bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective trial of adjuvant therapy after radical cystectomy for locally advanced bladder cancer: Analysis of the squamous cell carcinoma subgroup.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Zaghloul Tarek , Abdalla Ahmed , William Hany , Khaled Hussein Mustafa , Hwang Wei-Ting , Baumann Brian Christopher
Published: February 2020

524

Background: The role of adjuvant therapy after radical cystectomy (RC) is not well-defined for squamous cell carcinoma (SqCC) of the bladder. Several studies suggest limited efficacy for chemo while adjuvant RT improved disease-free survival (DFS) vs. observation in a previous trial. In this study, we report a post-hoc subgroup analysis of SqCC to compare adjuvant therapies. We hypothesized that adjuvant RT would improve DFS vs. chemo for locally advanced bladder cancer (LABC) (≥pT3N0-N+). Methods: A randomized phase III trial was opened to compare adjuvant RT vs. sandwich chemo+RT after RC for LABC at the NCI in Cairo. A 3rd arm, adjuvant chemo, was added later. Bladder cancer patients ≤70 y/o with ≥1 of the following (pT3b/pT4a, grade 3, or pN+) with negative margins after RC were eligible. RT was delivered to the pelvis with 3D conformal RT (45Gy in 1.5Gy BID). Chemo+RT included 2 cycles of gemcitabine/cisplatin before & after RT. Chemo alone included gem/cis x 4. Primary & secondary endpoints were DFS and overall survival (OS). Results: 198 patients were enrolled. 82 (41%) had SqCC & 77 had ≥pT3N0-N+ disease and were analyzed (34 RT, 27 chemo+RT, & 16 chemo). Median age was 53. Median F/U was 20 months (1-127 months). The RT vs chemo arms were well-balanced except for number of nodes removed (mean 12 vs. 9, p=0.05). On univariable analysis, RT was not significantly associated with DFS [HR 0.56 (95%CI 0.26-1.21), p=0.14]. On multivariable analysis, only pN+ was significant. 2-yr DFS was 60% for RT & 43% for chemo (log-rank p=0.13). OS was improved with RT (2-yr OS 71% vs. 43%, p=0.04). There was one death during treatment (chemo-related). There was no significant difference in DFS or OS for RT vs. chemo+RT with 2-yr DFS of 59% & 55% (p=0.65) & 2-yr OS of 67% & 74% (p=0.16). Conclusions: On post-hoc analysis, RT for locally advanced bladder SqCC was associated with significantly improved OS vs. adjuvant chemo. We hypothesize that the inferior OS with chemo was due to increased toxicity & limited efficacy. There was no difference in outcomes for RT vs. chemo+RT. Adjuvant RT should be a standard option for ≥pT3 SqCC of the bladder after RC. Alternative chemo agents for SqCC should be explored. Clinical trial information: NCT01734798.
Smoking status and PD-L1 mRNA-expression as a predictor of response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer.
Authors: Reike Moritz , Juette Hendrik , Wirtz Ralph , Erben Philipp , Tully Karl , Eckstein Markus , Weyerer Veronika , Hartmann Arndt , Kriegmair Maximilian , Wezel Felix , Bolenz Christian , Tannapfel Andrea , Noldus Joachim , Roghmann Florian
Published: February 2020

530

Background: Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival. Patients with a pathological complete response (pCR) usually have the best prognosis. In the literature, impaired response to immune checkpoint therapy has been reported in active smokers. The aim of our study was to examine the association of smoking status with pCR at RC after NAC. Moreover, we investigated the interaction of smoking status and Programmed Death Ligand 1 (PD-L1) mRNA expression at transurethral resection (TUR) and pCR prediction at RC after NAC. Methods: Clinical Data and formalin fixed paraffin embedded tumor tissue samples from TUR and RC of 49 patients with MIBC were retrospectively analyzed. Using RT-PCR PD-L1 mRNA expression was measured in 40-∆Ct values and normalized against the control gene CALM2. Smoking status was defined as never, former and active. After NAC, RC was performed and the specimens were evaluated for pCR, defined as ypT0N0M0. Statistical analyses comprised nonparametric and chi2 testing, partition models and spearman correlation analyses. Results: The study cohort had a median age of 63 years and consisted of 38/49 (78%) males. Regarding smoking status 11/49 (22%) were never, 17/49 (35%) were former and 21/49 (43%) were active smokers. After NAC, 17/49 patients (35%) had a pCR. Never/former smokers did not show a higher rate of pCR compared to active smokers (43%vs.24%, p=0.16). Comparing smoking status (never/former vs. active smokers) within the subgroup showing high PD-L1 expression (≥32.1∆Ct), a higher rate of pCR was found in never/former smokers (58% vs. 25%, p=0.047). Conclusions: Never and former smokers with MIBC that show high PD-L1 mRNA expression patterns are more likely to show pCR at RC after NAC. Smoking cessation is important for the management of MIBC patients undergoing NAC and RC.
The clinical prognostic impact of APOBEC3B protein expression in metastatic urothelial carcinoma.
Authors: Kim Hyunho , Kim In-Ho , Yim Kwangil
Published: February 2020

