bluuebunny/crossref_metadata_2025 huggingface dataset:
Next generation sequencing of primary prostate cancer tumors to reveal potentially actionable opportunities for clinical management: The UNC experience.
Authors: Crona Daniel James , Drier Anthony , Zhu Jing Daisy , Bell Emily Fox , Sketch Margaret Rose , Garrett Amy , Mitchell Khalis , Tomlins Scott A , Dees Elizabeth Claire , Godley Paul Alphonso , Dunn Mary , Rose Tracy L , Basch Ethan M. , Milowsky Matthew I. , Whang Young E.
Published: March 2019

305

Background: The Strata trial (NCT03061305) is a multi-institutional precision oncology collaboration structured as an observational protocol that aims to match patients to genomically-guided therapies. Methods: Selected University of North Carolina (UNC) metastatic prostate cancer (mPC) patients were enrolled on this IRB-approved study. Formalin fixed paraffin-embedded primary tumor specimens, without matched germline controls, were sent for targeted next generation sequencing (NGS) to detect actionable variants, including: mutations in 87 genes, copy number variations in 31 genes, and gene fusions in 46 gene drivers. mPC-related genes of particular interest included: AR, ATM, BRCA1/2, ERG, MSH2, MSH6, PTEN, RB1, and TP53. Results: Of the 92 cases sequenced, 5 [5%] failed testing. Of the 87 mPC patients (median age 69 years [47-86]) enrolled: 53 [61%] were white, 28 [32%] were black, 1 [1%] was Asian, and 5 [6%] declined to be identified. NGS data revealed 106 variants in 27 genes: 62 patients (71%) had at least one variant, 21 (24%) had 2 variants, 7 (8%) had 3 variants, and 4 (3%) had 4 variants. Among the 62 patients with at least 1 identified variant, TMPRSS2-ERG fusion occurred most frequently (50%), followed by TP53 (40%), and PTEN (16%). 6% of all sequenced patients had variants in DNA damage repair genes including ATM (3%), BRCA2 (2%) and MSH2 (1%). One patient had a SLC45A3-ERG fusion combined with PTEN deep deletion, which has been associated with a more aggressive phenotype. One patient with a microsatellite-instability high tumor was treated with pembrolizumab. Conclusions: The UNC experience shows that a high proportion of primary prostate cancer tumors from mPC patients have genomic variants, and one patient was treated based on these data. Limited actionability may reflect the landscape of currently FDA approved mPC treatments, and available clinical trials. It may also be due to a short follow-up, and these data could inform treatment planning upon progression.
The hematologic parameters in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate.
Authors: Cem Onal , Sedef Ali Murat , KOse Fatih , Oymak Ezgi , Guler Ozan Cem , Sumbul Ahmet Taner , Aksoy Sercan , Akkus Yildrim Berna , Besen Ali Ayberk , Mullaoglu Sadik , Mertsoylu Huseyin , Ozyigit Gokhan
Published: March 2019

308

Background: The aim of this study is to evaluate the prognostic implications of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline and after 4 and 12 weeks of treatment with abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively evaluated 102 mCRPC treated with abiraterone either pre- or post-chemotherapy between November 2012 and October 2017 in three institutions. We calculated NLR and PLR at baseline and at 4 and 12 weeks after initiation of abiraterone, and we evaluated prostate-specific antigen (PSA) response every 4 weeks. Fifty patients (49%) were treated with abiraterone post-docetaxel, and 52 patients (51%) received abiraterone pre-chemotherapy. Based on receiver operating characteristic analysis, patients were stratified as low NLR ( < 3.1) or high NLR (≥ 3.1), and low PLR ( < 163) or high PLR (≥ 163). The cutoff for anemia was < 12g/dL. Results: Median follow-up times for patients overall and for those who survived were 24.0 months (range, 0.3 – 54.9 months) and 25.5 months (range, 2.8 – 54.9 months), respectively. The median time of abiraterone treatment was 8.1 months (range, 2.4 – 40.1 months). The median overall survival (OS) was 20.8 months (interquartile range: 17.3–24.4). In univariate analysis, NLR, PLR, PSA response, and low hemoglobin (Hgb) were found significantly predictive of OS and progression-free survival (PFS). In multivariate analysis, declines in NLR and PSA of ≥ 90% emerged as significant independent predictors of OS and PFS. High-NLR patients who remained high or who returned to low NLR after 4 and 12 weeks showed significantly worse OS than patients with low baseline NLR. Patients with baseline Hgb > 12 g/dL had significantly longer median OS compared with patients with Hgb ≤ 12 g/dL; however, the significance of Hgb was lost at 12 weeks. Conclusions: NLR and PSA response to abiraterone was a significant predictor of OS and PFS in mCRPC patients treated with abiraterone delivered either pre- or post-chemotherapy. Furthermore, persistent increase in NLR during abiraterone has prognostic value for OS in patients with mCRPC.
Questioning the status quo: Should Gleason 3+3=6 PCa be considered a “negative core” for pre-RP risk nomograms?
Authors: Leong Joon Yau , Chandrasekar Thenappan , Tham Elwin , Teplitsky Seth , Trabulsi Edouard John , Gomella Leonard G. , Lallas Costas D.
Published: March 2019

