bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of sarcopenia on kidney function during neoadjuvant chemotherapy and post cystectomy complications in patients treated for localized muscle-invasive bladder cancer.
Authors: Regnier Pierre , De Luca Valeria , Brunelle Serge , Sfumato Patrick , Walz Jochen , Rybikowski Stanislas , Maubon Thomas , Branger Nicolas , Fakhfakh Sami , Durand Matthieu , Gravis Gwenaelle , Pignot Geraldine
Published: March 2019

387

Background: Sarcopenia is suspected to influence the complication rates in patients undergoing radical cystectomy. The aim of our study was to assess variations in sarcopenia in patients scheduled for neoadjuvant cisplatin-based chemotherapy (NAC) and radical cystectomy for muscle invasive bladder cancer (MIBC) and to explore the impact of sarcopenia on complications linked to NAC and surgery. Methods: Between January 2012 and December2017, 82 consecutive patients who underwent NAC and RC for cT2-T4 N0 M0 MIBC were retrospectively selected. Using CT scan before and after NAC, Lumbar Skeletal Muscle Index (SMI) was assessed by two observers blinded to patient’s status. We defined severe sarcopenia as SMI < 50 cm2/m2 for men and SMI < 35 cm2/m2 for women. We evaluated pre- and post-NAC cisplatin-based chemotherapy renal function and post-operative complication rates after cystectomy using the Clavien-Dindo classification. We explored risk factors of complications by logistic regression models. Results: According to the SMI cut offs, 47 patients (57.3%) were classified as sarcopenic and 35 patients (42.7%) non-sarcopenic. Patients’ characteristics between sarcopenic and non-sarcopenic patients were not significantly different except for BMI (p < 0.001). Among patients non-sarcopenic before NAC, 9 (19.1%) became sarcopenic after NAC. In multivariate analysis, sarcopenia was an independent significant predictor of renal impairment after NAC (OR 3.01; 95% CI 1.13–8.05; p = 0.02). There was a trend towards a higher rate of stage 3B kidney failure (GFR < 45 mL/min/1.73m2) after NAC in sarcopenic patients (OR 2.79; 95% CI 0.70–11.1) but the difference was not statistically significant (p = 0.14). Moreover, sarcopenia and ASA score were independent significant predictors of postoperative early complications ≤90 days (p = 0.01 and p = 0.02 respectively). Conclusions: We observed significant changes in sarcopenic status during NAC. Sarcopenia, estimated by the lumbar SMI measurement, was an independent predictor associated with the risk of renal impairment during NAC and early postoperative complications after RC.
NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02.
Authors: Siefker-Radtke Arlene O. , Fishman Mayer N. , Balar Arjun Vasant , Grignani Giovanni , Diab Adi , Gao Jianjun , Tagliaferri Mary Ann , Hannah Alison L. , Karski Erin E. , Zalevsky Jonathan , Hoch Ute , Rizwan Ahsan NAQI , Bilen Mehmet Asim
Published: March 2019

388

Background: Single-agent checkpoint inhibitors have changed the mUC treatment landscape; however, unmet need remains in first-line (1L) cisplatin ineligible mUC, particularly for PD-L1 negative (–) patients (pts). NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the IL-2 βγ receptor. PIVOT-02 is an ongoing study of NKTR-214 + nivolumab (nivo) in pts with advanced cancers, including mUC. Methods: Pts with mUC who were 1L cisplatin ineligible or refused standard of care (SOC) received NKTR-214 IV 0.006 mg/kg + nivo IV 360 mg q3w. Responses were assessed every 8 wks. Matched blood and tumor biopsies were evaluated for biomarkers including PD-L1 expression (assessed by Dako 28-8 PharmaDx IHC; PD-L1+ defined as ≥ 1% tumor cell staining). Results: As of 11 Oct. 2018, 34 pts received ≥ 1 dose of treatment (cisplatin ineligible [n=22]; refused SOC [n=12]). Median age was 70. Of 34 pts, 23 were efficacy evaluable (defined per protocol as having ≥ 1 post-treatment scan), 7 were pending a first scan, 1 pt was excluded for non-eligibility (no target lesion), and 3 discontinued prior to first scan. Thresholds for efficacy were exceeded in all 1L mUC cohorts under a pre-specified Fleming ORR analysis. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The ORR was 50% in PD-L1– pts (5/10; 95% CI 19–81%) and 56% in PD-L1+ pts (5/9; 95% CI 21–86%). PD-L1 status was unknown in 4 efficacy-evaluable pts. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of pts and 8.8% discontinued due to TRAEs. No G4/G5 TRAEs occurred. 22 pts had available baseline PD-L1 results (PD-L1+ [n=11]; PD-L1– [n=11]). 10 of the 11 PD-L1– baseline samples had matched wk 3 biopsies. Of these, 6/10 (60%) converted to PD-L1+ at wk 3. Updated results will be presented. Conclusions: NKTR-214 + nivo showed encouraging clinical activity, including CRs, and an acceptable preliminary safety profile in pts with mUC. Efficacy appears independent of PD-L1 status with a similar ORR in PD-L1– and + tumors. These data support further evaluation of the combination. Clinical trial information: NCT02983045.
Impact of Aurora kinase A and B expression on response to neoadjuvant chemotherapy and patient outcome in muscle-invasive bladder cancer (MIBC).
Authors: Burgess Earle Frederick , Livasy Chad , Trufan Sally J , Hartman Aaron , Guerrieri Renato , Naso Caroline , Clark Peter E , Grigg Claud , Symanowski James Thomas , Raghavan Derek
Published: March 2019

