bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvements in first-line systemic mRCC therapy: Challenging insights from a cross trial comparison of overall survival and subsequent therapies in recent phase III trials.
Authors: Casper Jochen , Henderson Samantha , Casper Hannah , Kohne Claus-Henning
Published: February 2020

705

Background: Using sunitinib (SUN) as the comparator, two out of three recent phase III clinical trials have shown an overall survival (OS) benefit in the alternative treatment arm (Checkmate 214 (C), Keynote 426 (K)). The Javelin 101(J) trial has yet to show a significant improvement. Methods: A cross-study comparison of OS for the sunitinib arms of C, K and J was carried out. Special focus was given to risk group stratification and subsequent therapies. Data from the SUN pivotal trial (SP) was also taken into account. Results: Across the C, K and SP trials, OS was similar at approximately 78%. Despite a lower percentage of favourable risk patients compared to K and SP, an OS of 82% was observed in J. At 18 months, OS survival curves split ranging from 65% ©, 72.1% (K) to 76% (J). OS in the SUN arm in J at 18 months was comparable to OS of Nivolumab/Ipilimumab in C (78%). The rate of subsequent therapies ranged from 34.3% (K), 39.2% (J) to 54% (C) in the SUN arms. At the time of the SP trial almost no subsequent therapy options existed. In the experimental arms, the rate of subsequent therapies was 51.8% ©, 20.5% (K) and 20.8% (J). The existing data give no clear evidence of a correlation between subsequent therapies and OS. However, an analysis of the subsequent therapies/patients discontinuing therapy ratio (ST/DIS) and type of subsequent therapy (PD1/L1 directed or therapy with proven OS benefit (pOS) in randomized trials) in the SUN arms may be more conclusive (see table). The rate of subsequent therapies (ST/DIS) as well as PD(L)1 or pOS therapies were highest in J, followed by K and C. Conclusions: Despite the difficulties of a cross trial comparison, this data should raise awareness of the influence of a more intense subsequent therapy. It points to the necessity to standardize subsequent therapies in 1st line trials if OS is a primary study aim. Given this analysis, it may be pertinent to ask if an optimal or near optimal subsequent therapy following SUN might be equal to a 1st line IO/IO therapy with regards to OS.[Table: see text]
Risk of fall and clinical fracture associated with androgen receptor inhibitors: A systematic review and meta-analysis.
Authors: Myint Zin , Momo Harry D. , Otto Danielle E. , Yan Donglin , DiPaola Robert S. , Wang Peng , Kolesar Jill
Published: February 2020

71

Background: Patients treated with androgen receptor inhibitors (ARIs) report a higher incidence of falls; although a potential mechanism of action is unknown. This systematic review evaluates the relative risk (RR) of fall and fracture in prostate cancer (PCa) patients that receive ARIs. Methods: We conducted a comprehensive literature search using Cochrane, Scopus and MedlinePlus databases from inception through August 2019, and evaluated all published prospective phase II, III and IV randomized controlled trials that treated PCa patients with ARIs. Reported fall and fractures as adverse events (AEs) were extracted for analysis. Retrospective, phase I, non-randomized phase II, and studies with control arms that used one of the ARIs were excluded. A mixed effects model was used to estimate effects of ARI on the RR, with the included studies treated as random effects and study arms treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Results: Eleven studies met our inclusion criteria. The total population was 11,382; 6536 were in the ARI arm and 4846 in the control (CTL) arm. Study types were: 8 phase III; 2 phase II; 1 phase IV. Subjects in the ARI arm received enzalutamide, apalutamide or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations while in the CTL arm received placebo, bicalutamide or abiraterone. Treatment duration ranged from 5.4 to 20.5 mo for ARI vs. 5.4 to 18.3 mo for CTL. The reported incidence of fall was 481 (7.4%) in ARI and 201 (4.1%) for CTL. The incidence of fracture was 204 (3.1%) in ARI and 93 (1.9%) in control. The use of ARI was associated with an increased risk: all fall grades (RR 1.83; 95% CI 1.56-2.15; p <0.01); high grade fall (RR 1.69; 95% CI 1.09 – 2.62; p=0.019); all grade fracture (RR 1.56; 95% CI 1.23-1.97; p <0.01) and likely high grade fracture (RR 1.62; 95% CI 0.97 – 2.69; p=0.063). Conclusions: The use of ARI significantly increases falls and fractures in PCa patients as assessed by this meta-analysis study. Further studies would be warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.
mTOR pathway alterations in chromophobe renal cell carcinoma: Impact on metastasis development and overall survival.
Authors: Maroto Pablo , Anguera Georgia , Roldan Jose Maria , Caleiras E. , Santos M. , García-Donas Jesús , de Velasco Guillermo , Lanillos J. , Martínez AM , Calsina B. , Leton R. , Leandro-Garcia Lj , Monteagudo M. , Montero-Conde Cristina , Cascon Alberto , Robledo Mercedes , Rodríguez-Antona Cristina
Published: February 2020