31

Background: Current pre-radical prostatectomy (RP) nomograms predicting RP pathology do not differentiate between Gleason 6 prostate cancer (Gl6 PCa) and clinically significant Gleason 7-10 PCa. As such, use of these nomograms can be problematic. We assess the impact of excluding Gl6 PCa on nomogram and RP outcomes. Methods: Utilizing a prospectively maintained database, all men who underwent prostate biopsy (PBx) prior to RP were identified. Each patient was assessed using the MSKCC Kattan and Briganti nomogram using the following iterations: 1) “Original” [ORIG] (all available core data) and 2) "Selective” [SEL] (only cores Gleason score ≥7). Nomogram outcomes (risk of LNI, ECE, SVI, and OCD), were compared across iterations and stratified based on pre-RP risk classification (3+3 [low], 3+4, 4+3, 8-10 [high]). Clinically significant impact on management [CSIM] was defined as a change in risk of LNI above or below 2% (Δ2) or 5% (Δ5), based on current guidelines recommendations for PLND. Nomogram outcomes were validated using RP pathology. Results: 1118 men met inclusion criteria. Using the Kattan nomogram, when compared to actual RP pathology, the SEL iteration was a better predictor of LNI, ECE and OCD than the ORIG iteration, but not SVI. Using the Briganti nomogram, the SEL iteration was a better predictor of LNI. As for CSIM, the greatest impact was on men with Gl7 PCa. In the 359 Gl 3+4 patients, Δ2 was 3.9-28.13% and Δ5 was 12.81-17.27%. In the 184 Gl 4+3 patients, Δ2 was 0% and Δ5 was 7.61-11.41%. In all cases, the change favored decreased need for PLND. Conclusions: As Gleason 3+3=6 PCa is increasingly being considered an insignificant prostate cancer, its inclusion in established pre-RP nomograms becomes problematic. We find that excluding Gl6 PCa cores from these nomograms can reduce the need to complete a PLND at the time of RP, and more importantly, may better reflect the true extent of cancer. [Table: see text]
Clinical drivers for imaging testing in nonmetastatic castration-resistant prostate cancer: May they be optimized?—Data of “IDENTIFICA” study.
Authors: Useros RodrÃguez Eduardo , Juárez Álvaro , Carballido Rodríguez Joaquín , Rubio Jose , Rodríguez Antolín Alfredo , Amores Bermúdez Francisco Javier , Medina González Antonio , Rodrigo Miguel , Moreno Jiménez Juan , Vázquez Fernando , Muñoz del Toro Jacobo , Garcia Angela , Cózar Olmo José Manuel
Published: March 2019

318

Background: Metastases (M+) detection is a critical event in non-metastatic castration-resistant prostate cancer (nmCRPC), as it entails a change in PC management and is a potential surrogate for survival at this stage. PSA doubling time (PSA-DT) has been described as a prognostic factor to develop M+. However, there could be other relevant factors to raise suspicion of progression in nmCRPC patients. The “IDENTIFICA” study tries to describe disease characteristics and clinical drivers that make physicians suspect the presence of M+ in nmCRPC patients in clinical practice in Spain. Methods: Observational, transversal, multicenter study. nmCRPC patients with physician’s suspiction of M+ were selected. Imaging tests to rule out metastases were requested; clinical drivers were described, along with clinical data related to prostate cancer (PC). Results: 197 nmCRPC patients were recruited (Jan-Jun 2018). Median age was 81.3 years. Median time from the onset of androgen deprivation therapy (ADT) to CRPC was 5.1 years (IQR: 2.5-8.2). ADT was the first PC treatment for 64.4% of , while 41.2% went through a curative-intent treatment. Median PSA-DT at CRPC diagnosis was 7.5 months. Time from PC diagnosis to CRPC was influenced by Gleason score at diagnosis ( p=0.001), primary curative intent treatment ( p<0.001), and PSA-DT at CRPC diagnosis ( p=0.04). Most important clinical drivers leading physicians to request imaging were PSA value, PSA-DT and PC guidelines recommendations. M+ were detected in 23 patients (16.5%). In the multivariate analysis, there was a statistically significant relation between positive imaging and time on ADT (OR 1.16; 95% CI 1.018-1.325; p=0.026) and time on CRPC status (OR 1.55; 95% CI 1.038-2.302; p=0.032). In this interim analysis, PSA and PSA-DT seemed not to be statistically related to M+ appearance. Conclusions: PSA and PSA-DT seem to be the most influential drivers to request imaging tests during follow-up of nmCRPC patients. Time on ADT and time on CRPC status could be relevant factors for M+ detection and phycisians should be aware of them and not just PSA or PSADT to properly ask for imaging tests.
Genetic testing patterns for homologous recombination repair (HRR) alterations in patients with metastatic prostate cancer (mPC): An assessment at the University of Rochester (UR).
Authors: Schaffer Kerry , Kyi Kaitlin , Lustig Carol , Sahasrabudhe Deepak M. , Shayne Michelle , Baran Andrea M , Fung Chunkit
Published: March 2019

322

Background: Germline and somatic HRR alterations are present in 12% and 20% of patients with mPC, respectively, and can have treatment implications. NCCN guidelines recommend offering genetic testing for patients with mPC. This study examines genetic testing patterns in patients with mPC at UR. Methods: We conducted a retrospective study of all patients (n = 240) with mPC who saw medical oncology at UR from 10/1/2017 to 4/1/2018. We abstracted the following data from medical records: patient demographics, mPC characteristics, types of genetic testing, and clinically significant (CS) HRR alterations as defined by Myriad, Ambry, and Foundation One. To compare characteristics of patients who had genetic testing to those who did not, we used non-parametric Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for categorical variables. Results: The median age at mPC diagnosis was 71 years (range: 42-93 years), 86.3% were white, and 35% had mPC at initial diagnosis. 64 patients (26.7%) were offered genetic testing and 40 patients (16.7%) completed germline (n = 12), somatic (n = 21), or both germline and somatic genetic testing (n = 7). Median time from diagnosis of mPC to germline and somatic genetic testing were 9 months and 35 months, respectively. Among the 24 patients who were offered, but did not have testing, the reasons were: patients’ refusal (n = 10), death/hospice care (n = 7), insurance issue (n = 3), patient’s preference to have somatic testing at disease progression (n = 3), and missed genetic counseling visit (n = 1). Compared to patients who did not have genetic testing, those who had testing were younger at the time of mPC diagnosis (63.5 vs 73.0 years; p < 0.0001). CS HRR alterations were identified in 8 of 40 patients tested (20%): somatic HRR alterations include BRCA2 (n = 2), ATM (n = 1), CDK 12 (n = 1), and C HEK2 (n = 1); germline HRR alterations include BRCA2 (n = 2) and CHEK2 (n = 1). Conclusions: We report that approximately one-fourth of patients with mPC at UR had genetic testing offered, with a 20% prevalence of HRR alterations in those tested. Future research should develop strategies to address barriers to genetic testing.
Multidimensional flow characterization of circulating immune cells in cisplatin-resistant metastatic urothelial cancer (mUC) patients (pts) treated with pembrolizumab (P) with or without acalabrutinib (acala).
Authors: Zhang Tian , Staats Janet S. , Chan Cliburn , Alva Ajjai Shivaram , O'Donnell Peter H. , Harrison Michael Roger , Batich Kristen A , Munugalavadla Veerendra , George Daniel J. , Weinhold Kent J.
Published: March 2019

