27%]), FANCD2 (3 [0.27%]) etc. Similar germline DRG mutation frequencies were observed between our cohort and Caucasian men. Noticeably, G84E mutation in HOXB13, a rare but recurrent missense mutation associated with a significantly increased risk of hereditary prostate cancer was not found in our cohort of patients. Furthermore, the frequency of HSD3B1 (1245C) allele in the Chinese patients is much lower than that in the Caucasian populations (11.7% vs 63%). Conclusions: Our study retrospectively analyzed germline mutation profile of prostate cancer in Chinese population. The frequency of HSD3B1 (1245C) allele varies across ethnic populations in spite of the similar DNA repair gene mutations rates. Considering the gene list should be tested based on clinical/familial scenarios from the Philadelphia Prostate Cancer Consensus Conference, a prevalence of certain mutations, G84E mutation in HOXB13 was unnecessary for genetic testing in Chinese population.
Evaluating the clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer (PCa).
Authors: Zarzour Ahmad , Morgans Alicia K. , Palmbos Philip , Jovanovic Borko , Tomlins Scott A. , VanderWeele David James , Yang Ximing J , Schaeffer Edward M. , Sharifi Roohollah , Meeks Joshua J , Abdulkadir Sarki , Hussain Maha H. A.
Published: May 2020

e17517

Background: Although PCa incidence has stabilized/decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years-old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years-old. Studies have described genetic abnormalities in aggressive localized or end-stage PCa, but early-onset cases are not included or are under-represented. The primary objective of this study is to characterize the clinical, environmental, genetic and genomic features of high-risk advanced PCa. Methods: Study cohort includes men with PCa ≤ 60 years old with N1 or M1 stage at diagnosis or who develop metastases in 5-years after local therapy. Clinical (race, family history (Hx), environmental exposure), laboratory,/pathology, cell-free DNA germline analysis were collected. Primary/metastatic tumor tissue tested via the Tempus-Xe platform (DNA sequencing, whole transcriptome expression profiling, copy number analysis, comprehensive fusion gene analysis and calculation of tumor mutational burden). We report interim analysis. Results: Study completed accrual with 30 pts. Median age 55 years (41-60), 87% are white, 13% are black, 77% had a family Hx of malignancy in 1-6 family members, including 40% with family hx of PCa. Only 33% had Hx of smoking. Median Gleason score 9. Only 27% had nodal disease, and 73% had metastatic disease at diagnosis. Molecular data are available in 25 pts. Most common germline mutations: BRCA2 (12%), ATM (12%), RB1 (8%), MSH3 (8%) and MYBPC3 (8%). Most common somatic mutations:TP53 (40%), TMPRSS2-ERG fusion (32%), MUC4 (16%), PTEN (12%), C2CD4D (12%), SPOP (12%), OBSCN (12%), MXRA5 (12%), and MYO15A (12%). Microsatellite stability status was available in 15 pts and all were stable. Tumor mutational burden was low in all pts, ranging between 0.7 to 2.7 mutations/megabase. Conclusions: Our preliminary data suggest high rates of germline mutations in early onset lethal PCa. This aggressive subset of disease requires further studying to better characterize the underlying clinical/genomic factors driving this disease.
A prospective study of 68Ga-RM2 PET/MRI in patients with biochemically recurrent prostate cancer and negative conventional imaging.
Authors: Baratto Lucia , Song Hong , Duan Heying , Mari Aparici Carina , Davidzon Guido , Moradi Farshad , Srinivas Sandy , Iagaru Andrei
Published: May 2020