544

Background: APOBEC3 enzymes function as a carcinogenic mutagens resulting in substitution of Cytosine to Thymine or Guanine in tCw motif. Mutation signature in urothelial (UC) carcinoma is mediated by APOBEC3 more than smoking which is well known as a risk factor. This study aimed to explore the association of APOBEC3 expression with survival in metastatic UC (mUC). Methods: We examined 94 patients treated with gemcitabine plus platinum chemotherapy for mUC. APOBEC3A and 3B protein expression was measured using immunohistochemistry from archived formalin-fixed paraffin-embedded tissue which was obtained before chemotherapy. Immunohistochemistry results were evaluated by H-score. The cutoff levels of APOBEC3A and 3B expression were calculated with time dependent ROC analysis. Results: APOBEC3B high expression exhibited longer overall survival (OS) and progression-free survival (PFS) than low expression (median OS: 16 months vs 9 months, p=0.032; median PFS: 7 months vs 4 months, p=0.017). APOBEC3A high expression was associated with longer OS (median OS: 13 months vs 9 months, p=0.036; median PFS: 6 months vs 4 months, p=0.405). Disease control (CR/PR/SD) rate (DCR) was higher in APOBEC3B high group than low group (DCR, 79.4% and 57.1%, respectively, p=0.045). Mean H-score of APOBEC3B was higher in disease control group than progressive disease group (mean H-score, 125.3 vs 101.3, p=0.029). APOBEC3A expression was not correlated with chemotherapy response. There was not a significant correlation between APOBEC3A and APOBEC3B (Spearman correlation coefficient=0.111, p=0.319). Conclusions: mUC with APOBEC3B high expression may be associated with better response from gemcitabine plus platinum chemotherapy and longer overall survival. Further functional studies are warranted to clarify the clinical significance of APOBEC3B protein expression in mUC.
Landscape of cyclin pathway genomic alterations across 7,207 non-prostate genitourinary tumors.
Authors: Fontes Jardim Denis Leonardo , Millis Sherri Z. , Woo Michele Sue-Ann , Ross Jeffrey S. , Ali Siraj Mahamed , Kurzrock Razelle
Published: February 2020

549

Background: Cyclin pathway genomic alterations can be a possible therapeutic target as well as a resistance mechanism for therapy. We describe the landscape of cyclin alterations (alt) in non-prostate genitourinary (GU) cancers. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation tissuesequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition). Results: Alterations in any cyclin pathway genes were found in 37.9% of bladder/urothelial, 33.8% of testicular, 25.2% of penile and 24.6% of kidney cancers. Most alterations were copy number changes and frequencies varied substantially for each tumor type (Table). The high number of cases permitted identification of interesting patterns of outliers for each histology (examples: testis rhabdomyosarcoma and leydig tumor, 50% and 54.5% CDK4 alt; ureter urothelial, 17% CCND1 amp; bladder squamous, 41% CDKN2A del; kidney malignant rhabdoid, 90% SMARCB1 alt; urethra urothelial, 14.7% CCNE1 alt). Alterations in possible resistance genes RB1 and CCNE1 were more frequent in bladder cancers (especially with a neuroendocrine component). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alt in cyclin activating and resistance genes (odds ratio for bladder 0.17, p<0.001; OR testis 0.49, p<0.001 and OR kidney 0.45, p<0.001). Conclusions: Cyclin pathway activating and resistance genomic alt are variable in non-prostate GU tumors. Activating alt often occur without simultaneous resistance alt. Our data may inform opportunities for targeted therapy, especially for rare subtypes.[Table: see text]
Serial circulating tumor DNA (ctDNA) measurement to predict progression in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Villamar Dario Martin , Shohdy Kyrillus , Cao Yen Thi Kim Hong , Trieu Janson , Price Kristin Sedgwick , Nagy Rebecca , Molina Ana M. , Tagawa Scott T. , Nanus David M. , Sternberg Cora N. , Sonpavde Guru , Grivas Petros , Vogelzang Nicholas J. , Faltas Bishoy Morris
Published: February 2020

558

Background: Next-generation sequencing (NGS) of plasma ctDNA is a promising non-invasive method to detect somatic genomic alterations (GAs). We investigated whether serial ctDNA measurements can predict disease progression and map the molecular evolution of advanced UC (aUC) through successive treatments. Methods: We analyzed cohorts from 2 academic centers, WCM and UNLV, with serial (≥2) ctDNA targeted NGS using the Guardant360 panel of 73 genes, ctDNA was collected within four weeks of restaging scans. Non-progressive disease (non-PD) was defined as stable disease or radiological response. Results: Our cohort included 176 individual ctDNA samples (median 3/patient) from 52 patients (38 men), the median age was 69 (range 38-88), 38 pts (73%) had metastatic disease, 20 pts (38.5%) had visceral metastases and 35 pts (67%) received first-line platinum-based combination chemotherapy for aUC. The median number of lines of therapy was 2. 49 pts (94%) had detectable GAs in at least one ctDNA sample. Most commonly identified GAs involved TP53 (67%), PIK3CA, EGFR, and ERBB2 (each in 19%). FGFR3 GAs were identified in 9 pts (17%, 2 FGFR3-TACC3 fusions, and 7 SNVs, including two novel mutations P250R and K650M). The mean variant allele fraction (VAF) significantly decreased in pts with non-PD (80 non-PD events) compared to pts with PD (45 PD events) with a mean VAF decrease of 2.06 % (p< 0.0001). This effect was consistent independent of the number of prior lines of therapy. The mean number of GAs per patient at each time point was significantly decreased in non-PD vs. PD group (2.8 vs. 4.4, p=0.004). Pts with detectable VAF in somatic alterations at any time point during the disease course had shorter overall survival (HR 1.18, 95% CI: 1.08 – 1.28, p<0.0001). Pts with sustained partial or complete responses were more likely to have VAF ≤0.2% suggesting that molecular remission was associated with clinical remission. Conclusions: Serial ctDNA testing is a promising dynamic tool to assess clonal evolution and predict progression in aUC pts.
Microsatellite instability (MSI-H) in metastatic urothelial carcinoma (mUC): A biomarker of divergent responses to systemic therapy.
Authors: Sarfaty Michal , Teo Min Yuen , Al-Ahmadie Hikmat , Funt Samuel Aaron , Lee Chung-Han , Aggen David Henry , Solit David B. , Ratna Neha , Regazzi Ashley Marie , Hechtman Jaclyn Frances , Zehir Ahmet , Rosenberg Jonathan E. , Bajorin Dean F. , Iyer Gopa
Published: February 2020