357

Background: Immunotherapy checkpoint inhibitors (ICIs) are now standard treatments (txs) in mUC, with response rates ranging 15-25%. A phase 2 randomized study (NCT02351739) treated 75 pts with mUC with either P or PA. We profiled peripheral blood mononuclear cells (PBMCs) to understand changes on tx. Methods: Comprehensive immune profiling of PBMCs was performed at baseline, weeks (wk) 4, 7, and 10. The Wilcoxon rank sum (WRS) test was used to compare tx arms, as well as pts with complete and partial response (CR/PR) vs disease progression (PD). Using the Benjamini-Hochberg (BH) method, results were deemed significant if they had false discovery rate (FDR) of 0.1 or less. Results: Clinical responses did not differ between tx arms (Zhang T et al, ESMO, 2017). The majority of patients showed largest immune changes from baseline at wk7. Comparing P vs PA pts, the PA group had statistically significant increases in PD-L1+ monocytes; CD8 T cells expressing: CD39, CTLA-4, ICOS, PD-1, TIM3, HLA-DR, Ki67, CD39/HLA-DR, CD39/Ki67, and PD-1/TIM-3; and exhausted (CD28-) CD8 T cells expressing ICOS and PD-L1 (Table). Comparing CR/PR vs PD pts, Treg subsets expressing CCR4/HLA-DR and CD39/HLA-DR were significant by WRS but not FDR criteria. Conclusions: From this extensive, exploratory, non-functional flow analysis of PBMCs, PA may potentiate immune changes of PD-L1+ monocytes and CD8+ T cell subsets. Increasing activated peripheral Tregs in CR/PR pts in either arm may indicate marginalization of Tregs from the tumor microenvironment. [Table: see text]
Re-examining an old trend: The association of human papillomavirus and bladder cancer.
Authors: Reinstatler Lael Suzanne , Shee Kevin , Stensland Kristian D. , Dagrosa Lawrence , Seigne John D. , Sverrisson Einar F.
Published: March 2019

362

Background: The Human Papilloma Virus (HPV) is a recognized carcinogenic factor. Previous studies have shown a possible association between HPV and bladder cancer, however HPV serology has not been reported. In this study, we assessed the correlation between bladder cancer and HPV positive serology. Methods: Using NHANES, a large nationally-representative population-based survey, we gathered clinical and demographic data on all patients with a diagnosis of bladder cancer over from 2007-2010 and analyzed their HPV serology status. We assessed the effects of positive serologic results for HPV18, HPV16, HPV11, and HPV6 on the rates of bladder cancer diagnosis. Results: Over the four-year period there was a weighted population of 155,650,000 Americans. The prevalence of HPV positive serology was as follows: HPV18–5.5%, HPV16–13.2%, HPV11–6.4%, HPV6–17.4%. There were 443,948 bladder cancer cases. Among cases there was a higher prevalence of male gender (80% vs. 53%, p = 0.0056), Caucasian race (93% vs. 66%, p = 0.001), and HPV6 positive serology (18.1% vs. 17.6%, p = 0.0005). There was no difference among the other three HPV types. On logistic regression controlling for race, gender, and smoking status, increasing body weight (OR 1.01, p < 0.0001) and HPV6 positivity (OR 1.9, p < 0.0001) were associated with increased odds of bladder cancer diagnosis while HPV11 positivity (OR 0.23, p < 0.0001) was associated with a decreased odds of bladder cancer diagnosis. Conclusions: Prior research has shown that there is a relationship between HPV and bladder cancer, but this relationship has previously been incompletely defined. In this large, nationally representative database, we describe a significant association of HPV6 positive serology with a diagnosis of bladder cancer. This finding is striking and might affect future investigation into the pathophysiologic basis of this relationship.
Circulating tumor cell (CTC) enumeration in patients (pts) with metastatic genitourinary (mGU) tumors treated in a phase I study of cabozantinib and nivolumab (CaboNivo) +/- ipilimumab (CaboNivoIpi).
Authors: Hu Zishuo , Mortazavi Amir , Pal Sumanta K. , Lara Primo , Mayer Tina M. , Steinberg Seth M , Mayfield Christian , Graap Katherine , Mallek Marissa , Costello Rene , Diaz Carlos , Schonhoft Joseph , Wang Yipeng , Dittamore Ryan , Chu Lincy , Trepel Jane B , Bottaro Donald P. , Apolo Andrea B.
Published: March 2019