712

Background: Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal cancer representing less than 5% of the kidney tumors. Molecular knowledge of this disease is limited, as well as prognostic factors for relapse if localized disease or response in the metastatic setting. Methods: From our database form different Spanish Hospitals, we identified a series of 89 chRCC with a localized stage and 3 patients stage IV at first diagnoses. We performed an in-depth characterization of mTOR pathway alterations, through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin and PTEN, and determined their impact on metastasis development and overall survival. Mutations in mitochondria and telomere maintenance genes were also assessed. TCGA kidney chromophobe project (KICH, n=64) was used for validation. Results: TP53, mTOR pathway ( MTOR, TSC2 or TSC1), telomere-related genes ( ATRX, TERT promoter or DAXX) and respiratory chain complex I, were mutated in 28%, 16%, 15% (26, 14, 12 of 87) and 15% (14 of 73) of primary tumors. PTEN and FLCN were mutated in four and three patients, respectively, two with bilateral tumors. IHC of phospho-S6 revealed positive staining in 37% of primary tumors (21 of 57), in association with MTOR, TSC2 and TSC1 mutations (P=0.009). Negative PTEN staining in 82% of cases (46 of 56) suggested PTEN loss as a chRCC characteristic, and was mutually exclusive with MTOR, TSC2 or TSC1 mutations (P=0.001). Weak or negative tuberin staining correlated with TSC2 mutations (P=0.02). Regarding metastasis development, TP53 mutations were enriched in malignant tumors (P=0.018), while telomere-related mutations showed a trend in the same direction. mTOR pathway mutations were associated with worse outcome. Overall survival in multivariable analysis adjusting for tumor stage gave a Hazard Ratio of 6.5 (P=0.009) This association was confirmed in TCGA-KICH (HR=11.9, P=0.05). Conclusions: Our study provides new genomic knowledge of chRCC and identifies novel markers of poor survival. Furthermore, we identified patients with mutations in mTOR pathway genes that showed high sensitivity to mTOR inhibitors.
Circulating ensembles of tumor-associated cells in genitourinary cancers.
Authors: Srinivasan Ajay , Akolkar Dadasaheb B. , Fulmali Pradip , Fulmali Pooja , Srivastava Navin , Patil Darshana , Patil Revati , Apurwa Sachin , Patil Sanket , Patel Shoeb , Datta Vineet , Sims Cynthe , Datar Rajan
Published: February 2020

718

Background: Detection of genitourinary cancers is based on histopathological analysis of tumor tissue obtained by invasive biopsies following manifestation of clinical or radiological symptoms. There is presently no non-invasive blood-based test with high specificity and sensitivity for detection of genitourinary cancers. Considering that unprovoked thromboembolism is a significant risk in multiple cancers, we hypothesized that tumor derived circulating emboli in peripheral blood could comprise cancer cells and would serve as a reliable biomarker for detection of genitourinary cancers. These Circulating Ensembles of Tumor Associated Cells (C-ETACs) are defined as clusters of 3 or more cells of tumorigenic origin (EpCAM+, CK+ and CD45±). Methods: We obtained 15ml of blood from 8828 individuals, including 103 cases of Renal cancer, 79 cases of bladder cancer, 153 cases of prostate cancers as well as from 8493 asymptomatic individuals with age related elevated risk and were negative in various screening investigations (CEA, AFP, CA19-9, CA125, PSA, LDCT, Mammography, PAP Smear). PBMC were isolated by centrifugation. C-ETACs were enriched, harvested and characterized by immunofluorescence staining for EpCAM, CK, CD45 as well as organ specific markers for renal, bladder and prostate cancers. Results: C-ETACs were detected in 87 (84.5%) of 103 renal cancers, 71 (89.9%) of 79 bladder cancers and 138 (90.2%) of 153 prostate cancers respectively irrespective of extent (stage / metastatic status) of disease and prior treatments. Overall sensitivity among 335 cancer patients was 88.4%. Among the 8493 asymptomatic individuals, C-ETACs were detected in 255 individuals (97% specificity). Conclusions: C-ETACs were ubiquitously detected in cancers of Kidney, Bladder and Prostate regardless of stage and treatment status, and pose significant latent risk of metastasis/recurrence. The relative undetectability of C-ETACs in the asymptomatic cohort indicates causative connection with malignancies and are hence suitable for screening for these cancers.
Targeting metabolic dysregulation of T cells in kidney cancer.
Authors: Beckermann Katy , Young Kirsten , Hongo Rachel , Ye Xiang , Contreras Diana , Barone Sierra , Roe Caroline E. , Smith Christof C. , Vincent Benjamin Garrett , Irish Jonathan M. , Rathmell Wendy Kimryn , Rathmell Jeffrey C.
Published: February 2020