566

Background: MSI frequently arises from deficiencies in mismatch repair mechanisms (dMMR) and are associated with higher response rates to anti-PD1/PDL1 checkpoint inhibitors (CPI) in different cancer types, including mUC (Iyer et al, ASCO 2017). Here, we sought to (1) assess the platinum-based chemotherapy response in MSI-H mUC, and (2) present an updated analysis of CPI response in MSI-H mUC from a database of > 1000 sequenced UC. Methods: From an institutional database of UC tumors genomically characterized using the MSK-IMPACT assay, we identified tumors with high MSIsensor score > 10 (MSI-H) for in-depth analysis. MSIsensor has been shown to correlate strongly with MSI status (Middha et al, JCO Precis Oncol 2017). Patient and disease characteristics, as well as response to (1) platinum-based chemotherapy and (2) CPI were analyzed. Results: A total of 1,333 UC from 1,194 pts were sequenced. 26 pts (2%) had an MSI score > 10. Of these, 20 (77%) were male, 17 (65%) were current or former smokers, and 20 (77%) had upper tract UC. 23/26 pts had alterations in MMR genes (MSH2, n = 15; MLH1, n = 6; MSH6 and PMS2, n = 1), 18 of which underwent germline testing which was positive in 14 cases (78%). 10/26 MSI-H patients developed metastatic UC. Six received first-line platinum-based chemotherapy with median PFS of 2.6 months, four with primary progressive disease. Ten patients received CPI in the mUC setting, two of them in combination with non-CTLA4 agents, six as second or third-line therapies, two following recurrence of disease within 12 months of peri-operative chemotherapy, and two as first line therapy. With a median follow-up of 24.3 months, PFS rate was 90% and 77% at 12 and 24 months, respectively, with near-complete or complete response in 9 patients. Conclusions: MSI-H status in UC predicts deep and durable responses to CPI and is associated with inferior chemotherapy responses. CPI should be considered for first-line treatment in this subset of patients. Pts with somatic MSI-H bladder or upper tract UC should be offered genetic testing for Lynch syndrome.
Feasibility of finding circulating tumors cells and assigning PD-L1 receptor status using single-cell technology combined with Celsee Genesis system.
Authors: Alanee Shaheen Riadh , Sharma Vishal , Chow William , Patterson Bruce Kendrick
Published: February 2020

567

Background: enumerating circulating tumor cells (CTC) may improve our ability to differentiate between localized and metastatic bladder cancer (BC) and predict response to systemic therapies. However, previously used CTC identification platforms had limited utility in managing patients diagnosed with this disease because they lacked the appropriate sensitivity level. Also, they did not report on the PD-L1 receptor status, which is becoming an essential component of modern immunotherapy of BC. Methods: We used a novel device to enrich and retrieve CTCs from blood samples of patients with high grade and low-grade BC, as well as benign conditions, treated with cystectomy by using a microfluidic chip. The Celsee Genesis (Celsee Inc) captures CTCs with high sensitivity and allows the captured CTCs to be retrieved for molecular analysis. It uses the microfluidic chip, which has approximately 56,320 capture chambers. Based on differences in cell size and deformability, each chamber ensures that small blood cells escape while larger CTCs of varying sizes are trapped and isolated in the chambers. PD-L1 expression on the isolated tumor cells was then evaluated using 4-color single-cell technology (IncellDX Inc.) directly on the chip. Results: Ten bladder cancer (5 low grade (LG) and 5 high grade (HG) disease) and two benign bladder pathology patients provided blood samples before their cystectomy. Circulating tumor cells were found in 3 patients (two LG and one HG disease). CTCs were four times higher in the HG sample than in the LG samples. PD-L1 expression was high on CTCs isolated from the HG patient’s blood sample and lower in the two LG blood samples. No CTCs were detected in patients with benign bladder pathology. Conclusions: Our results show the feasibility of using novel, high sensitivity CTC detection and PD-L1 single cell measuring technology in patients with BC. We also show that this technology has a potentially high sensitivity level for detecting CTC in patients with bladder malignancies by detecting low levels of CTCs in low-grade disease. More extensive studies are planned to validate our findings.
Association of metagene based on gene expression with response to atezolizumab (atezo) for metastatic urothelial carcinoma (mUC).
Authors: Ravi Arvind , Ravi Praful , Nassar Amin , Abou Alaiwi Sarah , Curran Catherine , Mariathasan Sanjeev , Tayama Daren , Shen Xiaodong , Banchereau Romain , Price Rich , Getz Gad , Sonpavde Guru
Published: February 2020