379

Background: CTCs may serve as biomarkers for clinical outcomes in GU tumor pts. We examined the association between baseline CTC enumeration, change in CTC enumeration post treatment, progression-free-survival, overall survival and response to therapy with combination CaboNivo or CaboNivoIpi. Methods: 128 samples from 52 pts with mGU tumors treated with CaboNivo (38 pts) or CaboNivoIpi (14 pts) were drawn at baseline, cycle (C) 2 Day (D) 1, and C3D1 and processed with Epic Sciences platform. CTCs were defined as cytokeratin (CK)+, CD45-, distinct morphology, intact nucleus. PD-L1 expression was assessed. Results: From 07/20/2016-09/01/2018, 52 pts were treated for metastatic [urothelial carcinoma (UC) N = 33; UC plasmacytoid N = 1; clear cell renal cell carcinoma N = 4; bladder adenocarcinoma (BAC) N = 8; bladder squamous cell carcinoma N = 2; bladder small cell carcinoma N = 2; renal medullary carcinoma N = 2]. Median age was 61.5 years (range 20-82); 35 (67%) were male; N = 37(71%) had visceral involvement, N = 15(29%) had liver involvement, N = 11(21%) had bone involvement. CTCs were found in the peripheral blood of 39 (75%) pts, 1 pt (BAC) had PDL1+ CTCs at baseline. Median CTC/mL at C1D1, C2D1, C3D1, were 0.5 (0-357.1), 0.4 (0-71.8), and 0.75 (0-18), respectively. Median (lower and upper quartile) CTCs in pts with complete or partial responses (responders) vs stable or progressive disease (non-responders) were: 0.0 (0 to 5.40) vs 0.7 (0 to 2.5) at baseline; -0.35 (-3.65 to 0) vs 0 (-2 to 1.7) change from baseline to C2D1; and 0 (-5.4 to 0.5) vs 0 (-0.9 to 0.65) change from baseline to C3D1 (all p > 0.15). CTC counts of > 2 and > 4 at C2D1 were potentially associated with shorter OS (p = 0.071 and p = 0.045 without adjustment for multiple cutoffs for evaluation). PFS results exhibited similar trends. Conclusions: CTC were detected in pts with mGU tumors treated with CaboNivo and CaboNivoIpi. CTC values were lower in responders than in non-responders. On treatment lower CTCs were associated with better clinical outcomes. Ongoing analyses with the CTCs include cell morphology and heterogeneity, single cell genomics, and T-cell populations.
Inflammatory markers at baseline (C1) and cycle 3 (C3) and their association with clinical outcomes in urothelial cancer patients (pts) treated with immunotherapy (IO).
Authors: Shabto Julie M. , Martini Dylan J , Liu Yuan , Ravindranathan Deepak , Kline Meredith R , Hitron Elise , Russler Greta , Caulfield Sarah , Kissick Haydn , Alemozaffar Mehrdad , Ogan Kenneth , Harris Wayne , Kucuk Omer , Carthon Bradley Curtis , Master Viraj A. , Bilen Mehmet Asim
Published: March 2019

390

Background: Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have been explored as biomarkers for response to IO. We investigated the association between these biomarkers and clinical outcomes in urothelial cancer pts treated with IO. Methods: We conducted a retrospective review of 67 urothelial cancer pts treated with PD-1 or PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were measured from first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. MLR, NLR, and PLR were collected at C1 and C3. The nonlinear relationship between log-transformed biomarkers and OS or PFS was examined by martingale residual plot and optimal cutoff (OC) values were determined. Multivariable analysis (MVA) used Cox proportional hazard model. Results: OC for C1 and C3 NLR, MLR, and PLR were 2.06 and 1.42, -0.331 and -0.153, and 5.7 and 5.6, respectively. Pts with C1 NLR and PLR above OC had worse OS and shorter PFS (all p<0.05) (Table). High C3 MLR portended shorter OS and PFS. NLR, MLR and PLR were highly correlated (Pearson correlation coefficients ≥ 0.67, p<0.0001). Conclusions: High NLR, MLR, and PLR at C1 and at C3 are associated with worse clinical outcomes in this cohort. These values warrant a larger study for validation. MVA† of MLR, NLR, and PLR at C1 and at C3 with OS and PFS. [Table: see text]
First survival outcomes and additional secondary analyses from PURE-01: Pembrolizumab (pembro) before radical cystectomy (RC) in muscle-invasive urothelial bladder carcinoma (MIBC).
Authors: Necchi Andrea , Bandini Marco , Gallina Andrea , Bianchi Marco , Raggi Daniele , Farè Elena , Messina Antonella , Chung Jon , Ali Siraj Mahamed , Madison Russell , Anichini Andrea , Colecchia Maurizio , Gandaglia Giorgio , Fossati Nicola , Scuderi Simone Luca Antonio , Pederzoli Filippo , Colombo Renzo , Briganti Alberto , Montorsi Francesco
Published: March 2019

391

Background: PURE-01 is a phase 2 study of Pembro before RC in MIBC: the primary endpoint (pathologic complete response [pT0]) was met in advance ( Necchi et al. JCO 2018). While the study is still recruiting patients (pts), we analyzed the interim long-term outcomes in terms of relapse-free survival (RFS) and the role of multiparametric bladder magnetic resonance imaging (mpMRI) in predicting major pathologic response (pT<2) in RC. Methods: Pts with clinical stage T2-3bN0M0 received 3 courses of 200mg Pembro, before RC. Pts were staged and re-assessed with mpMRI before RC. 1-y RFS (overall and by pathologic stage) after Pembro and RC was compared with that from clinical stage-matched cohort of San Raffaele Urological Institute (URI, n=1021) and of the RISC multicenter database (n=719, Bandini et al, Eur Urol Oncol 2018). mpMRI were performed in all pts through bladder catheterization. The apparent diffusion coefficient (ADC) changes post-Pembro were matched with pathologic response, qPCR and genomic data from RC samples (FoundationONE). Results: 70 pts have completed treatment thus far: with 27 pT0 (38.6%) and 44 pT<2 (62.9%), activity was confirmed. 21 pts had ≥1y follow-up and were analyzed. Overall, 1-y RFS (95% CI) in PURE-01, URI and RISC were: 95.2 (86.6-100), 79.0 (76-82), and 69.7 (66.2-73.4). 1-y RFS after neoadjuvant chemotherapy and RC in URI and RISC were: 76.7 (61-97), and 76.5 (71-83). 1-y RFS for pT3-4 and/or pN+ pts were: 88.9 (71-100), 71.2 (67-76), and 57.1 (52-62). 39/70 pts had measurable disease for pre-post mpMRI changes. Pts with pT<2 (n=16) on RC showed a median “mean ADC” of 0.98 mm2/s vs 0.84 mm2/s of non-responders (NR, n=23, p=0.098), despite an increased T-cell infiltrate. Pts with cell-cycle gene alterations in RC (n=8) were all NR and showed lower median “mean ADC” values (p=0.074). Conclusions: The early efficacy data further support the role of single-agent IO as neoadjuvant therapy in MIBC. Pembro may be beneficial at long-term also in pathologically high-risk pts, thus questioning the value of PD-L1 for pt selection. mpMRI and genomic data might help identifying those pts who may need re-TURB only instead of RC. Clinical trial information: NCT02736266.
Association of next generation sequencing characteristics of MIBC specimens with clinical outcomes: The USC experience.
Authors: Basu Arnab , Chang Jeremy , Haiber Karen , Dorff Tanya B. , Pinski Jacek K. , Quinn David I. , Sadeghi Sarmad
Published: March 2019

