bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene expression profiling (GEP) to identify metabolic gene signature predictive of recurrence after surgery in stage III clear-cell renal cell carcinoma (ccRCC).
Authors: Gulati Shuchi , Bhargav Vemuri , Cunningham Tom , Plas David , Landero Julio Alberto , Meller Jarek , Czyzyk-Krzeska Maria
Published: March 2021

355

Background: Management of patients with localized or locally advanced renal cell cancer (RCC) involves surgical resection. However, 20-40% of all localized kidney cancer patients experience a recurrence. Adjuvant treatment in high-risk kidney cancer has not proven to successfully improve overall survival (OS) and the only drug approved so far in this setting is vascular endothelial growth factor (VEGF) inhibitor, sunitinib. As multiple trials are evaluating drugs including immune checkpoint inhibitors in patients with high risk localized clear cell RCC, there is an urgent need to identify biomarkers to help with therapeutic decisions as well as for risk stratification. Here we present analysis pertaining to genes involved in metabolic reprogramming in kidney cancer. Methods: A deep transcriptomic analysis of patients with stage III ccRCC in the TCGA KIRC Firehose Legacy cohort was undertaken. Caucasian males with stage III ccRCC in the TCGA cohort for whom recurrence data was available with a minimum follow-up of 2 years were identified for the analysis. Expression profiles of differentially expressed genes were clustered using the Bayesian infinite mixture model and samples clustered using average linkage hierarchical clustering based on pairwise Pearson’s correlations as the measure of similarity. Enrichment analysis of up- and down-regulated genes was performed using logistic regression. R package was used to generate Kaplan-Meier curves and assess statistical significance of differences in overall and disease-free survival using log-rank test. Results: The cohort evaluated for this study included Caucasian male patients that remained disease free for at least 24 months after surgery (n = 22) and patients whose cancer recurred within 24 months (n = 20). We identified metabolic genes, encoding subunits of mitochondrial electron transport chain as well as malate aspartate shuttle (MAS), where loss of coordinated co-expression between these genes identified patients at risk of recurrence after surgery. The gene signature stratified the 42 patients into three subtypes: significantly enriched for a) recurrence (subtype 1), for b) disease free status (subtype 2) and b) intermediate (subtype 3). Work is underway to combine the use of individual gene expression and ratios of gene expression within the signature to optimize prognostic biomarkers for localized ccRCC. Conclusions: In this analysis, we have identified a novel metabolic gene signature which can help identify patients with localized ccRCC at high risk of recurrence after surgery to guide aggressive therapy. These findings require further validation in tumors collected from patients with stage III ccRCC.
The use of 3D printed models on trainee and patient experience for partial nephrectomies.
Authors: Scott E. Reilly , Morano Samuel , Quinn Andrea , Mann Erica , Ho Michelle , Karp Alice , Boyd Kaitlyn , Singh Abhay , Chandrasekar Thenappan , Mann Mark Jonathan , Trabulsi Edouard John , Desai Vishal , Lallas Costas D.
Published: March 2021

363

Background: 3D printing is a growing tool in surgical education due to the ability to visualize organs, tissue, and masses from multiple angles before operating on a patient. Previous studies using highly detailed and expensive 3D models costing between $1,000-250 per model have been shown to enhance patient and trainee comprehension of tumor characteristics, goals of surgery, and planned surgical procedure for partial nephrectomies. In our study we aim to use simpler and less expensive models in a greater range of patients receiving partial nephrectomies to determine the use of 3D models in patient, resident, and fellow education. Methods: 3D models of the effected kidney, mass, renal artery, and renal vein were created using preoperative imaging of undergoing partial nephrectomies at Thomas Jefferson University Hospital (TJUH) costing $35 per model. Residents and fellows filled out 3 surveys assessing their surgical plan and their confidence in the chosen plan at 3 time points: 1) Before seeing the model, 2) After seeing the model before surgery, and 3) After surgery. Ten patients filled out 2 surveys about their understanding of the kidney, their disease, the surgery they will undergo, and the risks involved with surgery before and after seeing the model. Results: Based on surveys to assess for surgical plan and confidence given to resident and fellow surgeons before and after seeing the 3D model, confidence significantly increased. Surveys given after surgery assessing anatomic and surgical comprehension found that resident and fellow surgeons rated the helpfulness of the models on their anatomical comprehension 7.6 out of 10 and the help of the models on their surgical confidence 7 out of 10. Patient understanding of their kidney, disease, and surgery significantly increased after seeing the 3D model, but the risks associated with surgery did not significantly increase. The extent that the model helped the patients learn about the kidney, their disease, the surgery, and the risks related to surgery were rated an average of 8.33, 9.67, 9.5, and 8.83 out of 10, respectively. Conclusions: Patient-specific 3D models for partial nephrectomies increase resident and fellow confidence in surgical approach and helped patients learn about their disease and feel comfortable going into surgery. Thus, it is important to continue to explore 3D models as an educational tool for both trainees and patients and potentially include 3D models as part of the standard of care. Further research could continue to explore the utility of 3D models as a pre-operative educational tool for both patients and trainees in other surgical fields.
Imaging modality and frequency in surveillance of stage I seminoma testicular cancer: Results from a randomized, phase III, factorial trial (TRISST).
Authors: Joffe Johnathan K. , Cafferty Fay Helen , Murphy Laura , Rustin Gordon J. S. , Sohaib Syed A , Swift Sarah , Noor Dipa , Wade Simona , James Elizabeth , Gabe Rhian , Stenning Sally P , Hall Marcia , Sharma Anand , Braybrooke Jeremy , Shamash Jonathan , Logue John , Hunter Taylor Henry , Kaplan Richard S. , Huddart Robert A ,   The TRISST Trial Management Group
Published: March 2021