722

Background: Cancer cells can inhibit effector T cells through both immunomodulatory receptors and alteration of the tumor microenvironment. Rather than efficient use of aerobic glycolysis by activated effector T cells, Renal Cell Carcinoma (RCC) infiltrating T cells (TIL) fail to increase glucose metabolism, and instead display increased reactive oxygen species (ROS) and mitochondrial dysfunction. CD8 RCC TIL also have notable differences in mitochondrial morphology compared to healthy control CD8 T cells and were punctate and dispersed rather than fused in networks. Here we test if RCC TIL can be re-activated and identify metabolic requirements for inflammatory TIL function. Methods: De-identified samples from tumor or adjacent normal tissue donations from patients with RCC were collected under an approved IRB protocol and processed into single cell suspensions of tumor and associated cells by mechanical dissociation to test TIL activation and metabolic requirements upon in vitro re-stimulation. Results: RNA-seq data suggested that CD8 from TIL rely on distinct metabolic pathways compared to control. While control T cells increased effector cytokine production and glycolysis with antigen receptor alone and further augmented this pathway with co-stimulation, single cell RNAseq showed that CD8 RCC TIL required co-stimulation for this transition. Co-stimulation can promote T cell glycolysis and we found antigen receptor stimulation with CD28-mediated co-stimulation increased function of CD8 RCC TIL as indicated by increased surface markers of activation and IFNγproduction. This was accompanied by rescue of metabolic markers, including increased mitochondrial mass and markers of electron transport. Improved functional capacity was dependent upon glycolysis because inhibition with 2-deoxyglucose limited CD8 RCC TIL activation following CD28 co-stimulation. Conclusions: Bypassing metabolic defects restore markers of TIL activation and effector function.These datademonstrate that CD8 RCC TIL can be functionally restored but that this requires the ability to increase glucose metabolism. These findings may allow for combined therapies to improve response rates of checkpoint inhibition in this disease.
Prognostic value of risk stratification using blood biochemical parameters in Japanese patients with metastatic renal cell carcinoma treated by nivolumab.
Authors: Yamamoto Yoshiaki , Matsuyama Hideyasu , Matsumoto Hiroaki , Sakano Shigeru , Fujii Nakanori , Oba Kazuo , Yamamoto Mitsutaka , Kamiryo Yoriaki , Hiragino Takeshi , Nagao Kazuhiro , Takai Kimio , Aoki Akihiko , Yoshihiro Satoru , Tsukamoto Manabu , Akao Jumpei , Kitahara Seiji , Misumi Taku , Komatsu Hirotaka , Oka Shintaro , Suga Akinobu
Published: February 2020

724

Background: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma (RCC). However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic RCC. Methods: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic RCC and who received nivolumab. MSKCC and IMDC risk, inflammation-based prognostic scores, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific and overall survival were compared using Cox proportional-hazards regression models. Results: Univariate analysis showed that MSKCC risk score ( P = 0.0052), lactate dehydrogenase (LDH) ( P = 0.0266), LMR ( P = 0.0113), and PLR ( P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that PLR and LDH were found to be independent prognostic factors for disease-specific survival ( P = 0.0008, RR = 7.95, 95% CI, 2.16–51.64 and P = 0.0123, RR = 3.92, 95% CI, 1.37–10.80, respectively). The combination of PLR and LDH was the most significant prognostic biomarker in metastatic RCC for disease-specific ( P < 0.0001) and overall ( P < 0.0001) survival. Changes in LMR and PLR in response to nivolumab were significant prognostic factors for disease-specific survival ( P < 0.0001 and P = 0.0477, respectively). Conclusions: The combination of PLR and LDH may be a potential biomarker for estimating disease-specific and overall survival in Japanese patients with metastatic RCC treated by nivolumab. If changes of inflammation-based prognostic scores in response to nivolumab treatment might be improved, nivolumab treatment should be continued.
Longitudinal multiplex cytokine analysis for patients (pts) with metastatic renal cell carcinoma (mRCC) treated with ipilimumab/nivolumab (I+N).
Authors: Zhang Tian , Wu Yuan , Agarwal Anika , Starr Mark D. , Reyes-Martinez Marco , Anand Monika , Runyambo Daniella , Harrison Michael Roger , Armstrong Andrew J. , George Daniel J. , Nixon Andrew B.
Published: February 2020

731

Background: I+N is an established treatment for mRCC, where circulating protein biomarkers are prognostic. In a longitudinal correlative study, we characterized circulating proteins in mRCC pts treated with standard of care I+N. Methods: mRCC pts treated with I+N were prospectively enrolled at Duke Cancer Institute (NCT02978118), contributing EDTA plasma at baseline, week(wk)-4, wk-12, and disease progression. Best overall responses were characterized as disease control (DC; stable disease, partial & complete responses) versus progressive disease (PD). Plasma was batch analyzed using a 46-plex MesoScale Discovery ELISA assay (IFN-g, interleukins [IL]-1b, 2, 4, 5, 6, 7, 8, 10, 12, IL-12-IL-23p40, 13, 15, 16, 17A, 21, 22, 27, 31, MIP-3a, Eotaxin, Eotaxin-3, IP-10, MCP-1&4, MDC, MIP-1a & 1b, TARC, TNF-a & b, GM-CSF, CRP, ICAM-1, SAA, VCAM-1, FGFb, FLT-1, PlGF, Tie-2, VEGF, VEGF-, and VEGF-D). Mean and standard deviations of cytokine concentrations are reported, along with a Wilcoxon rank sum test between PD and DC groups; unadjusted p-values are nominal. Results: We enrolled 25 pts with mRCC (15 DC and 10 PD). Baseline IL-7, IL-8, IL-12-IL-23p40, ICAM-1, TNF-a, VEGF-C, and VEGF-D were lower in PD pts than DC pts (Table). MIP-1b was significantly lower for PD than DC pts at baseline (Table) and wk-4 change (PD 0.30 +/- 1.82, DC 0.83 +/- 6.49, p = 0.056). Although baseline IFN-g did not differ between groups, wk-4 IFN-g significantly increased in DC and decreased in PD pts (DC 3.5 +/- 7.1; PD -1.33 +/- 5.47, p = 0.056). Conclusions: In this pilot exploratory analysis, a subset of ILs are higher at baseline in DC than PD pts. A wk-4 increase in circulating IFN-g is associated with DC vs PD and could be linked to increased early inflammation and response to I+N. Larger prospective studies are needed to validate these findings.[Table: see text]
Novel risk scoring system for metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (C).
Authors: Kline Meredith R , Martini Dylan J. , Liu Yuan , Shabto Julie M. , Carthon Bradley Curtis , Hitron Elise , Russler Greta , Caulfield Sarah , Yantorni Lauren Beth , Harris Wayne , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: February 2020