393

Background: Identification of robust biomarkers that predict likelihood of benefit from neoadjuvant chemotherapy (NAC) in patients with MIBC remains an unmet need. Previous studies have implicated tumor overexpression of aurora kinases A (AURKA) and B (AURKB) as a mechanism of chemo-resistance. Because overexpression of AURKA has also emerged as a potential biomarker for detection of high-risk urothelial carcinoma, we sought to characterize the expression of AURKA, AURKB with clinical outcomes in MIBC patients who received NAC and to test the hypothesis that tumor overexpression of AURKA and AURKB would predict for residual MIBC. Methods: 47 patients with MIBC who received NAC prior to cystectomy were retrospectively identified. Immunohistochemistry for AURKA and AURKB was performed on pre-treatment diagnostic transurethral resection of bladder tumors and matched cystectomy specimens. Logistic regression models were estimated to determine the impact of pre-NAC expression on pathologic staging at cystectomy. Receiver Operator Characteristic curves (ROC) were calculated to assess diagnostic predictive ability of AURKA and AURKB. AURKA and AURKB were assessed for association with relapse-free survival (RFS) and overall survival (OS) using Kaplan-Meier techniques and Cox proportional hazards models. Results: 22 of 47 [46.8%] patients had residual muscle-invasive (ypT2-4) urothelial carcinoma after NAC. Neither baseline tumor expression of AURKA (ROC = 0.54, p = 0.71) nor AURKB (ROC = 0.46, p = 0.98) predicted for ypT2-4 status. However, baseline expression of AURKA above the 75th percentile for this cohort, determined by the percentage of tumor cells positive, was associated with an inferior RFS, [HR = 3.79, [1.40, 10.26] p = 0.005] and OS, [HR = 5.84, [2.14, 15.98], p < 0.001]. Similar trends for worse survival outcomes were also observed for high AURKB levels. Conclusions: Although baseline tumor AURKA and AURKB expression did not predict for pathologic residual MIBC after NAC, high expression of AURKA and AURKB predicted for inferior RFS and OS. Further evaluation of AURKA and AURKB as potential biomarkers and therapeutic targets in MIBC is warranted.
Characterization of actionable genetic alterations to guide targeted therapy for metastatic urothelial carcinoma.
Authors: Almassi Nima , Pietzak Eugene J. , Funt Samuel Aaron , Schultz Nikolaus , Dalbagni Guido , Bochner Bernard H. , Al-Ahmadie Hikmat , Bajorin Dean F. , Rosenberg Jonathan E. , Iyer Gopa , Solit David B.
Published: March 2019

407

Background: Genetic alterations predicting response to targeted therapy are an area of active interest in developing novel therapies for patients with metastatic urothelial carcinoma (mUC). With the objective of characterizing the frequency of actionable alterations (AA) and the evidence supporting targeted therapy for these AAs, we report our experience with next-generation sequencing in mUC. Methods: Patients with sequenced mUC lesions were identified from our prospectively-maintained database. All AAs with clinical or biologic evidence supporting the alteration as predicting response to targeted therapy were identified and stratified by Oncology Knowledge Base (OncoKB) level of evidence (table). The relationship between strength of evidence and administration of targeted therapy was examined. Results: Ninety-nine of 134 patients (74%) harbored at least one AA, with 162 total AAs identified. Twenty level 2B AAs were identified, reflecting the highest level evidence in this cohort, with ERBB2 amplification (9), TSC1/TSC2 (6), and BRCA1/BRCA2 mutations (3) most common. Twenty-eight level 3A, 51 level 3B, and 62 level 4 AAs were also identified. Seventeen patients received targeted therapy, which was administered with greater frequency among patients with level 3B or higher AAs (21% vs 3%). Conclusions: Most patients with mUC harbor at least one AA, suggesting multiple targeted therapeutic opportunities in mUC. These findings highlight the need for additional clinical trials and the role of genetic testing in identifying candidates for targeted therapy. [Table: see text]
Novel perioperative parameters-based nomograms for survival outcomes in upper tract urothelial carcinoma after radical nephroureterectomy.
Authors: Tan Ping , Yang Lu , Xu Hang , Wei Qiang
Published: March 2019