374

Background: Survival after orchiectomy in stage I seminoma is almost 100%. CT surveillance is an international standard of care, and avoids adjuvant therapy. In this young population, who are unlikely to die from testicular cancer, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST, NCT00589537), assessed whether CTs can safely be reduced, or replaced with MRI, without an unacceptable increase in advanced relapses. Methods: TRISST is a phase III, multicenter, non-inferiority, factorial trial. Eligible men had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Randomization was to: 7 CTs (6, 12, 18, 24, 36, 48, 60 months (m) after randomization); 7 MRIs (same schedule); 3 CTs (6, 18, 36m); or 3 MRIs (same schedule). Follow-up was for 6 years. The primary outcome is 6-year incidence of RMH stage ≥IIC relapse, aiming to exclude an increase ≥5.7% (from 5.7% to 11.4%) with MRI (vs CT) or 3 scans (vs 7); target n=660, all contributing to both comparisons. Secondary outcomes include relapse ≥3cm, disease-free and overall survival (DFS, OS). Results: 669 men enrolled from 35 UK centers (2008-2014); mean tumor size 2.9cm, 358 (54%) were low risk (≤4cm, no rete testis invasion). Median follow-up was 72m. 82 (12%) patients relapsed. Incidence of stage ≥IIC relapse was low in all groups (n=10). More events occurred with 3 scans vs 7, though non-inferior based on design criteria: 9 (2.8%) vs 1 (0.3%), 2.5% increase, 90% CI 1.0% to 4.1% (intent-to-treat, ITT). 4/9 in 3-scan arms could potentially have been detected earlier with the 7-scan schedule. Fewer events occurred with MRI vs CT: 2 (0.6%) vs 8 (2.5%), 1.9% decrease, 90% CI -3.5% to -0.3% (ITT). Per protocol results were similar. Incidence of relapse ≥3cm was 3.7%; non-inferiority was shown for both comparisons. In all groups, most relapses were detected at scheduled imaging; very few occurred beyond 3 years (5 in 558 at risk, <1%). Relapse treatment outcomes were good (81% complete response) with no tumor-related deaths. 5-year DFS and OS were 87% and 99%, similar across groups. Conclusions:Surveillance is a safe management approach in stage I seminoma – advanced relapse is rare, salvage treatment successful, and long-term outcomes excellent, regardless of imaging frequency or modality. Relapse beyond 3 years is rare and imaging may be unnecessary. MRI is non-inferior to CT, avoids irradiation and should be recommended. Clinical trial information: NCT00589537.
Adaptation of chemotherapy to the decline tumor markers in patients with poor prognosis nonseminomatous germ cell tumors:Real-world French experience.
Authors: Rolland Marion , Faouzi Sara , Chaltiel Leonor , Dumont Clement , Geoffrois Lionnel , Gross-Goupil Marine , Laguerre Brigitte , Guerin Mathilde , Doucet Ludovic , Roubaud Guilhem , Tardy Magalie , Oudard Stephane , Flechon Aude , Tosi Diego , Mahammedi Hakim , Chevreau Christine , Pouessel Damien , Fizazi Karim
Published: March 2021

385

Background: Personalized chemotherapy based on tumor marker decline is the new standard in poor prognosis germ-cell tumor in Europe since 2014 (GETUG 13, Lancet, Fizazi et al). The purpose of this study was to analyze the reproducibility of the princeps study in patients not selected in clinical routine between 2014 and 2018. Methods: Patients (pts) were eligible if they had at least one criteria of IGCCCG classification for poor prognosis group. They had to be treated according the study terms of GETUG 13 study and did not received prior treatment. They had to received 1 BEP (Bleomycin, Etoposide, Cisplatin). Tumor markers (HCG and AFP) were dosed between day 18 and 21. Then, they received 3 additional BEP if they had favorable tumor marker decline or intensive chemotherapy if they had unfavorable decline. Results: This retrospective study included 104 patients in 14 french centers treated between 2013 and 2018: 22,1 % (n = 23) in the favorable group (Fav), 77,9 % (n = 81) in the unfavorable group (Unfav). Thirty-two pts had PS ≥ 2. In Unfav, there were more pts with HCG > 50 000 UI/L (44,2 % vs 13 %, p = 0,0067), neutrophil-to-lymphocyt ratio was also higher (median 6,4 vs 4,5, p = 0,0199). At cycle 1, all pts received BEP in Fav and 87,5 % (n = 70) in Unfav. After chemotherapy and surgery, 65,2 % in Fav and 41,3 % in Unfav obtained complete response. At 30 months (median follow-up), Fav-OS was 80,5 % (IC95% 55,8 – 92,2) and Unfav-OS was 64,4 % (IC95% 52 – 74,4). At 30 months, rates were 69,6 % (IC95% 46,6 -84,2) and 63.5 % (IC95% 51,9 – 73) respectively. In GETUG 13 study, 3-years OS was 84 % in Fav and 73 % on Unfav; 3-years PFS was 70 % and 59 % respectively. Seven pts died because of toxicity in Unfav (No one in Fav). Neuropathy, anemia and thrombopenia were more frequent in Unfav. Salvage high-dose chemotherapy with stem-cell transplant was required in 4 (66,7 %) pts in Fav and 8 (36,4 %) pts in Unfav. Conclusions: This study showed a reproducibility of the princeps study in terms of PFS and OS. Toxicity seemed more important in real world. For the congress, results will be reported with 50 additional pts.
Paclitaxel, ifosfamide & cisplatin (TIP) as second-line therapy for germ cell tumors (GCT):Long-term follow-up and expansion cohort.
Authors: Gleeson Jack Patrick , Knezevic Andrea , Bromberg Maria , Patil Sujata , Sheinfeld Joel , Carver Brett Stewart , Jones David Randolph , Bains Manjit S. , Bajorin Dean F. , Bosl George J. , McHugh Deaglan Joseph , Funt Samuel Aaron , Motzer Robert J. , Feldman Darren R.
Published: March 2021