e17536

Background: 68Ga-RM2 is a synthetic bombesin receptor antagonist targeting gastrin-releasing peptide receptors (GRPr) that are overexpressed in several human tumors, including prostate cancer (PC). Methods: We enrolled 114 men with BCR PC, 45-83-year-old (mean±SD: 68.2±7.0). Imaging started at 40-89 minutes (mean±SD: 51.3±9.2 after injection of 113.8-152.6 MBq (mean±SD: 140.7±6.4) of 68Ga-RM2 using a time-of-flight (TOF)-enabled simultaneous positron emission tomography (PET) / magnetic resonance imaging (MRI) scanner. Twenty-four and 23 patients also underwent 68Ga-PSMA11 and 18F-DCFPyL PET/CT, respectively. Results: All patients had rising PSA and negative conventional imaging prior to enrollment. 68Ga-RM2 PET identified recurrent PC in 78 of the 114 participants, while the simultaneous MRI was positive for PC in 45 of the 103 patients. Positivity rate of 68Ga-RM2 PET was: 31.8% for PSA < 0.5 ng/dl ( n= 22), 60% for PSA 0.5 – 1.0 ng/dl ( n= 15), 64.7% for PSA 1.0 – 2.0 ng/dl ( n= 17), 81.8% for PSA 2.0 – 5.0 ng/dl ( n= 22) and 87.2% for PSA > 5.0 ng/dl ( n= 38). PSA velocity values were 1.9±2.7 ng/ml/year (range: 0-9.1) in patients with negative PET scans and 5.8±9 ng/ml/year (range: 0.2-45.4) in patients with positive PET scans ( P: 0.01). Twenty-eight and 34 lesions were detected by 68Ga-RM2 PET and 68Ga-PSMA11 PET, respectively, while 25 lesions in 13 patients were identified by both radio-pharmaceuticals. The mean SUVmax ranged 1.6-51.2 (mean±SD:14.7±12.5) for PSMA and ranged 2.5-52.5 (mean±SD: 10.7±11.6) for RM2 ( P= 0.096). Three lesions in 2 patients were RM2-avid only (all lymph nodes) and 9 lesions in 7 patients were PSMA avid only (7 lymph nodes, 1 skeletal and 1 lung nodule). 32 and 48 lesions were detected by 68Ga-RM2 PET and 18F-DCFPyL PET, respectively. 28 lesions in 12 patients were identified by both radio-pharmaceuticals. The mean SUVmax ranged 1.7-79.3 (mean±SD: 22.2±23) for DCFPyL and ranged 1.7-46.8 (mean±SD: 7±9.2) for RM2 (P < 0.01). Four lesions in 2 patients were RM2 avid only (1 adrenal and 3 skeletal); 17 lesions in 6 patients were DCFPyL avid only (7 lymph nodes, 9 skeletal and 1 prostate). Conclusions: 68Ga-RM2 may identify higher risk patients given the highly statistically significant difference PSA velocity values between patients with negative and positive scans and may be a complementary radiopharmaceutical to the PSMA-targeting tracers to ultimately allow for personalized medicine. Clinical trial information: NCT02624518 .
Treatment of metastatic castration sensitive prostate cancer (mCSPC) by disease volume: A systematic review and a meta-analysis.
Authors: Sipra Qurat Ul Ain Riaz , Riaz Irbaz Bin , Asghar Noureen , Siddiqi Rabbia , Hwang Steven R , Husnain Muhammad , Adil Shahroz , Raina Ammad , Maheswari Deepa , Babiker Hani M. , Murad M. Hassan , Singh Parminder , Bryce Alan Haruo
Published: May 2020

e17539

Background: Chemotherapy with Docetaxel (D) or androgen pathway inhibition (API) with Abiraterone Acetate plus prednisone (AAP), Aplautamide(APA) and Enzalutamide(E) are acceptable, FDA approved treatment options for mCSPC. It is not clear whether the magnitude of benefit varies by the choice of initial agent [chemotherapy vs API] or by volume of disease [High vs Low]. Data is now available from all registration trials by volume status and motivated this analysis to inform initial treatment choice in mCSPC. Methods: We systematically searched MEDLINE(Ovid), Embase, and Scopus for randomized controlled trials of chemotherapy(D) or APIs (AAP, APA, ENZ) that had available hazard ratios (HRs) for overall survival (OS) and Progression Free Survival (PFS) according to patient’s volume of disease. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled overall survival HR and 95% CI by chemotherapy and APIs and by high volume(HVD) and low volume(LVD) using a random effect model, and tested for heterogeneity to assess the null hypothesis that no difference in the survival advantage exists by choice of initial agent and volume of disease. Results: Of 4456 studies identified in our search, there were 8 eligible randomized controlled trials that were included in the analysis. Both D and APIs significantly improved PFS [HR 0.48; 0.45-0.51] and OS [0.72; 0.64-0.81] when added to ADT, however the latter was associated with significantly higher improvement in PFS( P < 0.01) and OS (P = 0.03). In patients treated with D, patients with HVD derive significantly more benefit as compared to LVD( P = 0.046) and patients treated with APIs both HVD and LVD patients derive similar benefit( P = 0.80) (Table). Conclusions: mCSPC patients derive higher magnitude of survival benefit when treated with APIs as compared to D; however, D may be preferred in HVD patients. [Table: see text]
Completion time in prostate cancer treated with proton beam therapy: Do interruptions matter?
Authors: Hasan Shaakir , Rosen Lane , Tsai Henry , Sinesi Christopher , Laramore George E , Mishra Mark V. , Simone Charles B. , Gorovets Daniel
Published: May 2020