569

Background: Despite the benefits of PD1/L1 inhibitors in metastatic urothelial carcinoma (mUC), the durable benefits accrue mostly to a minority of patients (pts) who attain ≥partial response (PR) by RECIST 1.1. There is a pressing need to identify pts with a low probability of response, who may be diverted to other regimens or trials. Biomarkers associated with response such as PD-L1 expression, intrinsic subtype and tumor mutational burden (TMB) are suboptimal. We studied the ability of agnostic gene expression analysis for association with response. Methods: A retrospective cohort of FFPE tumor samples that underwent RNAseq utilizing pts from the phase II IMvigor210 trial were analyzed. In this study, pts received atezo, a PD-L1 inhibitor, in either the post-platinum or first line cisplatin-ineligible setting. All reads were collapsed to gene level transcript per million (TPM) values, followed by feature selection based on enrichment observed in patients with PR vs progressive disease (PD) as well as complete response (CR) vs PD. A transcriptional biomarker was then designed based on these gene-level enrichment scores, followed by generation of a synthetic “metagene” reflecting a composite of the top single gene predictors. Results: A total of 298 pts were evaluable from the IMvigor210 dataset. The favorable and unfavorable composite biomarker ‘metagene’ was robustly associated with high or low probability of ≥PR, regardless of line of atezolizumab therapy (Table). Area Under the Curve (AUC) for this biomarker was 0.73. Notably, an indeterminate category of the metagene was associated with ≥PR in an intermediate proportion of pts, consistent with meaningful discrimination of response categories. Conclusions: A metagene based on tumor gene expression robustly identified pts with mUC who exhibited ≥PR with atezo. With validation across other PD1/L1 inhibitors and refinement in combination with clinical factors, the metagene may enable the selection of the most suitable pts with mUC for PD1/L1 inhibitors.[Table: see text]
Genomic correlates of response to PD-1 axis inhibitors (IO) in metastatic urothelial cancer (mUC) using explainable artificial intelligence (AI).
Authors: Wesolowski Sergiusz , Nussenzveig Roberto , Santos Victor Sacristan , Esther John , Goel Divyam , Swami Umang , Gupta Sumati , Maughan Benjamin Louis , Yandell Mark , Grivas Petros , Agarwal Neeraj
Published: February 2020

570

Background: AI is increasingly being used in clinical cancer genomics research. Probabilistic Graphical Models (PGMs) are AI algorithms that capture multivariate, mutli-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can identify clinical and genomic features that correlate with IO response in patients (pts) with mUC. Methods: In this retrospective study eligibility criteria were: diagnosis of mUC, receipt of IO for mUC, comprehensive genomic profiling data available from CLIA certified labs. The Bayesian Network (BN, PGM based AI) was used to discover clinical characteristics and selected genomic alterations relevant to IO response by RECIST 1.1 (investigator assessed). Results: Overall, 95 pts (73 men) with mUC were evaluated. 45 (47%) were ever smokers.The presented BN correctly captured the clinical landscape of mUC explaining significant relationship between included variables (p<0.0001). Ever smokers and pts with de novo metastasis had higher TMB and better response to IO. Inactivating MLL2 alterations were more prevalent in non-smokers, and negatively correlated with response to IO. FGFR3 alterations did not predict response to IO. Significant associations are presented in Table. Conclusions: These hypothesis-generating data (by a novel approach, i.e. PGM based AI) showed that smoking and high-TMB were associated with improved response to IO; in contrast, inactivating MLL2 alternations and visceral metastasis predicted inferior response. FGFR3 alterations did not correlate with response. This model validated previous findings and found new hypothesis-generating relationship, such as altered MLL2 gene; external validation is needed.[Table: see text]
Comparing progression-free survival (PFS) in second-line (2L) urothelial carcinoma (UC) treatments from single-arm trials: Importance of using appropriate methods.
Authors: Kapetanakis Venediktos , Prawitz Thibaud , Schlichting Michael , Ishak K. Jack , Phatak Hemant , Kasturi Vijay , Yu Ting , Bharmal Murtuza
Published: February 2020

573

Background: Population-adjusted comparisons of PFS from single-arm trials of cancer treatments can be derived using matching-adjusted indirect comparison (MAIC); however, results are still susceptible to bias, particularly if the trials had different tumor assessment schedules (favoring longer intervals). This is shown with an MAIC of avelumab vs atezolizumab, nivolumab, durvalumab, pembrolizumab or chemotherapy in 2L UC. Methods: The MAIC used patient-level data for avelumab from the JAVELIN Solid Tumor trial (NCT01772004) and compared PFS with published curves for other treatments to obtain population-adjusted hazard ratios (HRs). The first assessment was scheduled at 6 weeks for avelumab and durvalumab and at 8 or 9 weeks for the others. The MAIC was repeated after aligning the first assessment time for avelumab to each comparator’s schedule with the Assessment Schedule Matching (ASM) method. Results: Naïve analyses (Table) suggest similar PFS for avelumab vs comparators. MAIC based on population adjustment (PA) altered the HR of avelumab vs atezolizumab and nivolumab (23.0% and 9.2% reductions in HR, respectively) but had little effect in other comparisons. ASM adjustment led to further changes in HR (13.2-32.7% reductions from naïve) favoring avelumab in MAICs where schedules differed. Of note, assessment schedule differences fully accounted for differences in PFS between avelumab and pembrolizumab. Conclusions: Indirect comparisons of PFS from single-arm trials must include adjustment for differences in both population characteristics and tumor assessment schedules. In this 2L UC MAIC, adjustment reversed some naïve comparisons, revealing more favorable PFS with avelumab up to 30%. Clinical trial information: NCT01772004. [Table: see text]
The impact of marital status on the survival of transitional cell carcinoma of the bladder.
Authors: Saad Anas M. , Baidoun Firas , Gad Mohamed M. , Ruhban Inas A. , Jazieh Khalid , Al-Husseini Muneer J. , Ornstein Moshe Chaim , Rini Brian I. , Gupta Shilpa
Published: February 2020