386

Background: TIP was established as an effective second-line regimen in a phase II study of 46 patients (pts) with relapsed GCT and favorable risk factors (Kondagunta, JCO 2005). Here, we report long-term follow up from this trial and outcomes for additional pts who subsequently received TIP off protocol. Methods: Eligiblepts included those who received TIP on the original phase II trial (original cohort) or who received TIP following study closure but would have met the trial inclusion criteria (expansion cohort). An additional exploratory cohort was comprised of pts with unfavorable risk factors who would not have met the original trial criteria. The primary endpoint was favorable response rate (FRR), which included complete responses (CR) and partial responses with negative markers (PR-). Overall survival (OS), progression free survival (PFS), and relapse rates were also evaluated. Results: Of 204 pts who received TIP for GCT at our institution from 5/1994 to 7/2019, 87 (original cohort, n=46; expansion cohort, n=41) met the inclusion criteria and were evaluable for the main analysis. An additional 17 pts were analyzed in the exploratory cohort (unfavorable risk factor: PR- lasting <6months or IR, n=13; prior adjuvant therapy, n=4). 100 pts were excluded due to participation in an ongoing clinical trial (n=17), receipt of TIP as their first regimen (n=74) or in the adjuvant (n=3) setting, or insufficient data (n=6). Baseline characteristics and efficacy data are displayed in the table below. In the main cohort, 70/87 (80%) pts achieved a favorable response. With median follow-up of 10.2 years (yrs) [original, 14.3 yrs; expansion 6.5 yrs] 26 deaths were observed. 5yr and 10yr OS rates were 72% (95% CI 63, 83) and 69% (95% CI 59, 80) respectively. 5yr and 10yr PFS were 70% (95% CI 61, 81) and 67% (95% CI 57, 78). In the exploratory cohort, there were 7 deaths at median follow-up of 6.2 yrs with 5yr OS of 56% (95% CI 35, 87) and 5yr PFS of 59% (95% CI 40, 88). Conclusions: Long-term follow-up and additional experience supports the use of TIP as second-line therapy for GCT. Similar outcomes were seen for our exploratory and main cohorts, suggesting benefit with TIP outside of those with a favorable prognosis. [Table: see text]
Is there value to routine oncologic surveillance after radical cystectomy? Comparative outcomes of symptomatic versus asymptomatic recurrence.
Authors: Khanna Abhinav , Zganjar Andrew , Shah Paras , Tollefson Matthew K. , Sharma Vidit , Tarrell Robert F. , Thapa Prabin , Pagliaro Lance C. , Costello Brian Addis , Frank Igor , Boorjian Stephen A.
Published: March 2021

421

Background: Reported rates of adherence to post-radical cystectomy (RC) surveillance guidelines in real-world practice have been as low as 9%, in part reflecting a nihilistic view held by many of the value of routine follow-up. Indeed, conflicting data exist regarding the outcomes of patients with cancer recurrence detected by scheduled surveillance versus symptom-directed evaluation. Herein, we assessed comparative outcomes of patients with symptomatic recurrence (SR) versus asymptomatic recurrence (AR) after RC. Methods: We reviewed our Institutional Registry of RC patients to identify patients with cancer recurrence following RC. Presenting symptoms in the SR cohort included pain, constitutional symptoms, gastrointestinal symptoms, and hematuria/voiding symptoms, whereas AR was defined as recurrence detected on routine surveillance in the absence of symptoms. Baseline demographic and clinical characteristics were compared between study groups using chi-square and t-test. Kaplan-Meier and Cox survival analyses were performed to compare cancer-specific survival (CSS) and overall survival (OS) between AR and SR groups. Results: Of 3822 patients who underwent RC from 1980-2018 (with a median follow-up after RC of 2.4 years (IQR 1.1,5.5), a total of 1100 were subsequently diagnosed with recurrence, including 311 (28.3%) with AR and 789 (71.7%) with SR. Median time from RC to recurrence was longer in the AR group (13.2 months) than in the SR group (10.8 months; p = 0.01). Presenting symptoms included pain (70.2%), constitutional symptoms (50.7%), gastrointestinal symptoms (23.3%), and urinary symptoms (23.3%). Median follow-up after recurrence was 2.4 years (IQR 1.1-5.5), during which time 997 patients died, including 840 who died of bladder cancer. Compared to patients with SR, patients with AR had a longer median CSS (54.5 months vs 27.3 months, p < 0.001) and OS (43.0 months vs 25.8 months, p < 0.001). On multivariable Cox proportional hazards models adjusting for demographic and clinical factors, SR was associated with a significantly increased risk of cancer-specific (hazard ratio [HR] 1.66 [95% confidence interval 1.41-1.96], p < 0.0001) and all-cause mortality (HR 1.48 [1.23-1.71], p < 0.0001). Conclusions: SR after RC is associated with worse oncologic outcomes than post-RC recurrence detected by routine surveillance. As such, continued surveillance is warranted, while further study is needed to determine the optimal follow-up regimen balancing patient and disease risks.
Genomic characterization of bladder cancer with variant histology.
Authors: Lenis Andrew Thomas , Clinton Timothy Nguyen , Hu Wenhuo , Almassi Nima , Reisz Peter , Truong Hong , Thomas Jasmine , Nagar Karan , Goh Alvin , Cha Eugene K. , Donahue Timothy F. , Bochner Bernard H. , Pietzak Eugene J. , Kim Kwanghee , Iyer Gopa , Solit David B. , Al-Ahmadie Hikmat A
Published: March 2021