e17553

Background: The association between completion time of proton therapy(PT) in prostate cancer and biochemical control is unknown. Methods: We queried the multi-institutional, prospectively collected, proton collaborative group registry for prostate cases treated definitively with PT. Kaplan meier methodology was used for biochemical failure free (bFF) rates and multivariable regression analyses (MVA) were used to identify correlates of treatment interruptions (TI) and bF. Results: After exclusion, 2794 men with 693 low, 869 favorable intermediate, 627 unfavorable intermediate, and 605 high risk prostate cancers had available data. The median age was 68 years(40-92), 90% were white and 8% were black. Androgen deprivation therapy (ADT) was given to 676 patients, 312 treatments were hypofractionated, and median EQD2 dose = 75(74-86) GyE1.5. Kaplan-meier median follow-up was 79 months. In total 900 patients (32%) had at least one TI. Shorter treatments (HR = 0.95 per day, P < 0.01) and high risk (HR = 0.72, P < 0.04) cases were less likely to have Tis on MVA. There was no difference in 5-year bFF rate with (92.7) and without (93.1%) TIs. In a subset of only high risk patients treated with ADT (n = 385), the 5-year bFF was 83% without TIs and 75% with TIs (HR = 2.10, P = 0.06). This discrepancy was significant with multivariable binomial regression (HR = 2.36, P = 0.03), and the bF difference was greatest when > 5 treatment days were missed per receiver operating characteristic curve. Conclusions: Largely, there was no correlation between TIs and bF in prostate cancer treated with PT, however completion time may play a more significant role in high risk disease.
Randomized multicenter open-label trial of GT0918 (proxalutamide) in patients with mCRPC that progressed on abiraterone or enzalutamide.
Authors: Vogelzang Nicholas J. , Rezazadeh Kalebasty Arash , Levin Richard , Malik Zulfiqar A. , Ross Ashley , Bolemon Britt Haley , Gabrail Nashat Y. , Zhang Phoebe , Zhou Karl
Published: May 2020

e17578

Background: Both abiraterone and enzalutamide have been approved for the treatment of mCRPC. GT0918 (proxalutamide) is a novel second-generation androgen receptor (AR) antagonist binding directly to the androgen receptor, impairing nuclear translocation and decreasing AR protein expression. This phase II portion of the Ph I/II study is being conducted to further evaluate safety and tolerability of GT0918 at 400 mg or 500 mg daily dosing. Methods: All eligible mCRPC pts with progressive disease based on rising prostate-specific antigen (PSA) or/and imaging while on either abiraterone or enzalutamide, but not both. One line of prior chemotherapy was allowed. Pts (n = 60) will be randomized to GT0918 either 400 mg or 500 mg po once daily for 6 months. The primary endpoint is safety and tolerability. Secondary endpoints are PSA reduction at 12 weeks, % radiographic progression at 6-month, time to imaging progression, and exploratory biomarker CTC & cf-DNA/RNA. PSA is assessed every 4 wks and tumor imaging is done every 12 wks. Results: 56 pts were screened June 2019 to January 15, 2020 and 40 pts were randomized to receive GT0918 either 400 mg or 500 mg po daily. 22 pts (55%) had enzalutamide as prior therapy and 18 pts (45%) had abiraterone as prior therapy. 17 pts (43%) had one or more lines of chemotherapy. The median age was 72 years (range 53-89) and median baseline PSA was 162 ng/mL (0.3-4195). 10 pts had 1 cycle or less of study drug due to rapid PSA progression, AEs and/or withdrawal of consent. The most common treatment-related AEs were fatigue (48%), loss of appetite/anorexia (25%), nausea (20%), lower leg extremity edema (18%), constipation (15%), weight loss (13%), vomiting (10%), and headache (8%). 8 pts (6 in 500 mg vs. 2 in 400 mg) required dose reduction due to AE. No seizures have been observed. As Jan 30, 2020, 3 pts (8%) and 8 pts (20%) had PSA reduction at 12 weeks and 4 weeks, respectively, but no 50% PSA reduction was observed. 2 pts (5%) received study drug treatment over 24 weeks and 10 pts (25%) received study drug over 16 weeks based on stable disease (SD) on imaging. Conclusions: GT0918 administrated orally once a day is well tolerated and first 40-pts taking GT0918 show some anti-tumor activities. Dose of 400 mg po daily is recommended for GT 0918 for further clinical trials. Clinical trial information: NCT03899467 .
A prospective trial of 68Ga-PSMA and 18F-FDG PET/CT in nonmetastatic prostate cancer patients with an early PSA progression during castration.
Authors: Wang Beihe , Chang Liu , Wei Yu , Meng Jin , Zhang Yingjian , Gan Hualei , Xu Xiaoping , Wan Fangning , Pan Jian , Ma Xuejun , Hu Silong , Freedland Stephen J. , Song Shaoli , Ye Dingwei , Zhu Yao
Published: May 2020