414

Background: Recently, several postoperative nomograms for cancer-specific survival (CSS) after radical nephroureterectomy (RNU) were proposed, while they did not incorporate the same variables; meanwhile, many preoperative blood-based parameters, which were recently reported to be related to survival, were not included in their models. In addition, no nomogram for overall survival (OS) was available to date. Methods: The full data of 716 patients were available. The whole cohort was randomly divided into two cohorts: the training cohort for developing the nomograms (n = 508) and the validation cohort for validating the models (n = 208). Univariate and multivariate Cox proportional hazards regression models were used for establishing the prediction models. The discriminative accuracy of nomograms were measured by Harrell’s concordance index (C-index). The clinical usefulness and net benefit of the predictive models were estimated and visualized by using Decision curve analyses (DCA). Results: The median follow-up time was 42.0 months (IQR: 18.0-76.0). For CSS, tumor size, grade and pT stage, lymph node metastasis, NLR, PLR and fibrinogen level were identified as independent risk factors in the final model; while tumor grade and pT stage, lymph node metastasis, PLR, Cys-C and fibrinogen level were identified as independent predictors for OS model. The C-index for CSS prediction was 0.82 (95%CI: 0.79-0.85), and the OS nomogram model had an accuracy of 0.83 (95%CI: 0.80-0.86). The results of bootstrapping showed no deviation from the ideal. The calibration plots for the probability of CSS and OS at 3 or 5-year after RNU showed a favorable agreement between the prediction by the nomograms and actual observation. In the external validation cohort, the C-indexes of the nomograms for predicting CSS and OS were 0.79 (95%CI: 0.74-0.84) and 0.80 (95%CI: 0.75-0.85), respectively. As indicated by calibration plots, optimal agreement was observed between prediction and observation in the external cohort. Conclusions: The nomograms developed and validated based on preoperative blood-based parameters were superior to any single variable for predicting CSS and OS after RNU.
Analysis of EGFR mutant upper tract and bladder urothelial carcinoma (UC) reveals distinct mutational landscape.
Authors: Madison Russell , Gupta Sumati , Ross Jeffrey S. , Schrock Alexa Betzig , Juckett Luke , Miller Vincent A. , Alexander Brian Michael , Pal Sumanta K. , Heymach John , Necchi Andrea , Koyner Jay L , Ali Siraj Mahamed , Chung Jon , Reddy Venkataprasanth P.
Published: March 2019

416

Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Results: EGFR alterations ( EGFRalt) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 66%) and TP53 (58% v 74%) were the most frequently mutated genes in EGFRalt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 63%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFRexon20), which made up a larger proportion of EGFRalt in UTUC than BUC (7/17, 38% v 13/93, 14%; p = 0.01). Compared to other EGFRalt, EGFRexon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (0% v 100%, p = 5.1E-5; 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFRalt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFRexon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.
Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN trial.
Authors: Feng Felix Y , Thomas Shibu , Gormley Michael , Lopez-Gitlitz Angela , Yu Margaret K. , Cheng Shinta , Ricci Deborah S. , Rooney Oliver Brendan , Mainwaring Paul N. , Olmos David , Saad Fred , Chowdhury Simon , Hadaschik Boris A. , Fishbane Nicholas , Davicioni Elai , Liu Yang , Small Eric Jay , Smith Matthew Raymond
Published: March 2019

42

Background: The SPARTAN trial recently demonstrated that addition of APA to androgen deprivation therapy (ADT) improved metastasis-free survival (MFS) and second progression-free survival (PFS2) in nmCRPC pts. We performed transcriptome-wide profiling of available primary tumor samples from pts in SPARTAN to evaluate potential biomarkers of response or resistance to APA+ADT. Methods: Pts included in SPARTAN were at high risk of developing metastasis.We used a commercially available genomic assay (DECIPHER prostate test, GenomeDx Biosciences, Inc., San Diego, CA) to assess gene expression in 233 archived primary tumors from SPARTAN pts. Using a Cox proportional hazard model, we assessed the association between scores and subtypes from previously derived prognostic and predictive gene signatures, such as DECIPHER and basal (BA) vs luminal (LU) subtyping. Results: Pts with high DECIPHER scores had greater treatment effect with APA+ADT than those with low scores. Pts with LU, a subtype known to be sensitive to ADT, greatly benefited from APA+ADT. Pts with BA, typically resistant to ADT, also benefited from APA+ADT. Conclusions: DECIPHER score and BA or LU subtype may be biomarkers of response to APA+ADT. DECIPHER may be useful for identifying pts for early treatment intensification with APA or other agents, and molecular subtyping may be an effective approach for pt selection in trials combining novel therapies with APA. Clinical trial information: NCT01946204. [Table: see text]
The impact of histologic variants of urothelial carcinoma on clinical outcomes following trimodal bladder-preserving therapy.
Authors: Nagumo Yoshiyuki , Kandori Shuya , Kimura Tomokazu , Kawahara Takashi , Kojima Takahiro , Kawai Koji , Ishikawa Hitoshi , Nishiyama Hiroyuki
Published: March 2019