397

Background: Muscle invasive bladder cancer (MIBC) is an aggressive disease. Several molecular subtypes have been identified. Commercial next generation sequencing (NGS) panels now provide significant genetic information on tumors. We conducted an exploratory analysis on MIBC tumor samples at our institution with commercial NGS data to evaluate if these assays provide novel prognostic information. Methods: NGS data (FoundationOne) from all locally advanced and metastatic bladder specimens were collected and combined with information on demographics, tumor characteristics (stage, grade, histology). Overall Survival (OS), post-cystectomy disease free survival (DFS), and Progression Free Survival (PFS) data were also compiled. Mutations in 353 genes were examined for alterations in TP53, Rb, FGF3-RAS-RAF and PI3K-mTOR-AKT pathways. Results: 48 samples were analyzed. Most samples were pure TCC (68.8%) followed by Squamous (16.8%) , Adenocarcinoma (6.3%), Small Cell (6.3%) and Plasmacytoid variants (2.1%). Most patients (91.5%) were locally advanced at diagnosis. Pathologic alterations were found in TP53 (54.2%) , Rb (60.4%), FGF3-RAS-RAF(89.6%) and PI3K-mTOR-AKT(70.8%) pathways. Squamous variants were more likely to have TP53 pathway alterations compared with others (100% vs 45% , p < 0.001) and predicted for poor overall survival. TP53 exons did not predict outcomes. In multivariable adjusted cox-regression models Rb alterations appeared to predict for improved post cystectomy DFS (p = 0.01). TP53 mutations predicted for worse PFS (p=0.01) while PI3K-mTOR-AKT pathway alterations were associated with poorer OS (p=0.02) after adjusting for all other predictors. Conclusions: In this limited single institution sample analyzed by commercial available NGS panels, some prognostic information was available. Analysis of a larger population could result in the validation of other predictive or prognostic markers.[Table: see text]
Circulating cellular biomarkers associated with delayed time to progression among bladder cancer patients treated with immune checkpoint inhibitors.
Authors: Koshkin Vadim S , Friedlander Terence W. , Li Patricia , Schonhoft Joseph , Krupa Rachel , Richardson Robin , Ontiveros Priscilla , Wang Yipeng , Dittamore Ryan , Paris Pamela
Published: March 2019

398

Background: Circulating tumor cells (CTCs) are an important emerging biomarker in bladder cancer that allow for a minimally invasive assessment of tumor activity and response to treatment. Characterization of CTC and other single cell populations associated with improved clinical outcomes can help guide treatment recommendations for patients with metastatic bladder cancer. Methods: Patients with metastatic bladder cancer who received treatment with anti-PD-1 or anti-PD-L1 agents were enrolled in this study. Patient response to treatment was assessed by treating physicians according to RECIST v1.1. Blood samples were prospectively collected from patients prior to the initiation of therapy and then while on treatment and shipped to Epic Sciences for processing. All nucleated cells were subjected to immunofluorescent (IF) staining and CTC and leukocyte identification by fluorescent scanners using algorithmic analysis. Kaplan-Meier analysis was utilized to compare time to progression of patients whose CTC and leukocyte values were above and below several pre-determined parameters. Results: A total of 27 patients (median age 74 years, 70% male) were enrolled in this study and were treated with anti-PD-1/PD-L1 agents pembrolizumab (n=15), atezolizumab (n=11), or nivolumab (n=1). For 20 patients who had evaluable responses, objective response rate (ORR) was 2/20 (10%), all partial responses; another 5/20 (35%) had stable disease. Increased CD4% (>8% of total leukocytes) was associated with delayed time to progression (TTP) (p=0.002) whereas increased baseline total CTCs (>2) had a statistically non-significant trend towards shorter TTP (p=0.09). Baseline CD8%, CD4/CD8 ratio and CTC PD-L1 status were not associated with TTP. Conclusions: In a preliminary analysis among metastatic bladder cancer patients treated with immune checkpoint inhibitors, patients with an increased baseline CTC count had a statistically non-significant trend towards shorter TTP whereas increased baseline CD4 cells had an association with delayed TTP. This prospective study is ongoing, and the results will be further validated in larger patient cohorts.
Impact of putative chemopreventative agents on prostate cancer diagnosis.
Authors: Goldberg Hanan , Moshin Faizan , Klaassen Zachary William Abraham , Chandrasekar Thenappan , Wallis Christopher , Herrera Cáceres Jaime Omar , Ahmed Ardalan , Woon Teck Sing , Kulkarni Girish S. , Berlin Alejandro , Saskin Refik , Hamilton Robert James , Alibhai Shabbir M.H. , Fleshner Neil Eric
Published: March 2019