578

Background: Marital status is one of the multiple lifestyle factors that affect the survival of several malignancies. Prior literature has demonstrated that married individuals have better survival in cases of transitional cell carcinoma (TCC). In this study, we aim to demonstrate the association in a large cohort of patients. Methods: Data of TCC patients with known marital status who were diagnosed between 1973 and 2015 in the US was obtained using the Surveillance Epidemiology and End Results (SEER) database. We compared the overall and cancer-specific survival of patients according to their marital status using Kaplan-Meier test and multivariable covariate-adjusted Cox models. Results: We reviewed 204,862 TCC patients, of which 64.26%, 10.64%, 1.01%, 7.31%, and 16.78% were married, single, separated, divorced, and widowed, respectively. Married patients had the highest overall survival (median 123 months), followed by single patients (median 111 months), divorced (median 102 months), separated (median 60 months), and widowed (median 43 months). Bladder cancer-specific survival followed relatively similar trends with married patients having significantly better survival when compared to other groups. When we adjusted for age, sex, race, stage, grade, and undergoing cancer-targeted surgery, married patients had better survival outcomes when compared to single patients (HR = 1.322, p-value < 0.001), separated patients (HR = 1.409, p-value < 0.001), divorced patients (HR = 1.358, p-value < 0.001), and widowed patients (HR = 1.242, p-value < 0.001). Conclusions: Our results demonstrate a clear survival advantage in cases of transitional cell carcinoma of the bladder with married individuals having the highest overall and cancer-specific median survival. These results shed the light on the lifestyle and the psychosocial factors, including the social support that married patients may have comparing to unmarried patients, and their effect on the disease prognosis and survival. Understanding the social and psychological factors associated with the observed disparity may help enhance management plans for affected patients.
Genitourinary oncology referral patterns to the cancer associated thrombosis clinic: The Cleveland Clinic experience.
Authors: Sheng Iris Yeong- Fung , Angelini Dana E , Khorana Alok A. , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. , Ornstein Moshe Chaim , Gupta Shilpa
Published: February 2020

583

Background: Cancer related thrombosis affects ~20% of all cancer patients. It is our standard practice to refer cancer patients with suspected venous thromboembolism (VTE) to our Cancer Associated Thrombosis (CAT) clinic. Referrals are based on a clinical suspicion of VTE or a Khorana score ≥3. We sought to evaluate the characteristics of patients with genitourinary (GU) cancer referred to the CAT clinic and their association with immunotherapy. Methods: The study population comprised of all cancer patients referred to the CAT clinic with a diagnosis of prostate cancer (Pca), bladder cancer (BC) or renal cell cancer (RCC) from August 1, 2014 to October 15, 2019. Results: Of the 147 patients with GU cancers referred to CAT clinic, 43 had a VTE (14/40 BC, 14/44 RCC, 15/63 PCa). Of which, 83% were DVT, 5% were PE, and 12% had both. The majority had stage 4 disease (98%), no prior clotting history, and ECOG 0-2 (86%). Average BMI was 28.63 and 22 patients had smoking histories (average 11 pack years). Major histology per cancer type were adenocarcinoma (100%) in PCa, 86.7% clear cell in RCC and 85.7% urothelial carcinoma in BC. Lower extremity pain or swelling (67%) was the major reason for referral. Thirty-four of the 43 patients were on active treatment; 7 patients on immunotherapy (average 4.9 months) and 13 patients on chemotherapy (average 2.6 cycles) at the time of VTE diagnosis. Of the chemotherapy regimens, patients were on the combination of gemcitabine with carboplatin (54%), docetaxel (23%), or cabazitaxel (23%). Atezolizumab was the most commonly used immunotherapy agent (57%). Other immunotherapy agents associated were nivolumab (29%) and the combination of ipilimumab with nivolumab (14 %). There was no VTE-related mortality. Conclusions: Our single center experience shows 16% of VTE events in patients with GU cancers were associated with immunotherapy and 33% were associated with cytotoxic chemotherapy. There is a growing body of literature exploring the association between thromboembolic events and immunotherapy. As more patients with GU cancers are treated with immunotherapy, it will be interesting to see how this influences the rate of CAT clinic referral and prevalence rates of VTE.
Prevalence and landscape of actionable genomic alterations in renal cell carcinoma.
Authors: Attalla Kyrollis , DiNatale Renzo G. , Reznik Eduard , Fong Christopher , Sanchez-Vega Francisco , Silagy Andrew W. , Weng Stanley , Coleman Jonathan , Lee Chung-Han , Carlo Maria Isabel , Russo Paul , Chan Timothy An-thy , Motzer Robert J. , Schultz Nikolaus D. , Voss Martin H , Hakimi A. Ari
Published: February 2020