470

Background: Up to 25% of tumors are of pure variant or mixed urothelial and variant histology. The presence of variant histology may be associated with more advanced stage at presentation and a poorer response to systemic therapy. While histomorphologic assessment provides important prognostic information, genomic analysis of tumors can provide important insight into the biology of disease and inform treatment. In this analysis we performed genomic sequencing of tumors from patients with bladder cancer with variant histology. Methods: Our prospectively generated institutional cohort of molecularly profiled bladder and upper tract tumors contains over 2,000 samples including nearly 300 primary bladder tumor samples from patients with variant histology. Targeted sequencing with MSK-IMPACT was used to identify alterations in cancer-associated genes and to describe trends across variant subtypes. To explore and compare tumor and immune cell heterogeneity, single-cell RNA sequencing (scRNA-seq) was performed on a subset of specimens. Results: Our cohort included patients with pure urothelial carcinoma not otherwise specified (NOS), as well as squamous, small cell, pure adenocarcinoma and urothelial carcinoma with glandular differentiation, micropapillary, nested, and plasmacytoid variants. Compared with urothelial carcinoma NOS, nearly all small cell tumors had mutations in TP53, RB1, and TERT. Squamous tumors had similar mutational frequencies as urothelial carcinoma NOS. Pure adenocarcinoma had frequent mutations in TP53, KRAS, and PIK3CA, resembling colorectal adenocarcinomas, while urothelial carcinoma with glandular differentiation resembled NOS. Micropapillary variant commonly had ERBB2 amplifications. Nested variant was more commonly found to have RHOA mutations and FOXA1 amplifications. Finally, nearly all plasmacytoid variants had pathognomonic alterations in CDH1. To further explore heterogeneity in tumor and immune cell populations, scRNA-seq was performed on four samples from patients with urothelial carcinoma NOS, squamous, micropapillary, and nested variants, showing distinct tumor cell clusters and varying contributions of immune cells from each variant. Conclusions: While the distribution of oncogenic mutations differed among distinct histologic variants, a pathognomonic DNA alteration was not found for most variant histologic subtypes. Within the context of a larger effort to characterize bladder cancer with variant histology, scRNA-seq may reveal differences in immune cell population infiltrates. Further efforts will aim to characterize these cohorts with whole exome sequencing and mutational signatures, and increase the number of samples per histology and representation of variant histologies for scRNA-seq.
Molecular subtype variation within metastasis of urothelial carcinoma.
Authors: Kozubenko Alla , Arora Sonali , Montgomery Robert B. , Wright Jonathan L. , Lam Hung-Ming , Hsieh Andrew Caleb
Published: March 2021

471

Background: Molecular subtyping of cancer based on gene expression is a new prognostic tool with potential to guide treatment in the future. Urothelial carcinoma is one such cancer for which numerous molecular subtyping systems have been developed, but the diversity of these systems has hindered their clinical application. Recently, a consensus classification system was derived from six independent systems, defining six molecular classes with distinct oncogenic mechanisms and mutations (Kamoun A, et al. 2020). Considering the high heterogeneity in urothelial carcinoma, we hypothesized that molecular subtype variation may occur between primary and metastatic samples. We further evaluated whether variation in subtype was associated with any unique patient characteristics. Methods: As part of the University of Washington Bladder Cancer Rapid Autopsy Program (BCRAP), primary and metastatic tumor tissue samples were acquired from 14 deceased patients with urothelial carcinoma within 6 hours of death. Patient history was collected and deidentified for analysis. RNA exome sequencing was used for assigning molecular subtype for each of the 61 tumor samples, using the consensus and six comprising systems. Results: Molecular subtype variation within metastatic tumors according to any classification system was detected in 8 out of 14 patients, independent of histologic morphologies. Amongst the patients with variation, on average 2.1 out of 7 classification systems identified a major difference in subtype between sites. Patients with variation (mean age 70 years (SD 7 years)) were older than those without variation (mean age 59 years (SD 11 years), P = 0.04). Furthermore, patients with variation tended to have decreased survival from diagnosis and received less chemotherapy, although these were not statistically significant (p > 0.05). Conclusions: Molecular subtype variation within metastasis is relatively common amongst BCRAP patients with urothelial carcinoma. Older patients are more likely to have variation, possibly due to a higher tumor mutation burden. Potential variation must be taken into account when considering prognosis and developing a recommended drug regimen specific to molecular subtypes.
Plasmacytoid urothelial carcinoma (UC) are luminal tumors with similar immune microenvironment as compared to conventional UC.
Authors: Kossai Myriam , Radulescu Camélia , Adam Julien , Dziegielewski Anaïs , Signolle Nicolas , Sibony Mathilde , Lebret Thierry , Allory Yves , Rouanne Mathieu
Published: March 2021