e17579

Background: To evaluate tumor heterogeneity and burden in nonmetastatic prostate cancer patients with an early PSA progression during castration by 68Ga-PSMA and 18F-FDG PET/CT. Methods: The trial prospectively included 37 patients who had an early PSA progression (≤2ng/ml) during castration, and high-risk (PSADT ≤10 months) nonmetastatic disease by conventional imaging. All patients underwent both 68Ga-PSMA and 18F-FDG PET/CT. Lesions were classified into PSMA-dominant lesions (PSMA+/FDG- and PSMA+/FDG+) and PSMA-/FDG+ lesions according to the tracer uptake status. The primary endpoint was the prevalence of PSMA-/FDG+ disease. Results: All patients were treated with RP (median duration of castration = 23 months). The median PSA at imaging was 0.57ng/ml. Overall, 114 lesions were detected in 29 of the 37 patients. A high prevalence (73%) of N+/M+ disease was observed. Of the 114 lesions, 81 were PSMA-dominant and 33 were PSMA-/FDG+. Per patient level, 9 men (24%, 95%CI: 10%-39%) showed at least one new PSMA-/FDG+ lesions. A short PSADT ( P= 0.009, OR = 8.000) were associated with PSMA-dominant disease, while a high Gleason grade group ( P= 0.022, OR = 13.091) with PSMA-/FDG+ disease. 19 patients (51%) with 51 lesions could be enrolled for oligometastases-directed therapy including 10 PSMA-/FDG+ lesions. Among different disease stages, PSMA-/FDG+ disease was rarely detected in the hormone-sensitive cohort, but frequently found in the castration-resistant cohort. Conclusions: Using 68Ga-PSMA and 18F-FDG PET, we observed a high prevalence of N+/M+ disease and a significant proportion of PSMA-/FDG+ disease in patients with an early PSA progression during castration. (ChiCTR 1900022634). Clinical trial information: 1900022634 . [Table: see text]
Real-world experience with sipuleucel-T (Sip-T) in Asian men with castrate-resistant prostate cancer (CRPC).
Authors: Zhang Jingsong , Liu Ming , Pan Jiahua , Wei Xiao X. , Harmon Matthew , Azzolina John , Flanders Scott
Published: May 2020

e17588

Background: Clinical trials of sip-T predominately included white men (over 90%). Previously we explored outcomes with sip-T in white and black patients (pts) (Kantoff PW, NEJM 2010; Sartor AO, ASCO 2019, #5035). In this retrospective analysis of data from electronic medical record and practice management systems, we explored the hypothesis that Asian and white pts who receive sip-T for CRPC exhibit similar overall survival. Methods: Data came from > 100 US community urology practices, predominantly large urology group practice associations. White and Asian pts were matched based on 5 criteria: sip-T treatment year; treatment pattern for oral and sip-T; metastatic site (Bone v. Nodal v. Visceral); prostate-specific antigen (PSA) within 10%; and age at treatment. Parameters retrieved include those listed in the table. Overall survival (OS) was analyzed using Kaplan Meier (KM) methodology with Cox Proportional Hazards Modelling used to generate the hazard ratio (HR) with Asians as the reference. Descriptive summary statistics were generated for other parameters. Results: The analysis identified 102 white and 77 Asian pts; treatment ranged from 2012 to 2019 with 60% receiving sip-T after 2016, impacting the ability to examine long-term outcomes. Characteristics of the 2 groups were broadly similar, although more Asians had Gleason scores ≥8 than whites (Table). In the KM analysis, most pts were censored. While the KM survival curves separate around month 25, favoring Asian pts, the difference is not significant (HR, 0.69 [95% CI: 0.4, 1.4]; P = 0.277). Conclusions: These real-world data do not show a significant difference in OS between Asian and white men. Both groups exhibited relatively low median PSAs near 5 ng/mL, an observation correlated with longer OS in previous studies. [Table: see text]
Effects of age on outcomes in men receiving treatment for metastatic castration-resistant prostate cancer (mCRPC): Analysis of Medicare fee for service (FFS) claims data.
Authors: Dorff Tanya B. , McKay Rana R. , Olsson Carl A. , Fitch Kate , Flanders Scott , Higano Celestia S.
Published: May 2020