734

Background: Cabozantinib (C) is an effective treatment for metastatic renal cell carcinoma (mRCC) patients (pts). The international mRCC database consortium (IMDC) criteria is the gold standard for mRCC risk stratification. We created a risk scoring system for mRCC pts treated with C. Methods: We performed a retrospective review of 87 mRCC pts treated with C at Winship Cancer Institute from 2015-19. Overall survival (OS) and progression free survival (PFS) were defined as months from C initiation. The baseline characteristics and inflammation biomarkers included were monocyte, neutrophil, and platelet-to-lymphocyte ratios (MLR, NLR, and PLR respectively), RCC histology, body mass index (BMI), metastatic sites (mets), and Eastern Cooperative Oncology Group performance status (ECOG PS). Upon variable selection in multivariable analysis (MVA), elevated baseline MLR (≥0.71), presence of sarcomatoid histology, ECOG PS > 1, and absence of bone metastases were assigned 1 point. A three-level risk scoring system was created: low (score = 0-1), intermediate (score = 2), and high risk (score = 3-4). The Kaplan-Meier method, Cox proportional hazard model, and Uno’s C-statistics were used to examine performance. Results: The majority of pts were males (71%) with clear-cell RCC (75%). Most pts (67%) received 1+ prior line of therapy. High and intermediate risk pts had significantly shorter OS and PFS compared to low risk pts (Table). The C-statistics for our risk scoring system were higher than IMDC in predicting OS (0.7 vs. 0.62) and PFS (0.65 vs 0.57). Conclusions: Pts treated with C may benefit from risk scoring using RCC histology, ECOG PS, mets, and MLR. These results are hypothesis-generating and should be validated in a larger study.[Table: see text]
Genomic alterations and tumor mutational features of Chinese Xp11.2 translocation renal cell carcinoma patients.
Authors: Qu Yuan-Yuan , Zhang Hailiang , Xu Wenhao , Wang Hongkai , Tian Xi , Cao Dalong , Qu Yueting , Shi Guohai , Ye Dingwei
Published: February 2020

736

Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) is a rare subtype of RCC which occurs predominantly in children and adolescents. Xp11.2 RCC is characterized by the gene fusions of transcription factor E3 (TFE3). Since there is a high false-positive and false-negative rate of immunohistochemistry (IHC) for TFE3 and an uncertainty of TFE3 fusion partners by fluorescence in situ hybridization (FISH), a genetic approach, such as DNA sequencing, is necessary for auxiliary diagnosis. Methods: Thirty Chinese Xp11.2 RCC patients with positive TEF3 fusion diagnosed by FISH were involved in this analysis. Formalin-fixed, paraffin-embedded (FFPE) samples were collected for a next-generation sequencing (NGS)-based 576 gene panel assay. Genomic alterations including single base substitution, copy number variations, gene fusions, and rearrangements were assessed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were also analyzed by an NGS algorithm. Results: The 30 patients in the Xp11.2 RCC cohort included 13 males and 17 females, and had a median age of 30 years. TFE3 fusions of these patients were confirmed by both FISH and NGS. Out of the 30 Xp11.2 RCC patients, 2 patients (6.7%) showed negative TFE3 IHC expression and 4 patients (13.3%) showed equivocal TFE3 IHC expression. ASPL (9/30), PRCC (5/30), PSF (5/30), and NONO (3/30) were the most common partners of TFE3 fusion in this cohort. Moreover, we identified uncommon or novel partner genes by NGS, including ZNF627 (1/30), PTPN12 (1/30), PBM10 (1/30), PARP14 (1/30), MED15 (2/30), MATR3 (1/30), LUC7L3 (1/30), KHSRP (1/30), and EWSR1 (1/30). Based on the NGS results, several actionable genomic alterations including CDKN2A, BRCA2, and ATM were found in this study. All samples were identified as microsatellite stable (MSS). The median TMB of the entire cohort was 1.35 muts/Mb (range, 0-9.2 muts/Mb). Conclusions: In summary, we identified the partner genes of TFE3 fusion in 30 Chinese Xp11.2 RCC patients by NGS. Ten uncommon or novel partner genes (33.3%) of TFE3 were identified in this study. Overall, our results provide evidence for diagnosis and therapeutic strategies for Xp11.2 RCC patients.
Screening and identification of novel promoter signatures in clear cell renal cell carcinoma metastasis.
Authors: Qu Yuan-Yuan , Tian Xi , Xu Wenhao , Anwaier Aihemutaijiang , Ye Dingwei , Zhang Hailiang
Published: February 2020