477

Background:Plasmacytoid urothelial carcinoma (UC) is a rare pathological variant of UC with low chemotherapeutic sensitivity and dismal outcomes. The molecular and immune profiles of such tumors remain poorly investigated. Herein, we investigated the phenotypical features of a cohort of plasmacytoid UC (n = 32) by comparison to a control group of conventional high-grade UC with matched clinicopathological characteristics (n = 30). Methods: Histopathological analysis included the following antibodies: p63, GATA3, CK5/6, CK20 and HER2. In addition, the density of intra-tumor CD8+ lymphocytes, and PD-L1 expression in tumor (TC) and immune cells (IC) were evaluated. Clinical data were collected. Results: Plasmacytoid UC expressed GATA3 (97% vs 86% p = 0.18), CK20 (59% vs 36% p = 0.08) markers and showed a significantly higher rate of HER2 overexpression (2+ and 3+ score: 25% vs 0%, p < 0.01) compared to controls. A significantly lower expression of CK5/6 (22% vs 56%, p < 0.05) and p63 (41% vs 80%, p < 0.05) was observed in plasmacytoid UC compared to controls. The density of tumor-infiltrating CD8+ cells was similar between plasmacytoid and conventional UC (p = 0.5). PD-L1 expression on IC was similar compared to conventional UC (p = 0.3). Overall survival at 5 years was significantly lower among patients with plasmacytoid UC compared to patients with conventional UC (p = 0.02). Conclusions: Together, our study demonstrated that plasmacytoid UC belong to the luminal subtype and display a rather inflamed microenvironment similar to conventional UC. These data support the inclusion of plasmacytoid variant of UC in clinical trials evaluating immune checkpoint inhibitors monotherapy or combination immunotherapeutic strategies.
Novel synthetic lethality (SL) anti-cancer drug target in urothelial bladder cancer (UCB) based on MTAP genomic loss: Incidence and correlations in standard of care (SOC).
Authors: Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Grivas Petros , Danziger Natalie , Sokol Ethan , Madison Russell , Ramkissoon Shakti H. , Graf Ryon , Mata Douglas A , Decker Brennan James , Ross Jeffrey S.
Published: March 2021

485

Background: When UCB presents or progresses to chemorefractory metastatic disease, the search for new therapy targets is paramount. Targeting PRMT5 arginine methyltransferase accumulation in tumors with MTAP (methylthioadenosine Phosphorylase) genomic loss has been proposed as a new SL based anti-tumor strategy and under consideration for development for UCB. We sought to evaluate the incidence of patients with candidate SL and correlate to treatment-guiding biomarkers currently evaluated in SOC. Methods: 2,683 cases of clinically advanced UCB underwent hybrid-capture based comprehensive genomic profiling in a standard of care setting using the F1CDx FDA-approved assay to evaluate all classes of genomic alterations (GA) among 324 genes. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 650 (24%) of UCB feature MTAP loss (MTAP-) (Table). The gene and age distributions were similar MTAP intact (MTAP+) and MTAP- UCB. The GA/tumor was higher in MTAP- UCB likely reflecting the significant GA co-deletions of CDKN2A/ B at the 9p21 locus. Of potential therapeutic targets, FGFR3 and PTEN GA were more frequent in the MTAP- UCB. In contrast, biomarkers of immunotherapy (IO) response included higher frequencies of high TMB and high PD-L1 IHC staining in the MTAP+ UCB. Conclusions: When compared with MATP+ UCB, MTAP- UCB differs in genomic signatures including an increase in potential for targeted therapies but a lower potential for IO drug benefit. Thus, the genomic landscape in MTAP- UCB may play a significant role in the design of clinical trials incorporating SL strategies when targeting PRMT5 in MTAP deficient tumors. [Table: see text]
Association between tumor mutational burden (TMB) and immune-related adverse events (irAEs) in patients (pts) with metastatic urothelial carcinoma (mUC) during checkpoint immunotherapy.
Authors: Akl Elie W. , Nuzzo Pier Vitale , Adib Elio , Nassar Amin , Alaiwi Sarah Abou , Ravi Praful , Mantia Charlene , Sonpavde Guru
Published: March 2021