40

Background: Prostate cancer (PC) is the most common non-cutaneous cancer in Canadian men and the third most common cause of cancer death in Canada. Several studies have shown that use of commonly prescribed medications, including those used for diabetes and hypercholesterolemia, is associated with improved survival in various malignancies, including PC. There has not been any large population-based study, examining the effects of these and other commonly prescribed medications, on the rate of PC diagnosis, over a 20 years follow-up period. Methods: A retrospective population-based study using data from the institute of clinical evaluative sciences, including all male patients aged 65 and above in Ontario who have had a negative first prostate biopsy between 1994 and 2016. We assessed the impact of commonly prescribed medications on PC diagnosis. The medications included Statins (hydrophilic and hydrophobic), diabetes drugs (metformin, insulins, sulfonylureas, and thizolidinedions), proton pump inhibitors, 5 alpha reductase inhibitors, and alpha blockers. Time dependent Cox regression proportional hazards models were performed determine predictors of PC diagnosis. Medication exposure was time varying and modeled as “ever” vs. “never” use or as cumulative exposure for 6 months of usage. A priori variables included in the model included age, ADG comorbidity score, rurality index, index year, and all medications. Results: A total of 51,415 men were analyzed over a mean (SD) follow-up time of 8.06 (5.44) years. Overall, 10,466 patients (20.4%) were diagnosed with PC, 16,726 (32.5%) had died, and 1,460 (2.8%) patients died of PC. On multivariable analysis increasing age and rurality index were associated with higher PC diagnosis rate, while a more recent index year, and usage of hydrophilic statins was associated with a lower diagnosis rate in both “ever” vs. “never” and cumulative models (HR 0.832, 95% CI 0.732-0.946, p = 0.005, HR 0.973 95% CI 0.951-0.995, p = 0.016, respectively). Conclusions: Hydrophilic statins are associated with a clinically significant lower PC diagnosis. To our knowledge this is the first study demonstrating a clear advantage of one group of statins (hydrophilic) over another (hydrophobic) in PC prevention.
Is the occurrence of higher adverse effects associated with better oncological outcome in metastatic urothelial carcinoma patients treated with pembrolizumab?
Authors: Hayakawa Nozomi , Kikuchi Eiji , Ogihara Koichirou , Hattori Seiya , Yoshimine Shunsuke , Shirotake Suguru , Okabe Takashi , Yamashita Ryo , Oya Mototsugu
Published: March 2019

405

Background: Pembrolizumab is an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody and a recently approved and long-awaited drug for the treatment of metastatic urothelial carcinoma (UC). It is an immune checkpoint inhibitor, which has been shown to trigger new autoimmune disorders. We investigated the association of occurrence of adverse effects (AE) with clinical outcome in Japanese UC treated with pembrolizumab. Methods: We identified 50 cases treated with pembrolizumab for chemo-resistant UC between December 2017 and August 2018 at our 5 institutions. Pembrolizumab-induced AE were reported by using Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. We evaluated the association between pembrolizumab-induced AE and response rate as well as patient survival. Results: The median age of the patients was 73 years (range, 46-89 years). The male/female ratio was 36/14. The primary tumor location was the pelvis in 10, ureter in 10, and bladder in 30. The median course of pembrolizumab was 4 (1-11). In the 50 patients, 36 AEs were observed, 11 of which were classified as CTCAE grade 2/3 . These patients were defined as the high AE groups. No grade 4 AE was encountered. In the high AE groups the most common AE was adrenal dysfunction (n = 4). Patients with no or CTCAE grade 1 were defined as the no/low AE groups. In the 45 cases who had measurable lesions, at the point of maximum effect the sum of the target lesion longest diameter (SLD) was decreased in 17 cases (37.8%) compared to baseline. SLD decreased in 7 (70%) patients in the high AE groups, which was significantly lower than those in the no/low AE groups (10, 28.6%, p = 0.027). The disease control rate defined by RECST ver. 4.0 at best response in the high AE groups was 81.8%, which was significantly higher than that in the no/low AE groups (46.2%, p = 0.046). The 6-month progression-free survival rate and the 6-month cancer-specific survival rate for the high AE groups was not different from that for the no/low AE groups. Conclusions: In patients with metastatic UC, the occurrence of CTCAE grade 2/3 might be associated with a better clinical response to pembrolizumab treatment.
A phase I study to assess the safety and tolerability of intravesical pembrolizumab in recurrent non-muscle invasive bladder cancer (NMIBC).
Authors: Woodcock Victoria K , Purshouse Karin , Butcher Chrissie , Haddon Caroline , Verrall Gillian , Elhussein Leena , Salio Mariolina , Middleton Mark R. , Cerundolo Vincenzo , Crew Jeremy , Protheroe Andrew
Published: March 2019

406

Background: Intravesical BCG has been the mainstay of therapy following TURBT for intermediate risk NMIBC for many years and is thought to act through activation of non-specific local immunity. With the recent success of checkpoint inhibitor treatment in metastatic bladder cancer, we sought to investigate the anti-PD1 inhibitor pembrolizumab as a potential agent for use in patients with intermediate risk NMIBC in a phase I/II study. The primary aim of the phase I safety run-in was to assess the safety and tolerability of intravesical pembrolizumab after TURBT in patients with intermediate risk NMIBC. Methods: Eligible patients had recurrent NMIBC for which adjuvant treatment post TURBT was a reasonable treatment option, ECOG PS 0-1 and adequate end organ function. Pembrolizumab was administered by intravesical instillation once weekly for a total of 6 doses. Intra-patient dose escalation was performed in three paired patient cohorts with doses starting at 50mg and increasing through 100mg to a maximum of 200mg. Adverse events (AEs) were assessed using CTCAE v4.03 with dose limiting toxicity (DLT) defined as a clinically significant, drug related, grade 4 haematological or ≥ grade 3 non-haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient. Results: In the first 4 patients treated, no DLTs were seen during dose escalation. Drug-related AEs included Grade 1 dysuria, fatigue and nausea. Grade 1-2 urinary tract infections, Grade 1 cystitis and Grade 3 urosepsis (SAE) were observed but assessed as probably not related to pembrolizumab. Recruitment of a final cohort of two patients at repeated doses of 200mg is ongoing to confirm safety and tolerability of this dose. Conclusions: Administration of intravesical pembrolizumab was safe and well tolerated in patients with NMIBC following TURBT. A randomised, parallel group, phase II marker-lesion study to assess the safety, efficacy and tolerability of either intravesical pembrolizumab or intravenous pembrolizumab in a larger cohort of patients with intermediate risk recurrent NMIBC is planned. Clinical trial information: NCT03167151.
Analysis of the National Cancer Data Base (NCDB) on impact and trend of neoadjuvant chemotherapy in upper urinary tract urothelial cancer.
Authors: Khan Rashad , Huang Danning , Basnet Alina
Published: March 2019