737

Background: Clear cell renal cell carcinoma (ccRCC) patient usually face aggressive progression when metastasis occurs. Therefore, in-depth investigation is needed to elucidate underlying mechanisms behind the metastasis of ccRCC to promote therapeutic benefits.This study aims to explore and investigate prognostic gene expression profiles based on multi-cohorts. Methods: Three microarray datasets were obtained from the Gene Expression Omnibus (GEO) database to screen and identify differentially expressed genes (DEGs) according to normalization annotation information. A total of 112 DEGs with functional enrichment were identified as candidate prognostic biomarkers. A protein–protein interaction network (PPI) of DEGs was developed, and the modules were analyzed using STRING and Cytoscape. Results: LASSO Cox regression suggested 31 significant involved genes, and 10 hub genes were identified as independent oncogenes in ccRCC patients. Distinct integrated scores of the hub genes mRNA expression showed statistical significance in predicting disease-free survival (DFS; p<0.001) and overall survival (OS; p<0.001) in TCGA and real-world cohorts. Meanwhile, ROC curves were constructed to validate specificity and sensitivity of the Cox regression penal to predict prognosis. The AUC index for the integrated genes scores was 0.758 for OS and 0.772 for DFS. Conclusions: In conclusion,the present study identifies DEGs and hub genes that may be involved in earlier recurrence and poor prognosis of ccRCC. The expression levels of ADAMTS9, C1S, DPYSL3, H2AFX, MINA, PLOD2, RUNX1, SLC19A1, TPX2 and TRIB3 are of high prognostic value, and may help us understand better the underlying carcinogenesis or progression of ccRCC.
The spinal distribution of metastatic renal cell carcinoma: Support for locoregional rather than arterial hematogenous mode of early bony dissemination.
Authors: Attalla Kyrollis , Duzgol Cihan , McLaughlin Lily , Flynn Jessica , Ostrovnaya Irina , DiNatale Renzo G. , Silagy Andrew W. , Coleman Jonathan , Lee Chung-Han , Carlo Maria Isabel , Voss Martin H , Russo Paul , Bilsky Mark , Hakimi A. Ari , Moss Nelson
Published: February 2020

742

Background: To investigate the distribution of spinal metastasis in metastatic renal cell carcinoma (mRCC) and to explore relationships between biological and clinical factors and patterns of spinal spread. Methods: An institutional database was queried to identify patients with mRCC and spinal metastatic involvement from June 2005 – November 2018. A blinded radiologist examined all cross-sectional imaging involving the spine and scored each level for absence or presence of disease. Clinical and biologic features including primary tumor size and degree of spinal and non-bony metastatic involvement (including regional lymph node and distant deposits) were collected. Spinal distributions were evaluated by the Kolmogorov Smirnov test and compared across radiographic and clinical parameters. Results: One-hundred patients with 685 spinal levels involved by mRCC were evaluated. A nonuniform spatial distribution was observed across the cohort; a preponderance of thoracolumbar involvement was noted with the mode at L3 (p<0.001). No difference in metastatic distribution was observed in right versus left-sided tumors. Tumors <4cm compared to >7cm, patients who had distant spread versus bone-only disease, and patients with increasing number of spine levels involved (1 versus >5 levels) had a significantly different distribution (p<0.001 for all comparisons). Smaller tumor size, distant spread, and greater number of involved levels appeared to have a more uniform distribution of spinal metastasis. Conclusions: These data support a dominant locoregional as opposed to arterial hematogenous mechanism for the early dissemination of mRCC to the spine. This is concordant with the theory of the valveless Batson plexus acting as a conduit for such spread, as the kidneys are compartmentally distinct from, but reside just anterior to the spine at L1-L3. Characterizations of the biologic molecular features contributing to osseous tropism and aggressive tumor biology (as seen in the subset of patients with uniform spread, such as outlier patients with small tumors), have implications for surveillance and are an area of active investigation.
Predicting toxicity-related docetaxel discontinuation and survival in metastatic castration-resistant prostate cancer (mCRPC) using open phase III trial data.
Authors: Parikh Anish B. , Martini Alberto , Sfakianos John , Galsky Matt D. , Oh William K. , Tsao Che-Kai
Published: February 2020

75

Background: Docetaxel (D) is widely used in mCRPC, however its optimal use remains unclear in the current treatment (tx) landscape. Biomarkers to predict D toxicity may help inform tx selection. Methods: Through Project Data Sphere, we pooled patient (pt) data from the control arms of three frontline mCRPC trials: ASCENT2, VENICE, and MAINSAIL. Tx in each control arm consisted of D 75mg/m2 every 21 days + prednisone 5mg twice/day. The primary outcome was occurrence of toxicity-related D discontinuation (TRDD). Reasons for D discontinuation were recorded and demographic/clinical data were considered in a competing risks regression (CRR) to develop a model to predict TRDD. Cumulative incidence (CI) of TRDD was estimated after accounting for the occurrence of competing events (death or progression). This model was used to build a risk calculator to predict TRDD, the output of which was used in a classification and regression tree (CART) to identify 3 risk groups. Overall survival (OS) for the pooled cohort and for each risk group was assessed via the Kaplan-Meier (KM) method. Results: 1568/1600 pts had complete data and were studied. 41.4% died from any cause during the trials; median follow-up for survivors was 12.1 months (mos). Median OS for the entire cohort was 21 mos. CRR yielded the following significant factors that were included in the predictive model and risk calculator: age, ECOG performance status, AST, bilirubin, use of analgesics, and diagnoses of diabetes and chronic kidney disease. Pooled CI of TRDD was 19% after accounting for competing events (death, 474 pts; progression, 59 pts) within 12 mos of starting tx. CART analysis defined the risk groups as low (model-derived TRDD risk ≤24%), intermediate (25-64%), and high (≥65%). In each risk group, probability of TRDD during tx was 14%, 58%, and 79%, and median OS was 24 mos, 20 mos, and 13 mos, respectively (p<0.001). Conclusions: Tx selection in mCRPC remains a challenge. Our model can help clinicians balance D toxicity and efficacy in order to make better-informed decisions.
Urological malignancy incidence rates over time by county rurality.
Authors: Gadzinski Adam John , Gore John L. , Odisho Anobel Y. , Porten Sima P. , Carroll Peter , Cooperberg Matthew R.
Published: February 2020