421

Background: The current guidelines for muscle-invasive bladder cancer recommend the use of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, a trimodal approach involving the combination of maximal transurethral resection (TUR) and combined chemoradiotherapy is an alternative in selected patients. Clinical outcomes of patients with histologic variants have not well been known. Methods: From 1990 to 2015, 148 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal TUR of the bladder tumor, intra-arterial chemotherapy and radiotherapy at our institution. We compared complete response rate (CRR) of bladder preservation, 5-yr cause-specific survival (CSS), and 5-yr overall survival (OS) for the patients with pure urothelial carcinoma (UC) or variant UC. OS and CSS were analyzed by using the Kaplan-Meier method and log-rank test. Results: The median follow-up was 38.3 months. All patients were T2-T3N0M0 (T2, n = 90; T3, n = 58). There were no significant differences in clinical characteristics between pure and variant UC groups. Eleven (7%) of the 148 patients had variant UC; 7 (64%) had UC with squamous and/or glandular differentiation, and 4 (36%) had other forms, including sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), and clear cell variants (n = 1). There was no significant difference between pure UC and variant UC for CRR of bladder preservation (85% vs 82%, p = 0.66), the 5-yr CSS (88% vs 75%, p = 0.86) and the 5-yr OS (81% vs 75%, p = 0.66). Conclusions: Our findings indicate that trimodal bladder-preserving therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients with variant UC.
Avelumab treatment in metastatic urothelial carcinoma: Post-hoc analysis of high-risk populations in the phase Ib JAVELIN Solid Tumor Study.
Authors: Apolo Andrea B. , Patel Manish R. , Ellerton John Allan , Dirix Luc , Manitz Juliane , Kasturi Vijay , Warth John , Rosen Galit , Gulley James L.
Published: March 2019

428

Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, patients (pts) in various subgroups had a favorable objective response rate (ORR) with avelumab. Here, we report further post hoc analyses of safety and efficacy outcomes with avelumab in high-risk mUC subgroups. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Best overall response (per RECIST 1.1) was adjudicated by an independent review committee. ORR, disease control rate (DCR), progression-free survival (PFS), and adverse event (AE) profiles for pre-specified subgroups of high-risk pts were compared. Results: 242 pts with mUC received avelumab and were followed up for ≥2 years (data cutoff, Apr 2018). No difference was found in ORR between pts with renal insufficiency (creatine clearance [CrCl], <60 mL/min; n=107) and pts with CrCl ≥60 mL/min (n=131; 17.8% [95% CI: 11.0-26.3] vs 15.3% [95% CI: 9.6-22.6]) or between pts with upper (n=56) vs lower tract tumors (n=186; 14.3% [95% CI: 6.4-26.2] vs 17.2% [95% CI: 12.1-23.4]). ORR in pts with baseline liver metastases (n=83) was 6.0% (95% CI: 2.0-13.5) vs 22.0% (95% CI: 15.8-29.3) in pts without (n=159). ORR in elderly pts (≥75 years; n=68) was 25.0% (95% CI: 15.3-37.0) vs 13.2% (95% CI: 8.6-19.2) in younger pts (n=174). ORR in pts with albumin ≥35 g/L (n=197) was 19.8% (95% CI: 14.5-26.1) vs 2.2% (95% CI: 0.1-11.8) in pts with <35 g/L (n=45). Except for the albumin levels and age subgroups (where the trend in ORR was not confirmed), subgroups showed DCR and PFS that were consistent with ORR trends. AE profiles did not exhibit any higher risk of adverse effects in these subgroups. Conclusions: Responses to avelumab occurred in select assessed subgroups previously defined as poor prognostic or high risk, suggesting that immunotherapy may achieve comparable efficacy irrespective of factors such as site of disease and renal status; no difference in safety profiles was identified. Clinical trial information: NCT01772004.
Validation and physiological association of changes in magnetic resonance imaging radiomic features in response to androgen deprivation therapy in patients with high-risk prostate cancer.
Authors: Tharmalingam Hannah , Beasley William , Alonzi Roberto , McWilliam Alan , Hoskin Peter , Choudhury Ananya
Published: March 2019

43

Background: Biochemical response to neoadjuvant androgen deprivation therapy (nADT) predicts relapse-free and overall survival for prostate cancer (PCa). Radiomic features change in response to nADT, showing potential as prognostic imaging biomarkers. Using multi-parametric MRI (mpMRI) before and after nADT, we aim to validate these changes, evaluate reproducibility and assess their association with previously described ADT-induced reductions in quantitative blood flow (BF) and blood volume (BV) imaging parameters. Methods: 20 patients with high-risk PCa received 4 mpMRI scans, 2 pre-nADT and 2 after 3 months therapy. T2-weighted sequences were used to define tumour regions-of-interest (ROI) which were subtracted from the prostate outline to form the benign prostate ROI. Established kinetic models were applied to dynamic contrast susceptibility MR sequences to derive changes in BF and BV in both ROI. Pyradiomics was used to extract homogeneity and energy features from both ROI. A paired student T-test compared feature values pre- and post-nADT. An inter-class correlation coefficient (ICC) calculated using mean values from consecutive scans assessed reproducibility. Feature changes and physiological parameters were correlated using Pearson’s coefficient. Results: In response to nADT, homogeneity and energy values significantly increased in benign prostate (p < 0.001) and decreased in tumour (p < 0.005). Both features exhibited high reproducibility pre- and post-nADT; all ICC ≥0.89. The reduction in tumour homogeneity and energy showed a positive association with the decline in BF and BV induced by ADT; all r 0.69-0.78, all p < 0.001. No correlation was seen in benign prostate. Conclusions: Energy and homogeneity radiomic features in benign and malignant prostate are reproducible and show significant reciprocal change in response to nADT. Validation of these changes and the strong association in tumour with ADT-induced physiological effects confirms their potential as prognostic biomarkers in high-risk PCa.
First-line PD1/PD-L1 inhibitors for platinum-ineligible advanced urothelial carcinoma (UC).
Authors: Agarwal Archana , Pond Gregory Russell , Drakaki Alexandra , Lee Jae-Lyun , Bilen Mehmet Asim , Di Lorenzo Giuseppe , Grivas Petros , Ornstein Moshe Chaim , Barata Pedro C. , Gupta Shilpa , Hussain Syed A. , Curran Catherine , Garcia Jorge A. , Sonpavde Guru
Published: March 2019