616

Background: We report our experience with next-generation sequencing to characterize the prevalence and genomic landscape of actionable genomic alterations in renal cell carcinoma (RCC). Methods: A query of our institutional clinical sequencing database was performed to include tumor samples sequenced across all cancers. Actionable alterations with clinical or biologic evidence supporting an association with response to targeted therapy were stratified by level of evidence using an oncology knowledge database (OncoKB). Results: Data from 35,668 patients was included, and the 15 cancer types with the highest prevalence of actionable alterations were selected for subsequent analysis (28,027 patients). Of these cancers, RCC ranked 13th in prevalence of actionable alterations. Of 708 RCC samples included, 259 (37%) were from metastatic sites. However, of the remaining 449 primary samples, 208 (29%) belonged to patients who had metastatic disease at the time of sequencing. Although 69% of patients with any RCC harbored at least one known oncogenic mutation, only 90/687 (13%) harbored alterations for which compelling clinical data currently exist to justify the use of a standard or an investigational agent (levels of evidence 1 to 3B). This represents an increase from the previously reported prevalence (5% in 2017). The most common histologic subtype, clear cell RCC harbored the vast majority of actionable alterations (52/421; 12%). Regarding the specific genes that harbor these alterations, 31 level 2A alterations were identified, all of which were TSC1/TSC2 mutations; 30 level 2B alterations were identified, of which PIK3CA (22) and BRCA1/BRCA2 (5) mutations were most common; 11 level 3A alterations, all of which were MTOR mutations, and 8 level 3B alterations, of which AKT1 (4) mutation was most common. Conclusions: Although the prevalence of actionable mutations in RCC seems to have doubled in recent years, the role of genetic testing in identifying candidates for targeted therapy in RCC is currently limited relative to other cancer types, emphasizing the need for additional research in this area to further inform targeted therapy decisions.
Overall survival results for durvalumab and savolitinib in metastatic papillary renal cancer.
Authors: Suarez Rodriguez Cristina , Larkin James M. G. , Patel Poulam , Valderrama Begona Pérez , Rodriguez-Vida Alejo , Glen Hilary , Thistlethwaite Fiona , Ralph Christy , Srinivasan Gopalakrishnan , Mendez Vidal Maria Jose José , Carter Abigail , Tyson Charlotte , Prendergast Aaron , Mousa Kelly , Powles Thomas
Published: February 2020

619

Background: There is a strong rationale for investigating MET and PD-L1 inhibition in metastatic papillary renal cancer (PRC). We previously reported response rates (RR) and progression free survival (PFS) for savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) together. Here we report overall survival (OS) data available 12 months after the last patient was enrolled. Methods: This single arm phase I/II trial explores durvalumab (1500mg Q4W) and savolitinib (600mg OD) together in PRC, with a 4wk savolitinib run in. Treatment naïve or previously treated patients with metastatic PRC were included. Confirmed RR (RECIST v1.1), PFS, tolerability (CTCAE v4.03) and overall survival (OS) were analysed. MET and PD-L1 biomarkers were explored (NCT02819596). Results: 42 patients were enrolled with 41 receiving at least one dose of study treatment. Safety and efficacy analyses were performed on these 41 patients. The median follow up was 14.3 months. IMDC good, intermediate and poor risk disease occurred in 29%, 63%, and 7% of patients respectively. Overall confirmed RR was 27% while median PFS was 4.9 months (95% CI: 2.5 – 12.0 months). Median OS was 12.3 months (95% CI: 5.8 – 21.3 months). Confirmed RR and median OS in the previously untreated cohort (N=27) were 33% and 12.3 months (95% CI: 4.7 – not reached (NR) months) respectively. Treatment related Grade 3/4 toxicity occurred in 34% of patients. No new safety signals were seen. PD-L1 and MET expression were not associated with higher RR (25% and 40% respectively) or longer OS. Conclusions: The combination of savolitinib and durvalumab has clinical activity in PRC and outcomes were not enhanced in biomarker positive cancers. Clinical trial information: NCT02819596.
The impact of metastasis location on overall survival among patients with renal cell carcinoma.
Authors: Patel Devin , Ghali Fady , Meagher Margaret , Meagher Margaret , Bradshaw Aaron , Patel Sunil , Keiner Cathrine , Miller Nathan , Dutt Raksha , Murphy James Don , Derweesh Ithaar
Published: February 2020

621

Background: Current staging guidelines define all patients with metastatic renal cell carcinoma (RCC) as a singular group. We sought to compare the impact of metastatic disease location on overall survival (OS) in patients with RCC. Methods: We queried our institutional database of consecutive patients with metastatic RCC. A confirmatory analysis was performed using the National Cancer Database (NCDB) for cases between 2010 to 2015. Only cases from which all metastatic disease location was known were used. Patients were grouped into having brain or bone metastases, liver or lung metastases or other metastases. From our institutional database, we performed a univariate analysis to determine the impact of metastasis location on OS. From the NCDB, univariable and multivariable Cox proportional hazards and Kaplan-Meier survival analysis with log-rank testing was performed. Multivariable models were adjusted for age, comorbidity, race, gender, and treatment with either palliative care, chemotherapy or immunotherapy. Results: A total of 95 patients were analyzed from our institutional database, with 30 (31.9%) having brain/bone metastases, 20 (21.3%) having lung/liver metastases, and 44 (46.8%) having other site metastases. On univariate analysis, patients with brain/bone metastases had significantly worse OS (HR 1.87; 95% CI 1.01-3.47). However, no significant difference was seen in patients with liver/lung metastases (HR 1.44; 95% CI 0.64-3.27). A total of 25,528 patients met inclusion for our NCDB analysis, of which 12,119 (47.5%) had brain/bone metastases, 10,004 (39.2%) had liver/lung metastases, and 3,405 (13.3%) had other site metastases. On univariate analysis, patients with lung/liver (HR 1.46; 95% CI 1.38-1.53) and patients with bone/brain (HR 1.69; 95% CI 1.60-1.77) had progressively worse OS with non-overlapping confidence intervals. Multivariable analysis again showed that patients with lung/liver disease (HR 1.51; 95% CI 1.43-1.59) and brain/bone disease (HR 1.66; 95% CI 1.60-1.75) had progressively worse OS. Conclusions: Our results highlight the heterogeneity of patients with metastatic renal cell carcinoma. Location of metastatic disease may drive differences in survival.
Progression-free survival (PFS) and overall survival (OS) across ethnicities for patients with metastatic renal cell carcinoma (mRCC) receiving targeted therapies (TT) as first-line (1L) treatment.
Authors: Salgia Nicholas , Dizman Nazli , Bergerot Paulo Gustavo , Bergerot Cristiane Decat , Hsu Joann , Pal Sumanta K.
Published: February 2020