750

Background: Approximately 20% of the U.S. population resides in non-metropolitan (rural) areas. We aimed to evaluate urological cancer incidence among populations residing in metropolitan (metro) and rural counties, categorized by adjacency to a metro area. Methods: Using data from CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology, and End Results Program, we compared incidence rates of prostate (PCa), kidney (KCa), and bladder (BCa) cancers diagnosed during 2007–2011 and 2012–2016 among adults age ≥ 20 years residing in metro and rural counties, as designated by rural-urban continuum codes. Rural counties were divided into those adjacent to a metro area (Rural-A) and those not adjacent to a metro area (Rural-NA). For the time period studied, these data cover approximately 97% of the US population. Rates were age-adjusted to the 2000 U.S. standard population. Results: We identified 1,980,168 PCa, 541,225 KCa, and 688,562 BCa cases newly diagnosed during 2007–2016. Patients from rural-A counties comprised 11% of all cases, rural-NA counties 6%, and metro counties 83%. Table shows the age-adjusted incidence per 100,000 with 95% confidence intervals. Overall, PCa and BCa incidence decreased over time; KCa incidence increased. PCa exhibited higher incidence rates in metro areas; KCa and BCa had higher incidence rates in rural counties (Table). Conclusions: Rural counties have higher BCa and KCa incidence relative to metro counties, but lower PCa incidence. Changes in PCa screening practices may have contributed to decreases in PCa incidence. Further investigation is needed to understand how rurality influences KCa and BCa epidemiology. Disclaimer: The findings and conclusion of this report are those of the authors and do not represent the official position of the CDC.[Table: see text]
The role of lymph node dissection in pT2-3 renal cell carcinoma: Analysis of the National Cancer Database.
Authors: Ghali Fady , Patel Devin , Meagher Margaret , Bradshaw Aaron , Patel Sunil , Dutt Raksha , Murphy James Don , Derweesh Ithaar
Published: February 2020

756

Background: We sought to assess the impact of LND in non metastatic pT2-3 patients utilizing a large population-based dataset. Methods: The National Cancer Database was queried for patients with cN0pT2-3 RCC that underwent radical nephrectomy (RN) +/- LND from 2004-2015. Descriptive analyses and Multivariable cox regression (MVA) were performed to elucidate factors associated with all-cause mortality (ACM) on a per stage basis (pT2 and pT3 RCC). Kaplan-Meier analyses (KMA) were used to determine the impact of LND on ACM. Results: 43,143 patients were analyzed, 9,491 (22.0%) underwent LND, 6.7% were positive (pN+). MVA demonstrated increasing age (HR 1.04, p<0.001), pN+ (HR 2.90, p<0.001), increasing Charlson score (CCI, HR 2.92, p<0.001), and high grade (HR 1.11, p<0.001), were associated with worsened ACM in pT2. MVA in pT3 revealed increasing age (HR 1.03, p<0.001), pN0 with 0-4 nodes removed (HR 1.24, p<0.001), pN+ (HR 3.06, p<0.001), papillary and non-specific histology (HR 1.17 p=0.002, HR 1.14 p<0.001 respectively), increasing CCI (HR 2.09, p<0.001), high grade (HR1.19, p<0.001), black race (HR 1.12, p=0.028), and increasing tumor size (HR 1.00, p<0.001) were associated with worsened ACM. MVA for increased likelihood of pN+ found high grade (HR1.23, p<0.001), Academic facility and integrated network cancer center (HR 2.13 and 1.17, p<0.001 and p=0.013 respectively), >10cm tumor (HR 1.67 p<0.001), clear cell histology (p<0.001), Caucasian race (p<0.001)and male sex (HR 1.06 P=0.026) were associated. KMA of pT2 patients demonstrates no significant difference in 5-year OS for LND compared to no LND (60.8% vs. 55.9%, p=0.21), and worsened OS for pN+ compared to pN0 and pNx (p<0.001). KMA of pT3 patients showed worsened 5-year OS for patients undergoing LND (p<0.001), and pN+ had worsened OS compared to pN0 and pNx (p<0.001). Conclusions: LND conveyed no ACM benefit in cN0 pT2 or pT3 RCC. pN+ was associated with decreased survival, with risk factors including Caucasian race, clear cell histology, high grade disease, tumors >10cm. LND in patients with cN0pT2-T3 disease may identify higher risk cohorts.
Exenterative surgery to improve quality of life on men with locally advanced, symptomatic castration-resistant prostate cancer.
Authors: Haidl Friederike , Hartmann Florian , Pfister David A. , Heidenreich Axel
Published: February 2020