489

Background: Immune checkpoint inhibition (ICI) has greatly improved clinical outcomes for pts with mUC and other cancers. ICI is associated with a class of AEs, deemed irAEs due to immune activation. Nonetheless, biomarkers associated with irAE are still lacking. We hypothesized that the immune response against neoantigens is partly responsible for irAEs and investigated the association between irAEs, TMB and response to ICI. Methods: We identified patients with mUC at Dana Farber Cancer Institute who were treated with ICI (monotherapy or combination) and had available tumor sequencing data through Oncopanel. TMB was calculated using the number of non-synonymous exonic mutations per megabase. The severity of irAEs was graded using CTCAE v.5.0. Mann-Whitney U test was performed to identify association between TMB, incidence and grade of irAEs. A cut-off of 10/mb was assigned for TMB. Fisher’s exact test was used to evaluate the radiologic response between pts with and without irAEs and low vs. high TMB. Multivariable linear regression was used to assess the relationship between TMB, irAEs and response. p-values were adjusted using Benjamini-Hochberg method. Results: Of 101 pts with mUC who met the inclusion criteria, 32 (32%) reported irAEs. 6 (6%) were grade (G)1, 20 (20%) were G2, and 6 (6%) were G3. Median(m) time on therapy was 84 days for pts without irAEs and 88 days for pts with irAEs. Pts with irAEs had higher mTMB (15.4/mb) compared to pts with no irAEs (9.8) ( p = 0.01). In pts on monotherapy (93), those with irAEs (n=27) had a higher mTMB (15.13/mb) compared to pts with no irAEs (n=66) (mTMB = 10.20/mb) ( p = 0.01). Out of 94 pts with radiological data, response was achieved in 16 (50%) pts with irAE vs 10 (16%) pts with no irAE ( p < 0.001). When both irAE and response were included in a multivariable regression, the association between irAE and TMB was not significant ( p = 0.4). Pts with both irAE and high TMB had a response rate of 56% which was significantly higher than those with either irAE but low TMB (28.6%) or high TMB but no irAE (21.2 %) or low TMB and no irAE (10.3%) (Chi-square test p = 0.002; FDR corrected p-values for individual comparisons in Table). There was no association between TMB and irAE grade. Conclusions: Higher TMB was associated with higher incidence of irAEs in pts with mUC on ICIs. Moreover, pts with both high TMB and irAEs exhibited better response rates than those with only high TMB or irAEs, suggesting that they may provide complementary tumor and host characteristics. Further evaluation in mUC is needed to confirm this relationship between TMB, irAEs and response in a larger cohort and explore specific mutational signatures that may be associated with irAEs. [Table: see text]
Impact of primary tumor location, histology, and host factors on objective response to immune checkpoint inhibitors in metastatic urothelial carcinoma.
Authors: Dawsey Scott , Khan Mohammad Siddique , Radakovich Nathan , Wei Wei , Mian Omar Y. , Ornstein Moshe Chaim , Gilligan Timothy D. , Gupta Shilpa
Published: March 2021

493

Background: Factors affecting response to immune checkpoint inhibitor (ICI) are poorly understood in metastatic urothelial carcinoma (mUC). While tumor PD-L1 status is often used as a biomarker, it is not always predictive and ICI also benefits patients (pts) with PD-L1 negative tumors. Therefore, we sought to study the effect of some host and disease-related variables like gender, ethnicity, body mass index (BMI), platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ration (NLR) on objective responses in pts with mUC treated with ICI. Methods: We performed a retrospective analysis of adult pts with mUC who received ≥2 cycles of ICI (pembrolizumab or atezolizumab) at the Cleveland Clinic from 2015 to 2020. Tumor and host-related factors evaluated are listed in the table below. We focused on meaningful treatment response, so only partial response (PR) and complete response (CR) were included as responders, while stable disease (SD) and progressive disease (PD) were counted as non-responders. Analysis was carried out with Fisher’s exact test and Wilcoxon rank sum test as applicable. Results: A total of 124 pts with mUC that received ICI were included. Gender did not correlate with response (p>0.99) or duration of response (p=0.37). Ethnicity did not correlation with response (p=0.78) or duration of response (p=0.24). Histology (UC, mixed variant histology or non UC) did not correlate with response (p=0.13) or duration of response (p=0.87). Location of primary malignancy (upper tract versus lower tract) did not correlate with response (p>0.99) or duration of response (p=0.36). BMI (p=0.23), PLR (p=0.9), and NLR (p=0.9) did not correlate with objective response. Conclusions: In our single center experience of pts with mUC treated with ICI, host factors (gender, ethnicity, histology, BMI, NLR, PLR) and location of primary tumor did not correlate with treatment response or duration of response. Although there were few African Americans represented in this study as commonly seen for minority representation, it is encouraging that no significant differences in responses were observed. The role of BMI and gender in response to ICI treatment in mUC was not observed. While there are limitations of a retrospective analysis, our study warrants investigation into predictive factors of response to ICI in mUC. Ongoing work integrating radiomics and pathomics will further our understanding and develop potential predictive biomarkers of response to ICI in mUC. [Table: see text]
Role of CA 125, CA19-9 and CEA in predicting outcome following neoadjuvant chemotherapy in muscle invasive bladder cancer.
Authors: Ahmadi Hamed , Ladi Seyedian Seyedeh Sanam , Reddy Sharath , Nguyen Charles , Bhanvadia Sumeet , Schuckman Anne K. , Djaladat Hooman , Daneshmand Siamak
Published: March 2021

496

Background: We have previously shown the prognostic value of three tumor markers (TMs) including Carbohydrate Antigen 125 (CA-125), Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) in muscle invasive bladder cancer (MIBC). Current report presents an update on TM levels before and after neoadjuvant chemotherapy (NAC) and their association with oncological outcomes. Methods: Serum levels of three TMs were prospectively measured in patients with MIBC who underwent NAC between 2011 and 2019. Rate of pathological upstaging (Path-U) and recurrence-free (RFS) was compared between patients with: (1) Elevated versus normal pre-NAC TM (2) Elevated versus normal post-NAC TM, and (3) Elevated pre-NAC TMs with normalized post-NAC TMs (TM responders) versus persistently elevated post-NAC TMs (TM non responders). Results: Of a total of 199 patients, 63 patients had both pre- and post-NAC TMs. 33/63 (52%) patients had elevated pre-NAC TM of whom, 15/33 (45%) were TM responders. Patients with elevated pre-NAC TM had significantly higher rate of Path-U compared to those with normal pre-NAC TM (62% vs. 22.5%, respectively; P < 0.001). There was no significant difference in Path-U in the other two comparison groups. Patients with elevated pre- and post-NAC TM had significantly lower RFS. Compared to TM responders, TM non responders had significantly higher rate of recurrence (70% vs 34%) and shorter median time to recurrence (4.2 months vs 13.5 months) (P = 0.03). In six patients with recurrence who had complete post cystectomy TM, TM recurrence preceded clinical recurrence by median of 1.2 months (IQR 0.8 – 2.4 months). Conclusions: Elevated TM prior to NAC is associated with pathologic upstaging. TM elevation pre- or post-NAC predicts a worse outcome. Post-cystectomy TM might play a role in earlier detection of recurrence.
Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) patients.
Authors: Chamie Karim , Chang Sam , Gonzalgo Mark L. , Kramolowsky Eugene V. , Sexton Wade J. , Reddy Sandeep K. , Bhar Paul , Garner Chad , Soon-Shiong Patrick
Published: March 2021