645

Background: Recent efforts have sought to characterize differences in clinical and pathological characteristics across ethnicities in mRCC (Batai et al CGUC 2018), however, the relationship between ethnicity and treatment outcomes has yet to be explored. We sought to compare survival outcomes across ethnic groups for patients receiving 1L TT for treatment of mRCC. Methods: Patients receiving 1L systemic treatment for mRCC were retrospectively identified from a single institution database from 2009 to present. Patient ethnicity data were collected from electronic health records. Due to the demographics of the patient population, ethnicity was categorized as Non-Hispanic Caucasian American (CA), Hispanic American (HA), or Asian American (AsA). Patients prescribed tyrosine kinase and/or mTOR inhibitors as 1L therapy were included for analysis. PFS and OS were analyzed across ethnic groups and comparisons were performed using the Kaplan Meier Survival Function in SPSS. Results: Of 294 (77:217 F:M) patients with documented survival data, 183 (62%) were CA, 82 (28%) HA, and 29 (10%) AsA. The most frequently used TTs were sunitinib (63%), temsirolimus (10%), pazopanib (7%), sorafenib (5%), and cabozantinib (4%). Median PFS for CA was 5.6 months (95% Confidence Interval [CI]: 4.1-7.1) vs. 4.7 months (95% CI: 3.1-6.2) for HA vs. 4.7 months (95% CI: 2.1-7.3) for AsA. Median OS was 32.0 months (95% CI: 26.2-37.8) for CA vs. 31.7 months (95% CI: 21.1-42.4) for HA vs. 51.7 months (95% CI: 31.6-71.8) for AsA. No significant difference in PFS or OS was calculated across the three ethnic groups (p=0.652 and p=0.435, respectively). Conclusions: The lack of a statistically significant difference in both PFS and OS across ethnic groups is a promising assessment for the current landscape of health disparities in mRCC. As these data are distinct from recent findings identifying disparities in other malignancies (e.g., prostate cancer), multicenter collaborations should be encouraged to validate these findings.
The role of cytoreductive nephrectomy (CN) for patients with metastatic renal cell carcinoma (mRCC) in the setting of retroperitoneal lymphadenopathy: An analysis of the National Cancer Database (NCDB).
Authors: Reddy Akshay , Sparks Andrew D , Whalen Michael Joseph
Published: February 2020

688

Background: Recent evidence has suggested systemic therapy alone (ST) may be comparable to CN in treating mRCC. This study aims to understand oncologic outcomes and survival of those with node positive mRCC treated with ST compared to CN and explore the role of LAD at the time of surgery. Methods: A retrospective cohort analysis of patients who had undergone either ST or CN for clinically node-positive mRCC was performed using the NCDB. The CN group was subdivided into no LND vs. LND (based on reported lymph node yield, “LNY” (i.e. 0 vs. ≥1). Demographic and clinicopathological variables were compared to adjust for confounding covariates in multivariable analysis. Patients who underwent palliative treatments or LAD without nephrectomy were excluded. Results: The majority of CN were performed via open approach (70.1%). CN was associated with decreased mortality hazard relative to ST, while no difference in survival was detected between LAD and no LAD (Table). Median LNY was 2. Inpatient stay was significantly longer for LAD relative to no LAD (median 5 vs. 4 days; P=0.02). CN was associated with increased odds of 30 day hospital readmission relative to ST (aOR=8.6; 95% CI: 5.5 – 13.4; P<0.01), while LAD was significantly associated with decreased odds of 30 day hospital readmission relative to no LAD (aOR=0.6; 95% CI: 0.4 – 0.9; P=0.02). Conclusions: CN is associated with a significant survival advantage but potentially greater complications compared to those receiving ST in node-positive mRCC. Despite offering diagnostic information via a more aggressive approach, there does not appear to be therapeutic benefit of LAD with CN in the metastatic setting where patients receive concomitant ST.[Table: see text]
Transcriptomic profiling as proof of concept for investigation of collecting duct carcinoma (CDC).
Authors: Procopio Giuseppe , Verzoni Elena , Sepe Pierangela , Mennitto Alessia , Claps Melanie , Guadalupi Valentina , Stellato Marco , Zattarin Emma , De Braud Filippo G. , Sensi Marialuisa , Gargiuli Chiara , Dugo Matteo
Published: February 2020

714

Background: Collecting duct carcinoma is a rare, highly aggressive and molecularly uncharacterized kidney disease with poor outcome. To date, no standard therapies are available and treatment choice is based on retrospective data. Identifying molecular features of this tumor could provide a biologic rationale for novel targeted systemic therapies. Methods: Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissues of 6 CDCs, 5 clear cell renal carcinomas (ccRCCs) and 4 adjacent normal tissues. Samples were profiled by GeneChip Human Transcriptome Array 2.0 (Affymetrix) and constituted the Istituto Nazionale dei Tumori (INT) dataset. Data were pre-processed using the robust multi-array average method and differentially expressed genes were identified according to the limma pipeline. Genes with a false discovery rate < 0.25 were selected. Pathway analysis was performed by gene set enrichment analysis (GSEA), single sample (ss) GSEA, DAVID Bioinformatics Resources 6.8 and Pathfinder Bioconductor package. Moreover, a list of genes representing angiogenesis and immune biology, previously used in the IMmotion150 study, was chosen to explore further functional subcategories of CDC. Available RNA-Seq data of 7 CDCs and 5 matched normal tissue from GSE89122 dataset were used for validation. Results: Comparison of transcriptome profiles of CDCs and ccRCCs versus normal tissue led to the identification of a core of 14 genes specifically up-regulated in CDC, 5 of which (SFN, S100A11, CKAP5, CDH1 and CD44) were significantly involved in extracellular matrix organization. Other deregulated genes were related to immune system, cell cycle progression, glucose and pentose phosphate metabolism and EGFR-signaling. In addition, ssGSEA permitted to identify two major distinct biological subgroups in CDC of both INT and GSE89122 datasets, based on relative expression levels of angiogenesis and immune genes. Conclusions: Our study reveals novel insights into the biology and heterogeneity of CDCs. Although further validation using larger samples is needed, the current findings suggest that this heterogeneity could have clinical implications for the treatment of patients with this rare kidney cancer.
The impact of surgical resection on circulating tumor-reactive cytotoxic T cells for patients with renal tumors.
Authors: Packiam Vignesh T. , Bhindi Bimal , Zhang Henan , Lohse Christine M. , Shah Paras H. , Tsivian Matvey , Pagliaro Lance C. , Costello Brian Addis , Thompson R. Houston , Boorjian Stephen A. , Cheville John , Dong Haidong , Leibovich Bradley C.
Published: February 2020