432

Background: FDA modified the label for the use of 1st-line pembrolizumab or atezolizumab therapy to PD-L1 high cisplatin-ineligible or platinum-ineligible UC patients (pts) regardless of PD-L1 expression. However, the outcomes when using PD1/PD-L1 inhibitors for platinum-ineligible pts are unclear. We conducted a retrospective study to evaluate clinical outcomes with first-line PD1/PD-L1 inhibitors for platinum-ineligible pts with advanced UC in a real-world setting. Methods: We collected data retrospectively from 6 institutions. The following criteria were deemed to render pts platinum-ineligible although physician discretion was also allowed: Cr Cl < 30 ml/min, ECOG-PS 3, Both Cr Cl 30 to < 60 AND ECOG-PS 2. Demographic and clinical variables and outcomes (overall response rate [ORR], overall survival [OS]) were collected. A Cox regression analysis was done to study the association of baseline variables with response and survival. Results: Data were available for 45 pts. Pts received atezolizumab [n = 24], pembrolizumab [n = 11], nivolumab [n = 7] and durvalumab [n = 3]. The mean age was 72.2 (range 45-90) years. The reasons for platinum-ineligibility were: Cr Cl < 30 ml/min (n = 17), ECOG-PS 3 (n = 3), ECOG-PS 2 plus Cr Cl < 60 ml/min (n = 7), elderly with co-morbidities (n = 12), and reason was unavailable for 6 pts. The median OS was 37 weeks (CI 30-80). ORR was 27.3%: Complete response in 3 pts [6.8%], partial response in 9 pts [20.5%], stable disease in 11 pts [25%] and progressive disease in 21 pts [47.7%] and data for 1 patient was unavailable. Toxicity of any grade were seen in 42.2% of pts and Grade ≥3 toxicity in 9 pts’ [20%]. There were no treatment-related deaths. Anemia (HR = 0.75, 95% CI 0.62 - 0.92, P = 0.005) and liver metastasis (HR = 1.17, 95% CI 0.47 - 2.93, P = 0.017) correlated with shorter OS. Conclusions: To our knowledge, this is the 1st report of efficacy and toxicity of PD1/PD-L1 inhibitors as1st-line therapy for platinum ineligible UC. Data appear comparable to those reported previously in unselected cisplatin-ineligible pts receiving pembrolizumab or atezolizumab in phase II trials. Validation is needed in larger datasets and prospective trials.
Blood myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) are correlated with neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS).
Authors: Sheng Iris Yeong- Fung , Diaz-Montero C. Marcela , Rayman Patricia A. , Wei Wei (Auston) , Fallah Jaleh , Finke James , Kim Jin Sub , Pavicic Paul G. , Lamenza Marcelo , Company Donna , Stephenson Andrew J. , Campbell Steven , Haber Georges-Pascal , Lee Byron H , Mian Omar Y. , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. , Grivas Petros , Ornstein Moshe Chaim
Published: March 2019