510

Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL-15RαFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase Ib data in BCG-naive patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. An open-label, 3 cohort multicenter phase II/III study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) was opened. We report here the interim analysis of Cohort A, BCG-unresponsive (CIS) [with or without Ta or T1 disease], as of December 2020 data cutoff. Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A of this phase II/III study is incidence of complete response (CR) of CIS at any time. Results: To date, 80 patients have enrolled in cohort A of this phase II/III trial. Evaluable analysis at this time shows CR rate at any time of 72% (N=51/71); for patients achieving CR, the probability of maintaining a CR for 12 months is 59%, with a median duration of complete response of 19.2 (7.6, 26.4) months. Low-grade treatment related AEs include dysuria, hematuria, and pollakiurua (all 16%), urgency (14%), and bladder spasm (8%), all other AEs were seen at 6% or less. A total of 9 subjects experienced at least 1 treatment emergent SAE (Severe Adverse event), the SAE rate is 1% for any given AE. No treatment emergent SAE’s were considered treatment related. No immune related SAE’s have been seen. To date, 10/80 (12.5%) patients proceeded to cystectomy in this BCG unresponsive population. Conclusions:With a CR rate of 72%, N-803 has met its primary endpoint with 59% probability of CR patients maintaining CR for at least 12 months. With the observed strong efficacy and an SAE rate of 1%, N-803 represents a novel treatment option for BCG unresponsive CIS with a favorable benefit:risk ratio, in a therapeutically challenging disease. Clinical trial information: NCT03022825.
Cardiac risk factors and events in patients with prostate cancer commencing androgen deprivation therapy: Analysis from a tertiary care center in the Middle East.
Authors: Hassan Mona , Telvizian Talar , Abohelwa Mostafa , Skouri Hadi , Mukherji Deborah
Published: March 2021

73

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer, improving symptoms and prolonging survival. There is an association between ADT use and cardiovascular events, particularly in men with pre-existing risk factors. There are no definite guidelines to stratify patients based on cardiovascular risk prior to ADT initiation. This is the first study on cardiac risks and events in patients on ADT from Lebanon and the Middle East region, a population known to have a high prevalence of cardiovascular risk factors. Methods: A retrospective chart review of 236 patients with prostate cancer who received ADT therapy at a tertiary care center in Lebanon was performed. 167 had a full set of data and were included in analysis. Cardiovascular risk factors at baseline and cardiovascular events on ADT were reviewed. Results: The median age of our cohort was 68, range 48-92 years. The majority of patients had stage 4 diseases at diagnosis (49.8%) with a median duration of 12 months on ADT. In our cohort 24.4% had body mass index > 30, 52.1% had smoking history, 27.4% were diabetic, 28.8 % had history of coronary artery disease, 10.6% had heart failure history and 54.6% had hypertension. Less than half of the patients had a documented lipid profile at baseline. Twenty two patients (9.5%) had documented cardiac events following ADT initiation. Conclusions: In this cohort of patients from the Middle East we found that one third of the population had established coronary artery disease at baseline and 9.5% had documented cardiac events on ADT initiation. Our study highlights the gaps in cardiovascular risk assessment for this high risk group of patients with prostate cancer. Risk and resource-stratified algorithms are needed before starting ADT therapy for optimal cardiovascular health. Increased awareness, collaboration and referral mechanisms between oncologists, urologist and cardiologists are also needed.
Impact of treatment and frailty on elder-relevant physical function outcomes in older adults with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Yang Helen , Breunis Henriette , Timilshina Narhari , Kim Seungyeon , Alibhai Shabbir M.H.
Published: March 2021