77

Background: Invasion of the urinary bladder and/or the rectum by locally advanced castration sensitive (CSPC) or castration resistant PCA (CRPC) can result in debilitating symptoms with a significant negative impact on the patient’s well-being. Local progression might develop despite the application of new life prolonging agents. It was the purpose to retrospectively review the surgical and oncological outcome following pelvic exenteration surgery (PES) for locally advanced and symptomatic CRPC. Methods: Retrospective, single-centre, dual surgeon study of 103 men with symptomatic locally progressive and symptomatic CS- and CRPC treated between 2008 and 2019. Primary endpoint was symptomatic free survival (SFS) and the secondary endpoint were overall survival (OS) and complications defined by Clavien-Dindo criteria. Statistical tests were two-tailed with a p-value <0.05 considered to indicate significance. Symptom-free survival and cancer specific survival were calculated using Kaplan-Meier analysis. Results: 9 (8.7%), 71 (68.8%) and 21 (22.4%) patients underwent radical prostatectomy, radical cystoprostatectomy or anterior and posterior exenteration, resp. After a median follow-up of 36.5 (3 – 123) months, the SFS at 1 and 3 years was 89.2% (n=89) and 64.1% (n=66). The median SFS was 27.9 months. 78.6% of the patients were symptom-free during their remaining lifetime. OS at 1 and 3 years was 92.2% and 43.7%, respectively, and the median OS was 33.6 months. Clavien-Dindo grade 2, 3 and 4 complications developed in 31 (30.6%), 12 (12%) and 8 (8.1%), respectively. Conclusions: PES is a technically feasible approach in well-selected patients resulting in symptom relief of > 90% of patients which covered almost 80% of the remaining life time. Adequate preoperative imaging studies, endoscopic evaluation and extensive surgical experience is mandatory to achieving a benefit for the individual patient with improvement of quality of life.
Treatment outcomes for metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) following docetaxel (D) for hormone sensitive disease.
Authors: Schmidt Andrew Lachlan , Anton Angelyn , Wong Shirley S. , Azad Arun , Kwan Edmond Michael , Spain Lavinia Anne , Torres Javier , Muthusamy Arunbalaji , Parente Phillip , Parnis Francis , Goh Jeffrey C. , Joshua Anthony M. , Pook David William , Gibbs Peter , Tran Ben , Weickhardt Andrew James
Published: February 2020

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Background: There is no prospective data to guide optimal selection of treatment for first line (1L) mCRPC after D and androgen deprivation therapy (ADT) is given in the hormone sensitive setting. We explored efficacy of 1L treatment in this group. Methods: Pts with mCRPC treated with D for hormone sensitive disease were identified from a prospectively maintained multi-site mCRPC database (ePAD) of patients treated in a community and academic setting in Australia. 1L treatment, clinicopathologic and outcome data were extracted. Results: We identified 93 pts, median age 65y (range 43–85), who received median 6 cycles of D-ADT and developed mCRPC between May 2013 and Jun 2019. 58% had Gleason ≥ 8, median PSA at diagnosis was 53 ng/mL (range 0.67–7086), 65% had de-novo metastatic disease. Median time to mCRPC was 14.8mo (range 1.3 to 56.9) with median time to 1L 16.3mo (range 2.1–57.2). Eighty-five patients (91%) received at least one further active treatment for mCRPC with outcomes below. Conclusions: Abiraterone, enzalutamide, and cabazitaxel all demonstrate activity for 1L mCRPC following progression on D-ADT. Compared to historical controls, PSA responses appear less than pre-docetaxel, but greater than the post-docetaxel setting.[Table: see text]
Time to second progression (PFS2) in patients (pts) from TITAN with metastatic castration-sensitive prostate cancer (mCSPC) by first subsequent therapy (hormonal vs. taxane).
Authors: Agarwal Neeraj , Chowdhury Simon , Bjartell Anders , Chung Byung Ha , Pereira de Santana Gomes Andrea Juliana , Given Robert W. , Juárez Soto Álvaro , Merseburger Axel Stuart , Ozguroglu Mustafa , Uemura Hirotsugu , Ye Dingwei , Londhe Anil , Lopez-Gitlitz Angela , McCarthy Sharon Anne , Mundle Suneel , Chi Kim N.
Published: February 2020

82

Background: TITAN, a phase 3, randomized, double-blind study of apalutamide (APA) vs placebo (PBO) added to androgen deprivation therapy (ADT), demonstrated significant improvement in radiographic progression-free survival and overall survival in a broad pt population with mCSPC who received APA (Chi KN et al. NEJM 2019). This post hoc analysis evaluates whether type of 1st life-prolonging subsequent therapy (hormonal vs taxane) has an effect on PFS2 benefit shown with APA + ADT. Methods: PFS2 (the time from randomization to disease progression on 1st subsequent therapy for prostate cancer or death, whichever occurs first) was evaluated for pts from TITAN based on 1st subsequent life-prolonging therapy (hormonal vs taxane) after study treatment. Analysis censored all other 1st subsequent systemic therapies after start of treatment. Results: 277 pts (APA, 87; PBO, 190) received subsequent systemic therapy for prostate cancer; 86 pts (APA, 24; PBO, 62) received hormonal therapy (abiraterone acetate + prednisone or enzalutamide) and 99 (APA, 30; PBO, 69) received taxane (docetaxel or cabazitaxel) as 1st subsequent therapy. Baseline demographic and disease characteristics were generally similar between groups. The taxane group had a higher proportion of pts with high volume and pts with > 10 bone metastases, and a lower proportion with prior docetaxel exposure when compared with the hormonal group. Median treatment duration with APA and PBO was 11.9 and 11.1 mos in the hormonal group and 11.0 and 11.3 mos in the taxane group. Regardless of subsequent therapy, PFS2 was significantly longer for APA vs PBO (HR 0.66 [95% CI 0.50-0.87], p = 0.0026). Pts in both groups who received APA had a significant reduction in risk of 2nd progression compared with PBO (hormonal: HR 0.68 [0.48-0.97], p = 0.0326; taxane: HR 0.67 [0.48-0.94], p = 0.0189; medians not reached). Safety analyses were not conducted; all pts had discontinued therapy, most due to disease progression. Conclusions: The addition of APA to ADT for treatment of mCSPC results in risk reduction of 2nd progression regardless of choice of hormonal or taxane as the 1st life-prolonging subsequent therapy. Clinical trial information: NCT02489318.
Phase II study of cabazitaxel (CAB) plus enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Graff Julie Nicole , Cheng Heather H. , Vuky Jacqueline , Alumkal Joshi J. , Kreitner Dustin , Petreaca Delia , Grivas Petros , Schweizer Michael Thomas , Higano Celestia S. , Chen Yiyi , Yu Evan Y. , Beer Tomasz M.
Published: February 2020