436

Background: MDSC have been linked to the chronic inflammatory microenvironment of tumor cells and pathologic outcomes in UC patients (pts) undergoing cystectomy. NLR is an established inflammatory biomarker with prognostic properties in mUC. We hypothesized that MDSCs correlate with NLR and OS in mUC. Methods: MDSCs were measured in blood samples from mUC patients by fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UC-MDSC: CD15-/CD14-). MDSC populations were presented as % of live nucleated blood cells from PB and absolute numbers from WB. Spearman’s correlation assessed correlations between MDSC & NLR. Kaplan Meier curves and log rank test estimated OS from the time of MDSC collection to last follow up or date of death. Results: Of 79 pts, 77% were men and 42% were never smokers with a median age of 69 (31-83). Overall, 71% had pure UC and 81% had lower tract UC. Prior therapies include intravesical therapy (22%), neoadjuvant chemotherapy (31%), and cystectomy/nephroureterectomy (61%). Median follow up was 12 months (range: 0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p≤0.001). Negative correlation was noted between NLR and WB UC-MDSC:PMN-MDSC ratios (rho = -0.27, p = 0.03), as well as NLR and PB UC-MDSC:PMN-MDSC (rho = -0.28, p = 0.02). Median survival was 17.7 months (95% CI: 11.0-NA months). Overall 1-yr and 3-yr survival were 0.60 (95% CI: 0.49-0.73) and 0.15 (95% CI: 0.03-0.67), respectively. Higher WB UC-MDSC levels were associated with shorter OS (HR 2.85, 95% CI: 1.43-5.65, p = 0.003). Conclusions: Specific MDSC subsets correlate with NLR. Higher WB UC-MDSC levels have negative prognostic roles for OS. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow up are needed.
Genomic biomarkers to predict outcome in Gleason Score 9-10 disease.
Authors: Kishan Amar Upadhyaya , Romero Tahmineh , Elashoff David , Grogan Tristan , Rettig Matthew , Reiter Robert Evan , Tran Phuoc T. , Nguyen Paul L. , Nickols Nicholas George , Davicioni Elai , Spratt Daniel Eidelberg , Feng Felix Y , Weidhaas Joanne B.
Published: March 2019

44

Background: Gleason score (GS) 9-10 prostate cancer (PCa) has classically been considered the most aggressive form of clinically localized disease. However, outcomes remain heterogeneous. Whether specific biomarkers may help guide prognostication within GS 9-10 disease remains unknown. Methods: Microarray-derived gene expression data were obtained from six retrospective radical prostatectomy cohorts (n=1076) and two prospective cohorts with data from the Decipher GRID (n=7000). A total of 957 patients had GS 9-10 disease. Clinical outcomes data (i.e., distant metastasis [DM] and prostate cancer-specific mortality [PCSM]) were available for 1077 patients (201 with GS 9-10 disease). We filtered for genes with high expression levels and differential expression between GS 9-10 and GS ≤8 (via Wilcoxon test with adjustment for false discovery rate [FDR]), and then used using weighted gene co-expression network analysis [WGCNA] to identify distinct modules. Genes with both a low p-value and a high connectivity within each module were included as potential predictors in logistic regression models constructed using elastic net regularization. We also chose genes within the GS 9-10 cohort with q-value <0.01 and <0.3 after FDR correction for outcomes of DM and PCSM, respectively. We used the cross-validated AUC for quantifying the discrimination of each gene set. Results: We identified a set of 12 genes with an AUC of 0.81 for discriminating GS 9-10 vs. GS ≤8. A separate set of 7 genes had an AUC of 0.83 for predicting DM within GS 9-10 patients, compared with an AUC of 0.68 within GS ≤8 patients. A third set of 13 genes had an AUC of 0.93 for predicting PCSM within GS 9-10 patients, but an AUC of only 0.57 for predicting PCSM within GS ≤8. Conclusions: These data suggest that a genomic biomarker signature can strongly discriminate GS 9-10 from GS ≤8. Separate gene sets can also predict DM and PCSM within GS 9-10 patients with high fidelity, but are not as predictive of these outcomes within GS ≤8 patients. These data support the hypothesis that GS 9-10 disease is a biologically distinct yet heterogeneous entity, and biomarker discovery efforts to better guide upfront treatment intensification in this subset are feasible and warranted. (NCT02609269).
Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.
Authors: Funt Samuel Aaron , Solovyov Alexander , Faltas Bishoy Morris , Iyer Gopa , Boyd Mariel Elena , Cipolla Catharine Kline , Regazzi Ashley Marie , Teo Min Yuen , Lee Chung-Han , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Greenbaum Benjamin , Bajorin Dean F.
Published: March 2019

443

Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was > = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]
Intra-vesical therapy using 4N1K-peptide in bladder cancer and its effects on tumor growth and angiogenesis.
Authors: Miyata Yasuyoshi , Araki Kyohei , Yuno Tsutomu , Nakamura Yuichiro , Sagara Yuji , Matsuo Tomohiro , Ohba Kojiro , Sakai Hideki
Published: March 2019