76

Background: Maintenance of physical function is a key consideration in treatment decision-making for older adults with metastatic cancer, many of whom are frail. However, physical function outcomes with treatment, and effects of frailty, have not been adequately explored in the mCRPC setting. We evaluated the effects of frailty status and treatment with docetaxel (CHEMO), abiraterone (ABI), enzalutamide (ENZA), and radium 223 (RAD) on elder-relevant physical function outcomes in older men with mCRPC. Methods: Men aged 65+ were enrolled in this multicenter prospective observational cohort study. Daily function was evaluated with the OARS instrumental activities of daily living (IADL). Objective physical function was assessed by grip strength and the Short Physical Performance Battery (SPPB). Falls were documented during interviews. We also collected FACT-G physical well-being (PWB) and functional well-being (FWB) subscales. Assessments were performed at baseline, 3 months, and 6 months. We identified frailty status with a validated frailty index. Mixed effects regression models were used to examine the difference in primary outcomes over time by treatment group or frailty status adjusted for baseline characteristics. Factors associated with falls within 6 months of treatment initiation were determined with logistic regression. Results: A total of 70, 38, 67, and 23 men starting CHEMO, ABI, ENZA, and RAD were included. Mean age, education, race, number of medications, and BMI were similar at baseline between treatment groups. In treatment-stratified analyses without considering frailty, no significant changes over time were reported for any physical function outcome. Frailty was significantly associated with lower IADL function (p < 0.0001), worse grip strength (p < 0.0001), worse SPPB score (p < 0.0001), worse PWB (p < 0.0001), and worse FWB (p < 0.0001) at baseline. In frailty-stratified analyses, grip strength (p = 0.0345) worsened, but SPPB (p = 0.0147) improved significantly over time. Also, changes in SPPB (p = 0.0394) and PWB scores (p = 0.0269) over time differed by frailty status, where frail cohorts had greater improvement over time in both scores. Frailty and treatment type were not predictors of falls whereas prior falls history (OR: 3.52, 95% CI: 1.40-8.86) and age (OR: 1.07, 95% CI: 1.01-1.14) were significant predictors. Conclusions: Frail older men receiving treatment for mCRPC have worse IADL function, grip strength, SPPB scores, PWB, and FWB at baseline. Although grip strength worsened over time, they had greater improvement in SPPB scores and PWB over time than fit patients. Contrary to our hypothesis, most older adults do not experience significant worsening in elder-relevant physical function outcomes over time regardless of treatment. The impact of frailty requires further study.
Cabazitaxel multiple rechallenge in metastatic castration-resistant prostate cancer: A therapeutic option to increase overall survival?
Authors: Pobel Cedric , Auclin Edouard , Teyssonneau Diego , Laguerre Brigitte , Cancel Mathilde , Boughalem Elouen , Noel Johanna , Brachet Pierre Emmanuel , Maillet Denis , Barthelemy Philippe , Helissey Carole , Thibault Constance , Oudard Stephane
Published: March 2021

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Background: Cabazitaxel rechallenge could be a more efficient therapy with an acceptable toxicity than docetaxel in the treatment of patients with a metastatic castration resistant prostate cancer (mCRPC). The aim of this study was to assess the feasibility and efficacy of cabazitaxel multiple rechallenge. Methods: This is a multicenter, retrospective cohort study including patients from 9 centers in France who received 3 lines or more of cabazitaxel from February 2012 to July 2020. Cabazitaxel schedule differed between patients: 25 mg/m2 q3w, 20 mg/m2 q3w, 16 mg/m2 q2w or 10 mg/m2 weekly. Efficacy was assessed by overall survival (OS) and progression-free survival (PFS) from each cabazitaxel line start. Only toxicities grade ≥ 3 were reported. Results: Twenty-two patients were included. The median follow-up from mCRPC was 94.7 months, median age at initial diagnosis was 59.5 years old, median ISUP score at diagnosis was 4 and median PSA at diagnosis was 55 ng/ml. Median number of cabazitaxel cycles was 7 at first-line, 6 at first rechallenge, and 5 for subsequent rechallenges. Median OS from mCRPC diagnosis was 105 months. Median PFS from cabazitaxel line start was 11.8 months at first use, 9.6 for first rechallenge and 5.6 in second rechallenge (table). Only one case of febrile neutropenia and 6 events of grade ≥ 3 toxicity were reported. Conclusions: Cabazitaxel multiple rechallenge could efficiently extend OS with manageable toxicities for patients. Even if anti-PARP therapy and immunotherapy are promising treatments, cabazitaxel rechallenge could be also a relevant therapeutic option for long responder patients. Specific biomarkers should be explored to predict the efficacy of cabazitaxel rechallenge. [Table: see text]
A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti–PD-1) in patients with metastatic castration-resistant prostate cancer.
Authors: Zhang Jingsong , Stein Mark N. , Kelly William Kevin , Tsao Che-Kai , Falchook Gerald Steven , Xu Yuanfang , Seebach Frank A. , Lowy Israel , Mohan Kosalai Kal , Kroog Glenn , Miller Elizabeth
Published: March 2021

TPS174

Background: Bispecific antibodies (bsAbs) are emerging as a protein-based therapeutic strategy for directing T-cell-mediated cytotoxicity in a tumor antigen-specific manner, typically by binding to both tumor antigen and the CD3 receptor on T-cells. REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T-cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. At the tumor site, REGN5678 may synergize with PD-1 inhibitors. In mouse models, REGN5678 in combination with a PD-1 antibody has improved anti-tumor activity compared with either therapy alone (Waite JC et al. Sci Transl Med. 2020:12;549). Methods: This is an open label, Phase I/II, first-in-human study evaluating safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in patients with metastatic castration resistant prostate cancer (mCRPC) who progressed after prior therapy (NCT03972657). For inclusion, patients must have received at least two prior lines of systemic therapy (in addition to androgen deprivation therapy) approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. REGN5678 is administered weekly; cemiplimab (350 mg) is administered once every 3 weeks. During dose escalation, a 3-week safety lead-in of REGN5678 monotherapy will be administered prior to addition of cemiplimab. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate safety, tolerability, and PK of REGN5678 alone and in combination with cemiplimab. Expansion cohort(s) will be enrolled once a maximum-tolerated REGN5678/cemiplimab dose is reached, or if a recommended Phase 2 dose or doses have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate of REGN5678 in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, prostate-specific membrane antigen PET/CT scans are performed at baseline and select time points on study. This study is currently open to enrollment. Clinical trial information: NCT03972657.