408

Background: Five year cancer specific survival rate is between 12- 70% for pT2 and higher UUTUC tumors. Adjuvant platinum based therapies have proven to improve Overall survival (OS) in observational series. Compromised renal function after surgery, delayed recovery from surgery pose challenge for adjuvant chemotherapy (AC). Thus, neoadjuvant chemotherapy (NAC) is an appealing option. However, there is only limited evidence on the role of NAC in UUTUC. Methods: We conducted a retrospective study of UUTUC (stage I- III) who underwent complete or partial nephroureterectomy with peri-operative chemotherapy. We then compared OS outcome among NAC vs AC groups. OS was calculated using Kaplan Meier analysis. Multivariate analysis was performed with Cox proportional hazard regression model to adjust for different variables. Results: Out of 50539 UUTUC patients reported in NCDB (2004-2016), 20121 met our inclusion criteria. 360 patients received NAC, 2617 received AC and 17144 received only surgery. Patients who received NAC were more likely to be younger, treated at academic centers, have Medicare and private insurance, have clinical T3 and higher tumor, have lower Charlson-Deyo Score (CDCC) score and undergo complete nephroureterctomy. One, three and five year OS among NAC and AC is depicted in table 1. With 150 months (m) follow up, median OS was 73.89 m for NAC and 54.14 m for AC group. A log rank test with p value=0.3437 shows no significant difference in survival rates of the two groups. Though consistent upward trend is observed in the use of NAC from 2004 to 2015, significantly higher percentages of patients still undergo only surgery without perioperative chemotherapy. Conclusions: Numerically higher mOS in NAC group was not statistically significant different from AC group. Use of perioperative chemotherapy appears to be much lower in UUTUC. Limitations that exist with this registry based study include lack of randomization, differences in surgical and radiation techniques, duration of chemotherapy, and provider/patient selection bias. Overall survival among two groups. [Table: see text]
Fierce-21: Phase II study of vofatmab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC).
Authors: Necchi Andrea , Castellano Daniel E. , Mellado B , Pang S , Urun Yuksul , Park Se Hoon , Vaishampayan Ulka N. , Currie Graeme , Abella-Dominicis Esteban , Pal Sumanta K.
Published: March 2019

409

Background: Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. About 20% of them usually respond to immune checkpoint inhibitors (ICI). Also, 20% of pts with mUC harbor FGFR3 mutations or fusions (M/F), and this feature may be associated with lower sensitivity to ICI. Vofatamab (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. FIERCE-21 is a Phase 1b/2 study designed to evaluate vofatamab monotherapy (VM) or in combination with docetaxel (VD). Methods: The study consists of a P 1b lead-in (P1b with VD), previously reported followed by P2 expansion cohort in FGFR3 M/F+ pts (identified with the FoundationONE CDx™ assay on archival samples). The study enrolled mUC pts with failure to ≥ 1 line prior chemotherapy (including prior taxane treatment) or ≤12 months of (neo)adjuvant chemotherapy, measurable disease and ECOG ≤ 1. Treatment consisted of vofatamab at 25 mg/kg alone (VM) and in combination with D (VD) at 75 mg/m2 q3w. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and activity (objective response-rate [ORR]). Results: 55 pts have received treatment. In the Ph 2 study, 21 pts received VM, 15 pts received VD. 35% of pts were included as 2nd line therapy, 65% in 3rd or later line of treatment. For pts receiving VD, safety was consistent with Ph 1B data. For pts receiving VM, median age was 67 yrs, ECOG 1 = 71.4%, Hgb < 10 gm/dL 13%, liver metastases 19%, ≥ 2 prior regimens 57%, (best response to prior therapy PD 31%). TEAEs occurring in ≥5% patients were asthenia (19%), diarrhea (9.5%), flushing 14%, chills (9.5%), hypotension (9.5%), decreased appetite (19%) and creatinine increased (9.5%). The majority of TEAS were grade 1 and 2. Only 1 patient on MF had a grade 3 TEAE and only 1 patient discontinued treatment due to an AE. The ORR have been seen in 7 pts to date including those receiving both VM and VD. Conclusions: Vofatamab both alone and combined with D in an every 3-week schedule are well tolerated with a low frequency of grade 3 TEAEs. Both VM and VD have demonstrated efficacy in terms of ORR, and mature results with PFS data will be presented. Clinical trial information: NCT02401542.
The role of phosphoglycerate mutase 2 in UM-UC3 bladder cancer cell metabolism.
Authors: Didde Ryan , Liu Weiya , Pirani Karim , Kaushik Gaurav , Woolbright Benjamin L. , Abbott Erika , Taylor John Arthur , Anant Shrikant , Holzbeierlein Jeffrey M. , Lee Eugene K.
Published: March 2019