446

Background: The 4N1K-peptide (KRFYVVMWKK), which is derived from thrombospondins has anti-cancer activities in several cancers. We previously found that 4N1K-peptide expression was negatively associated with tumor invasion and prognosis in patients with bladder cancer (BC). The main aim of this study is to clarify whether intravesical therapy using 4N1K-peptide has anti-cancer effects in BC by in vivo and in vitro studies. Methods: Change in tumor growth and apoptosis due to transfection of 4N1K-peptide were evaluated in the BC cell line, T24 cells. Next, to clarify the anti-cancer effects of 4N1K-peptide as intra-vesical therapy, cell survival, apoptosis, and microvessel density (MVD) were investigated in chemical (BBN)-induced BC mouse model. In this study, natural saline (Ns) and 4NGG-peptide which has a similar structure to 4N1K-peptide but does not have any biological activity were used. In addition, survival analyses are performed in these mouse model. Results: In T24 cells, mean/SD of AI in 4N1K-peptide-transfected cells was 7.9/1.1%, which was remarkably higher (P < 0.001) than that in 4NGG-peptide-transfected cells (1.6 / 0.2%). In mouse model, 7 of the 20 mice treated with Ns died because of cancer-related symptoms, and invasive cancer was detected in 9/13 (69.2%). In contrast, in mice treated with 4N1K-peptide, 1 of 15 mice was died and invasive disease was observed in 1/14 (7.1%) at 24 weeks of age. Kaplan-Meier survival cures showed mice treated with 4N1K-intarvesical therapy had better prognosis compared to others (P = 0.036). In mouse tissues, apoptotic index in mice treated with 4N1K-peptide was significantly higher (P < 0.01) than that in others. In contrast, MVD in mice with 4N1K-peptide was significantly lower (P < 0.05) compared to others. In normal urothelium of mouse treated with 4N1K-peptide, change of morphological characteristics was not detected. Conclusions: 4N1K-peptide played as tumor-suppressor by regulating apoptosis and angiogenesis in BC animal model. Therefore, there is the possibility that 4N1K-peptide is a potential useful and safety therapeutic agent for intra-vesical therapy in BC patients.
Potential markers of response and resistance to programmed cell death-1 blockade in first-line therapy of cisplatin-inilegible advanced urothelial cancer.
Authors: Carretero-Gonzalez Alberto , Homet Moreno Blanca , Dueñas Marta , Martínez-Fernández Mónica , Manneh Ray , Bernardini Alejandra , Rubio Carolina , Villacampa Felipe , García Martín Rosa M. , García Escudero Ramón , Rodríguez Peralto José L. , Rueda Daniel , De Velasco Guillermo , Castellano Daniel E. , Paramio Jesús M
Published: March 2019

449

Background: Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit in advanced urothelial cancer (UC) patients. An alert was issued about a decrease in survival for bladder cancer patients with PD-L1-low status receiving immunotherapy versus chemotherapy as first-line therapy. We studied a small series of UC patients treated with first-line PD-1 checkpoint inhibition in order to analyze their characteristics and patterns of response to therapy. Methods: Eleven UC samples were obtained from patients before undergoing therapy with ICIs. Patients were classified according to their benefit from therapy in responders (n=5) and non-responders (n=6). Genomic and immunohistochemistry analyses were performed. Results: Both luminal and basal UC subtypes showed benefit from ICIs. Tumors from non-responders showed increased mutations in chromatin remodelling genes and the amplification of 3q26-28 region. Transcriptome analyses showed that tumors from responders displayed a significant enrichment of genes associated with interferon γ and α response, TNFα via NFκB, genes upregulated by MYC or E2F1, genes involved in G2/M checkpoint and epithelial-mesenchymal transition compared to non-responders. Specific immune cell subsets were present in the tumor microenvironment of tumors from responders and non-responders. Immunohistochemistry showed that none of the immune cell markers analyzed individually was sufficient to discriminate between responders and non-responders. However, the increase in FOXP-3, PD-L1, PD-1, CD8, β2 microglobulin and CD68 and the decrease in CD4 and CD163 cells identified UC patients that responded to ICIs. Conclusions: Our findings confirm that the evaluation of pre-treatment UC tumor samples provides valuable information that could influence treatment decisions. Despite the clinical benefit of PD-1/PD-L1 inhibition in UC, only a fraction of patients benefit from therapy. Our data suggest that responders and non-responders display diverse genomic and transcriptome changes as well as specific immune cell subsets in the tumor microenvironment that can be identified by conventional IHC staining.
Lentiviral interferon: A novel method for gene therapy in bladder cancer.
Authors: Mokkapati Sharada , Duplisea Jonathan J , Plote Devin , Narayan Vikram M , Lim Amy , Metcalfe Michael J. , Dunner Kenneth , Czerniak Bogdan , Nieminen Tiina , Heikura Tommi , Yla-Herttuala Seppo , Parker Nigel , Schluns Kimberly , McConkey David James , Dinney Colin P.N.
Published: March 2019

456

Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. Unlike the adenovirus, LV can infect non-dividing cells and integrate into the host’s genome, making it one of the most efficient gene delivery vectors. The objective of this study was to investigate lentiviral interferon-alpha (LV-IFNα) BLCA gene therapy in preclinical models. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα using a multiplicity of infection (MOI) of 2:1. IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, p53+/- C57/B6 mice were exposed to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) to induce CIS and then treated with LV-IFNα or control virus, and sacrificed when moribund. Results: Efficient LV-IFNα transduction of BLCA cells was observed at an MOI of 2:1, resulting in increased expression of IFNα and its target genes PDL-1, TRAIL, and IRF7 (p<0.001), and reduced cell viability vs. controls (p<0.001). Mechanistically, TRAIL dependent cytotoxicity in the LV-IFNα cells was rescued by Caspase 8 inhibition. βGal expression confirmed efficient transduction of murine urothelium. Urinary IFNα levels were elevated in mice receiving LV-IFNα compared with control virus. BBN mice treated with LV-IFNα had longer overall survival than mice treated with control virus (p=0.04). LV-IFNα induced intratumoral CD8+ T cell infiltration, high expression of PD-L1, and inhibited angiogenesis. Conclusions: LV-IFNα effectively upregulated IFNα target genes, was cytotoxic to murine BLCA cells, and improved the survival of BBN tumor-bearing mice. LV appears to be a promising vector for intravesical gene delivery.
The impact of intratumoral heterogeneity on prognostic biomarkers in localized prostate cancer.
Authors: Brastianos Harry , Murgic Jure , Salcedo Adriana , Chua Melvin Lee Kiang , Meng Alice , Fraser Michael , Brundage Michael Donald , Fleshner Neil Eric , van der Kwast Theodorus , Bristow Robert G. , Boutros Paul Christopher , Berlin Alejandro
Published: March 2019