725

Background: The impact of surgical resection of renal tumors on peripheral immune related cells is not well characterized, and has potential implications as biomarkers for systemic immune therapy are being developed. We sought to assess the effect of surgical resection on circulating cytotoxic T-cells (CTLs) for patients with renal tumors. Methods: We prospectively enrolled 40 patients undergoing partial, radical, or cytoreductive nephrectomy (PN, RN, CN) for unilateral primary renal tumors between 2016 and 2018. Blood draws were performed pre-op, 1 day post-op, and 3 months post-op. Flow cytometry was performed on peripheral blood mononuclear cells (PBMCs). The % of PBMCs expressing CD11a/CD8 (CTLs) were assessed. The % of CTLs expressing PD-1, Bim (a downstream PD-1 pathway pro-apoptotic mediator), CX3CR1/GZMB (an effector memory T-cell phenotype), and Ki67 (a proliferation marker) were assessed. Median changes in % of CTLs were evaluated with the Wilcoxon signed rank test. Comparisons between aggressive (pT3-4, N1, M1, or aggressive histology (high-grade, coagulative necrosis, sarcomatoid dedifferentiation, or specific RCC-variant histologies)) versus indolent tumors were assessed using the Wilcoxon rank sum test. Results: Twenty, 12, and 8 patients underwent RN, PN, and CN, respectively. Thirty, 7, and 3 patients had clear-cell RCC, non-clear cell RCC, and oncocytoma, respectively. Twenty-three and 17 patients had aggressive and indolent tumors, respectively. While there was no significant change at 1 day, by 3 months there were significantly increased CTLs among PBMCs (+1.3%; p=0.004). There was significant decrease in CX3CR1+GZMB+ CTLs (-2.9%; p<0.001) and significant increase in Bim+ CTLs (+3.0%; p=0.03) at 1 day but not 3 months. Interestingly, Ki67+ CTLs increased at day 1 (+0.6%; p<0.001) but decreased by 3 months (-0.6%; p=0.001). There were no significant changes in PD-1+ CTLs at either time point. There were no significant changes in any CTL characteristics at 1 day or 3 months between aggressive and indolent tumors. Conclusions: These findings characterize changing CTL profiles over time with surgical resection of renal tumors which may help guide biomarker development.
Evaluation of RNA-sequencing (RNA-seq) signatures with pembrolizumab (pembro) in patients (pts) with renal cell carcinoma (RCC) from KEYNOTE-427 cohort A.
Authors: McDermott David F. , Lee Jae-Lyun , Bjarnason Georg A. , Larkin James M. G. , Gafanov Rustem Airatovich , Kochenderfer Mark D. , Malik Jahangeer , Poprach Alexandr , Tykodi Scott S. , Signoretti Sabina , Perini Rodolfo F. , Lunceford Jared , Predoiu Raluca Andreia , Loboda Andrey , Zhao Qing , Snyder Alexandra , Schloss Charles , Atkins Michael B.
Published: February 2020

729

Background: We evaluated the association (assoc) of baseline RNA-seq–based signatures with response/resistance to pembro from the phase 2 KEYNOTE-427 study (NCT02853344) in pts with advanced clear cell RCC enrolled in cohort A (n = 110). Methods: In pembro-treated pts with RNA-seq and clinical data (N = 78), we analyzed the assoc of signatures (18-gene tumor T-cell–inflamed GEP; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying the TME with clinical outcomes. Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were also analyzed through regression testing of response and the residuals of consensus signatures after adjusting for T-cell–inflamed GEP and IMDC scores in the model. P values were adjusted for multiplicity. Database cutoff date for clinical data: March 12, 2019. Results: Pt characteristics for this analysis were similar to those of the overall cohort A population. T-cell–inflamed GEP was statistically significantly assoc with ORR ( P = 0.021) but not PFS ( P = 0.116). When adjusting for PD-L1 expression (CPS by IHC) and IMDC scores, T-cell–inflamed GEP remained statistically significantly assoc with ORR ( P = 0.059). The angiogenesis signature was not assoc with response. PD-L2 RNA-seq expression was not assoc with response with multiplicity-adjusted P values. Like PD-L1 IHC, PD-L2 RNA-seq expression moderately correlated with T-cell–inflamed GEP and did not show independent predictive value when adjusted for T-cell–inflamed GEP and IMDC scores. Conclusions: RNA-seq–based, T-cell–inflamed GEP was assoc with ORR in pts with clear cell RCC receiving first-line pembro monotherapy; no canonical signatures showed statistical significance. Future directions for these data include whole exome sequencing analysis. Clinical trial information: NCT02853344.