e17590

Background: Because elderly patients may exhibit differences in immune activation, we evaluated outcomes in men receiving first line treatment for mCRPC with sip-T or oral agents (ie, abiraterone acetate or enzalutamide) by age. Methods: Claims data from the 2013-2017 Centers for Medicare and Medicaid Services Fee for Service 100% Medicare Identifiable Database for Parts A, B and D were examined. We evaluated with index dates in 2014 and 3 years of follow-up. Patients were categorized by age (Table) and agent use as per Healthcare Common Procedure Coding System codes and National Drug Codes. First line use of sip-T vs oral agents was examined as was any line use of sip-T vs oral agents (without sip-T). Kaplan-Meier methodology was used to assess survival with Cox proportional hazards regression modelling used to calculate hazard ratios (HR). Results: Mean ages of men receiving sip-T and orals were 76 and 78 years, respectively. Most (84%) were white. Regardless of line of use, the risk of death among men receiving sip-T was lower than the risk in men receiving orals, except in men over 90 years old (Table). Conclusions: Based on these claims data, benefits of sip-T use were evident across all ages except for the men 90+ years old with decreasing differences between agents with increasing age, as would be expected. While the oral agents may be perceived as more convenient, greater survival with sip-T suggests that clinicians should consider use of sip-T therapy for mCRPC, irrespective of age. [Table: see text]
Fracture risk and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) sequentially treated with abiraterone acetate (AA) and radium-223 (RA223).
Authors: Caffo Orazio , Frantellizzi Viviana , Tucci Marcello , Galli Luca , Monari Fabio , Baldari Sergio , Masini Cristina , Bortolus Roberto , Facchini Gaetano , Alongi Pierpaolo , Zichi Clizia , Biasco Elisa , Fanti Stefano , Pignata Salvatore , Filice Angelina , Borsatti Eugenio , Rossetti Sabrina , Spada Massimiliano , Cortesi Enrico , De Vincentis Giuseppe
Published: May 2020

e17593

Background: The increased incidence of bone fractures found in pts who received the AA-RA223 combination compared to those treated with AA alone in the ERA223 trial led to restrictive recommendations by the European Medicines Agency which limited the use of RA223 to pts who have received at least two previous treatments for mCRPC or who cannot receive any other treatment. Moreover, clinicians started to debate the risk of RA223-related fractures associated with the sequential administration of AA and RA223. The aim of this retrospective study was to assess the safety of administering RA223 to pts who have progressed during AA treatment mainly in terms of the rate of skeletal fractures. Methods: We retrospectively reviewed the records of mCRPC pts who received RA223 after progressing during an AA treatment line in everyday clinical practice in ten Italian Hospitals. Results: We reviewed data of a consecutive series of 94 mCRPC pts. Most of the pts (85.1%) received RA223 as second- or third-line treatment and had a Soloway score 2 or 3 (90%). RA223 treatment was well-tolerated: there were only four cases of grade 3 anemia, two case of grade 3 leukopenia, and one case of grade 3 neutropenia. The overall fracture rate of 2.1%: one fracture was recorded during the course of RA223 treatment, and one was recorded one month after its end. The fractures both occurred at metastatic sites in pts who were not treated with antiresorptive agents. Median overall survival (OS) from RA223 start was more than 14 mos and the pts who received Ra223 in second line (which is not allowed today in Europe) had the same median OS as those who received this agent in later lines. Conclusions: The findings of this study showed that the treatment with RA223 as subsequent treatment line after AA was active and safe with a very low risk of a fracture. The OS outcomes indicated that the administration of RA223 in early treatment lines is not detrimental, even after AA. Thus the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including RA223 in the therapeutic algorithm.
Identification of actionable BRAF mutations and their genomic associations in advanced prostate cancer.
Authors: Cittolin Santos Giordano Fabricio , Prophet Malshundria , Gourdin Theodore Stewart , Drusbosky Leylah , Ledet Elisa Marie , Sartor A. Oliver , Sonpavde Guru , Lilly Michael B.
Published: May 2020