46

Background: Genomic biomarkers can identify patients that harbour aggressive disease. The utility of these biomarkers is uncertain due to genomic variation between prostate biopsy specimens. To quantify the robustness of genomic biomarkers, we performed spatio-genomic characterization of distinct tumor foci. We scored three validated DNA-based biomarkers of early biochemical recurrence: percentage of genome with a copy number aberration (PGA), a 100-loci biomarker, and an optimized 31- loci biomarker derived from the previous. For each biomarker, we determined their robustness to intratumoral heterogeneity in association with predicting early biochemical recurrence (eBCR; ≤18 months) and long term control (LTC; ≥48 months). Methods: We queried a registry of 1054 patients with high-risk prostate cancer who underwent a radical prostatectomy (RP). We developed a cohort (n = 42) risk matched by clinicopathologic prognostic indices. Half of the patients had eBCR, while the other half had LTC. We profiled multiple tumor foci per patient, analyzing 119 tumor foci. For each focus, CNA profiles were generated, and three biomarker scores were calculated. For each patient and biomarker, we calculated the score of the lowest-score region, the highest-score region, or sampling of all foci and use the mean score. Results: All three biomarkers distinguished LTC from eBCR. PGA scores separated the two groups with an area under the receiver operator curves (AUC) ranging from 0.75-0.80. The 100- and 31-loci signatures, had AUCs ranging from 0.76-0.85 and 0.76-0.80 respectively. Using Cox proportional hazards modeling, we found that PGA was associated with LTC (Hazard ratio (HR) range: 2.56-6.22; p < 0.05. This was replicated for the 100-loci signature (HR range: 3.55-5.23; p < 0.05). The 31-loci detected associations with eBCR independent of how different foci were summarized (log-rank p-value range: 5.1 x 10-4- 5.9 x 10-3). Conclusions: Despite divergence in biomarker scores, all three predicted eBCR. Our study suggests that genomic biomarkers can overcome intratumoral heterogeneity, making discrete samples potentially adequate in patients with high-risk disease to determine the risk of eBCR after radical treatment.
MRI-guided prostate brachytherapy dose escalation to the dominant intraprostatic lesions: A retrospective analysis of urinary toxicity and biochemical response.
Authors: Wakil George , Côté Nicolas , Lymberiou Timothy , Aaron Lorne , Antebi Elie , Arjane Philippe , Derashodian Talar , Do Vien , Jolicoeur Marjory , Nachabe Mahmoud , Van Nguyen Huynh Thu , Duguay-Drouin Patricia
Published: March 2019

47

Background: Magnetic resonance imaging (MRI) allows for delineation of the dominant intraprostatic lesions (DIL) thus minimizing the risk of a geographic miss. At our center, using MRI planning following the brachytherapy implant, the DIL is defined as the gross tumor volume (GTV) and receives at least the prescribed dose. This retrospective analysis studies the biochemical response and urinary symptoms of a MRI-guided escalated dose to the DIL during prostate brachytherapy. Methods: Intermediate- or high-risk patients with a visible DIL on the diagnostic MRI, treated between 2013 and 2016, with combined external-beam radiation therapy (46 Gray) and a high-dose rate whole prostate brachytherapy (15 Gray), were analyzed. Baseline characteristics and dosimetric values were obtained as well as PSA and International prostate symptom score (IPSS) at baseline, 3, 6, 12, 18, 24, 36 and 48 months (mos). Results: A total of 117 patients were studied, of which 58% were intermediate-risk and 42% high-risk. Median follow-up was 31 months (10-69 months). The biochemical progession-free survival (bPFS) was 97.4%. The median GTV D100 (dose to 100% of the GTV) and CTV V100 (percentage of the clinical target volume, defined as the whole prostate, receiving 100% of the prescribed dose) were 119% and 97.97%. The median PSA at 12, 24, 36 and 48 months for all patients and for patients treated without androgen deprivation therapy (ADT), was 0.18, 0.11, 0.06, 0.07 μg/L, and 0.73, 0.35, 0.1, 0.08 μg/L, respectively. The median IPSS score at baseline was 6 and remained stable over time. Conclusions: MRI-guided dose escalation to the GTV during brachytherapy boost yields an excellent bPFS and a rapid PSA drop without an increase in urinary symptoms. [Table: see text]