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Background: There are six agents that improve survival in mCRPC, each administered as a single agent. Combinations of agents with distinct mechanisms of action have the potential to improve outcomes. Methods: We performed a multi-institution phase I/II study to examine safety and efficacy of CAB plus ENZ with mandatory granulocyte-colony stimulating factor support in mCRPC. Results: A sample size of 3 to 12 subjects for the phase I portion and 33 for the phase II portion provided 82% power to detect PSA response rate (decrease ≥90%) of 50% compared to the null hypothesis of 24%. The main eligibility criteria allowed prior abiraterone/prednisone (AAP) and docetaxel (in the metastatic hormone sensitive setting). Baseline characteristics: median age 69 years (47 - 82), median PSA 20.2 ng/dl (0.2 - 966.3); 7 subjects had visceral disease, 10 received prior AAP, and 8 received prior docetaxel. In the phase I portion, there were no dose limiting toxicities using CAB 25 mg/m2 IV Q3wks up to 10 cycles and ENZ 160 mg PO QD, hence this dosing was used for the phase II portion. 33 men with mCRPC were treated with CAB plus ENZ in the phase II arm. PSA response rates are listed in Table. Prior exposure to AAP decreased PSA response, but subjects who had prior AAP also had higher pre-treatment PSA. There were no treatment related deaths. Dose reduction of CAB to 20 mg/m2 was needed in 7 subjects. Over the course of the study, 14 Grade 3 adverse events occurred that were deemed possibly related to treatment: fatigue (n=2, 6%), febrile neutropenia (n=2, 6%), leukopenia (n=2, 6%), thrombocytopenia (n=2, 6%), anemia (n=1, 3%), hypertension (n=1, 3%), leukocytosis (n=2, 6%), fracture (n=1, 3%), failure to thrive (n=1, 3%). Conclusions: CAB plus ENZ was tolerable and associated with promising anti-tumor activity, particularly in abiraterone-naïve subjects. Further evaluation of this regimen is warranted. This project was managed by the Prostate Cancer Clinical Trials Consortium and funded by Astellas Inc. and Sanofi. Clinical trial information: NCT02522715. [Table: see text]
Impact of upstream use of novel hormonal therapy on progression of patients (pts) to metastatic castration-resistant prostate cancer (mCRPC) in the United States (US).
Authors: Scher Howard I. , Saad Fred , Mehra Maneesha , Nair Sandhya , Dearden Lindsay , Potluri Ravi C.
Published: February 2020

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Background: Novel hormonal therapies (nHTs) provide significant delay in disease progression in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic (nm)CRPC. The impact of earlier use of these agents on the epidemiological burden of PC in the US was assessed. Methods: A disease stage transition model capturing pt flow through eight clinical states and tracking pt treatment history was used, with each nHT being used once. Progression-free survival (PFS) and overall survival (OS) data for each drug/regimen were derived from published sources where available. We analyzed scenarios 1) no nHTs and 2) with nHTs: (abiraterone acetate + prednisone [AAP], apalutamide [APA] and enzalutamide [ENZA] in high-risk mCSPC, and APA and ENZA in low-risk mCSPC and in high-risk nmCRPC). Resultant state progression parameters were compared, evaluating the impact of nHTs. The assumed nHT utilization was 17.2% in high-risk mCSPC, 7.1% in low-risk mCSPC, and 60.0% in high-risk nmCRPC. Results: For 2018, the model resulted in PC incidence of 240,150 and prevalence of 2,445,173; 49,450 pts progressed to mCRPC, 42% from PSA biochemical recurrence, 31% from mCSPC, and 27% from nmCRPC states. Longer PFS and OS afforded by novel treatments extended the mean time spent from 4.4 to 4.7 yrs in mCSPC and from 2.4 to 3.0 yrs in nmCRPC. This further resulted in reduction in inflow to mCRPC over 2019 – 2025 (table). Conclusions: Novel hormonal therapies are currently used earlier in PC, a trend anticipated to intensify. The disease model shows this change in the treatment paradigm to result in delaying progression to mCRPC and increasing OS in PC.[Table: see text]
A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).
Authors: Yu Evan Y. , Laidley David , Pouliot Frederic , Probst Stephan , Saad Fred , Sabbagh Robert , Sartor A. Oliver
Published: February 2020

TPS260

Background: PSMA is a transmembrane glycoprotein expressed in normal human prostate epithelium at low levels, but highly upregulated in metastatic prostate cancer (PC). 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown highly promising diagnostic performance for detection of metastatic disease, with potential to identify disease amenable to theranostic targeting. 1095 is a novel PSMA-targeted small molecule that binds to the extracellular domain of PSMA selectively with high affinity. The complex is internalized, allowing the beta emitter, I-131, to kill PC cells. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at ~40 sites in the US and Canada. Eligible male pts must be at least 18 yo with metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional dose(s) administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Clinical trial information: NCT03939689.