e17597

Background: Circulating tumor DNA (ctDNA) can be used to identify mutations and amplifications in patients with prostate cancer (PC). Identification of actionable mutations in BRAF may allow the use of targeted therapeutics not typically used in prostate cancer. Methods: We analyzed a ctDNA-based genomic profile database (Guardant Health) with 2274 unique advanced-stage patients, and a tissue-based genomic database (TCGA) with 3178 unique patients (73% locoregional, 27% metastatic). We compared the frequency and types of BRAF anomalies found in those datasets. We calculated the odds ratio of observing other genetic anomalies based on the BRAF mutation and amplification status. Finally, we utilized Principal Component Analysis (PCA) to study the utility of BRAF as a discriminator in identifying genetic subtypes of PC. Results: BRAF missense mutations in PC were found in 3.34% of the 2274 patients in the ctDNA cohort and in 1.1% of the 3178 patients in the TCGA cohort. Variants of Uncertain Significance (VUS) mutations were more commonly identified by ctDNA (53.8% of all mutations) vs TCGA (16.1% of all mutations). Biologically-significant mutations of all classes (I, II, III) were found in both datasets. BRAF mutations were mainly non-V600E and most mutations were clonal. Significant mutations common to both the ctDNA and TCGA cohorts include K601E, G469A, D594G, V600E, G466E, G446R, Q257K, I300V and R271H. Mutations unique to either ctDNA or TCGA datasets were found as well. BRAF mutations are highly associated with additional mutations in CDKN2A, TERT, and KRAS, as well as amplifications of CCNE1, KRAS, CDK6 (p < 0.01). BRAF amplifications are highly associated with multiple other gene amplifications, and with AR mutations (p < 0.01). Tumors with BRAF mutations and with BRAF amplifications are genetically distinct, and PCA indicates that BRAF status accounts for a significant amount of the difference. We described two patients that were treated with MEK targeted therapy with treatment response. Conclusions: 1. The use of ctDNA-based genomic analysis identified BRAF anomalies with a higher frequency than tissue-based techniques, but this is mostly due to higher numbers of VUS mutants found with ctDNA. Biologically significant BRAF mutations are mostly clonal and non-V600E mutations. 2. BRAF mutations and amplifications are associated with other specific gene anomalies. 3. ctDNA is a useful tool for identifying the genomic profile of PC in the clinical setting. 4. PC subjects with BRAF mutations identified by ctDNA may respond to MEK inhibitor therapy.
The impact of complications after diagnostic biopsy on repeat biopsy in men: Results from the Prostate Cancer Research International: Active surveillance (PRIAS-JAPAN) study.
Authors: Tohi Yoichiro , Kato Takuma , Matsumoto Ryuji , Shinohara Nobuo , Yokomizo Akira , Mitsuzuka Koji , Nakamura Masaki , Kume Haruki , Sugimoto Mikio
Published: May 2020

e17616

Background: Active surveillance(AS) is the strategy to avoid the overtreatment for favorable prostate cancer. For safer AS protocol execution, repeat protocol biopsy is essential in evaluating cancer aggressiveness accurately. However, some men on AS refuse repeat protocol biopsy because of burdens on biopsy. We aimed to assess the complications of prostate biopsy and the impact of complications after diagnostic biopsy on repeat protocol biopsy from the analysis Japanese cohort forming part of the Prostate cancer Research International: Active surveillance (PRIAS) study. Methods: PRIAS-JAPAN started in January 2010, 39 institutions are participating in this study. Men are prospectively followed and repeat protocol biopsy are planned at 1 year and 4 years thereafter, or if prostate specific antigen-doubling time is < 10 years. Data was collected on the complications such as infection, hematuria, hematospermia, pain, and antibiotics, and approach of biopsy, retrospectively. We compared the complications in diagnostic biopsy between repeat biopsy acceptance group and repeat biopsy non-acceptance group at 1 year. Results: From 2010 to 2018, 862 men with low-risk prostate cancer were prospectively enrolled in PRIAS-JAPAN. 794 men (92%) actually proceeded to protocol at 1 year. Of the 794 men, repeat protocol biopsy non-acceptance rate at 1 year was 18.4%(146 men). According to differences in the complications of diagnostic biopsy, hematuria(p = 0.003) and pain(p < 0.001) rate were significantly higher in repeat biopsy non-acceptance group, but infection(p = 0.105) and hematospermia(p = 0.224). Approach of biopsy(p = 0.651) was not different in two groups. Conclusions: Hematuria and pain in diagnostic biopsy were significantly more frequent in repeat biopsy non-acceptance group. Our study supports the importance of adequate explanation and management of the complications at biopsy to improve the rate of protocol biopsy acceptance. [Table: see text]