410

Background: Bladder cancer remains the fourth most common cancer in American males with a higher risk of recurrence and progression for patients with diabetes mellitus. Urothelial bladder cancer is characterized by aerobic glycolysis with upregulation of glycolytic enzymes (known as the Warburg effect) such as phosphoglycerate mutase. Phosphoglycerate mutase 2 (PGAM2), a reversible glycolytic enzyme expressed highly in muscle, represents a target for modulation because of its differential expression from another isoform, phosphoglycerate mutase 1. PGAM2 knockdown may impact bladder cancer growth significantly via its effect on glucose metabolism at different glucose concentrations seen in patients with diabetes mellitus. Methods: UM-UC3 bladder cancer cells were assessed for PGAM2 expression at different glucose concentrations via Western blot and quantitative PCR. One native UM-UC3 line, three PGAM2 knockdown lines, and one vector control cell line were included in the western blot study. Cellular proliferation was analyzed using an enzyme based hexoseaminidase assay and was further supported with an automated cell counter. The effects of cisplatin were also investigated. Results: Increased PGAM2 expression at increased glucose concentrations in UM-UC3 was confirmed by Western blot and quantitative PCR. PGAM2 knockdown cells responded differently to changes in glucose concentration compared to the control cell lines, with a large increase in growth at a low glucose level of 25mg/dL after day 4. Cell proliferation demonstrated similar growth between the knockdown and controls at higher glucose concentrations of 100 and 200mg/dL. Proliferation data using automated cell counter demonstrate the same growth trend. Conclusions: Increased cell growth of PGAM2 knockdowns, most notably at 25mg/dL, suggests that PGAM2 may play a different role in glycolysis than expected, possibly serving as a modulator in cell growth instead of a simple reversible enzyme. We are currently investigating its differential expression compared to PGAM1, an enzyme recently characterized to have an opposite effect to PGAM2.
Serum cytokeratin 19 fragments: A novel preoperative prognostic marker in patients with upper urinary tract urothelial carcinoma.
Authors: Endo Yuki , Kimura Go , Akatsuka Jun , Obayashi Kotaro , Takeda Hayato , Hayashi Tatsuro , Kondo Yukihiro
Published: March 2019

412

Background: Current guidelines do not yet provide any recommendations for any serum tumor markers in patients with upper tract urothelial carcinoma (UTUC). Even today radiological images cannot diagnose muscle invasion correctly. Previous studies have shown that serum cytokeratin levels were correlated with depth of tumor invasion and metastases in patients with bladder cancer. In this study we evaluated whether preoperative serum cytokeratin 19 fragment levels (sCK19) could be a prognostic marker for survival in patients who received nephroureterectomy (NU). Methods: 160 cases with UTUC underwent NU from December 2003 to 2014 at our institution. The median age was 73 years. Preoperative sCK19 was measured in 138 cases. The patients were divided into two groups, high sCK19 group (HG) and low group (LG) based on sCK19 (a cut-off value: 3.5 ng/mL). Cancer-specific survival (CSS) and progression-free survival (PFS) were measured by Kaplan–Meier curves and statistical analysis was performed by the log–rank test. Multivariate analysis was carried out using the Cox proportional hazards model. Results: Of 138 cases ≤pT1 was 54 (39%), pT2 in 31 (22%), pT3 in 45 (32%) and pT4 in 8 (5%). 37 cases (23%) were the HG and 101 (78%) were the LG. sCK19 were significantly correlated with pT (rs 0.213, p=0.013, Spearman rank correlation). The median follow-up time was 34.0 months. In all cases the 5-year CSS was 78% and PFS was 60%. The 5-year CSS of the HG (57%) was significantly lower than the LG (86%) (p=0.001). The 5-year PFS of the HG (36%) was significantly lower than that of the LG (67%) (p<0.001). On univariate analysis, pT stage, lymphovascular invasion, positive margin (PM) and sCK19 were the significant factors for CSS. On multivariate analysis, sCK19 (HR4.2, p=0.001) and PM (HR2.9, p=0.001) were the independent poor prognostic factors. Conclusions: Preoperative sCK19 was the prognostic factor for the patients with UTUC. Systemic chemotherapy should be considered before NU in patients with high preoperative sCK19 levels independent of radiological findings.
Development of myeloid-derived suppressor cells (MDSC) targeted therapy for the treatment of cisplatin-resistant bladder cancer.
Authors: Takeyama Yuji , Kato Minoru , Shimizu Yasuomi , Hamada Kosuke , Iguchi Taro , Tamada Satoshi , Nakatani Tatsuya
Published: March 2019

415

Background: The emergence of immune checkpoint inhibitors (ICI) has brought hope for cure and survival for those suffering from various cancers, including bladder cancer. However, the response rate of ICI monotherapy is modest, and recent reports indicate that myeloid-derived suppressor cells (MDSC) might play a role in the resistant mechanism of ICI. In this study, we assess the effect of chemokine signal on the proliferation of bladder cancer and investigate whether MDSC could be a new target for the treatment of cisplatin-resistant bladder cancer. Methods: We established a cisplatin resistant strain (MB49R) of mice bladder cancer cell line MB49, and examined the alteration of the expression levels of inflammatory chemokines by chemokine array. Next, we isolated MDSCs from spleen and tumor in tumor-bearing mice to examine gene expression levels of chemokine receptors (CXCR2 and CCR2) and immunosuppression genes (Arg-1 and iNOS). Furthermore, we assessed the efficacy of CDDP, α-PD-L1 and chemokine antagonists against the proliferation of tumors in MB49 and MB49R xenograft models. Results: Expression levels of CCL2 and CXCL1/2, which are involved in the migration of MDSC, were significantly increased in the culture supernatant of MB49R compared to those in MB49 cell lines. This result was confirmed by real-time RT-qPCR of tumor extract, and this increase was also observed in human bladder cancer cell lines (T24 and T24R). CXCR2 and CCR2 were highly expressed in PMN-MDSC and M-MDSC, respectively, which were isolated from spleen or tumors in tumor-bearing mice, and gene expression levels of Arg-1 and iNOS were dramatically increased in M-MDSCs from the tumor tissues compared to those from spleen. Also, analysis by flow cytometry revealed that PMN-MDSC dramatically decreased in MB49R compared to parental MB49 tumors, while the proportion of M-MDSC was not changed in MB49R, which indicates that M-MDSC could be a target for the treatment of CDDP resistant bladder cancer. Conclusions: The results in the present study might indicate that the combination treatment with ICI and MDSC-targeting therapy could be an option for the treatment of cisplatin-resistant bladder cancer.