bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 2 study of HDAC inhibitor tucidinostat in combination with anti-PD-1 antibody in patients with locally advanced or metastatic urothelial carcinoma.
Authors: Liu Zhuowei , Jiang Lijuan , Li Xiangdong , Ye Yunlin , Wu Zhiming , An Xin , Shi Yanxia , Yao Kai
Published: June 2023

e16563

Background: Tucidinostat (also known as chidamide), a novel histone deacetylase (HDAC) inhibitor, has been approved for treatment of patients (pts) with relapsed or refractory peripheral T-cell lymphoma and advanced hormone receptor-positive breast cancer in China. Tislelizumab (a PD-1 checkpoint inhibitor) is currently approved for pts with PD-L1-high locally advanced or metastatic urothelial carcinoma (UC) who progressed during/following platinum-containing therapy in China. However, the response rate of tislelizumab as monotherapy is limited in UC. The aim of this study was to evaluate the efficacy and safety of tucidinostat combined with tislelizumab in pts with locally advanced or metastatic UC. Methods: This study is an open-label, single-center, phase Ⅱ trial. Patients who previously failed systemic platinum-based chemotherapy with UC were included, regardless of PD-L1 status. Eligible pts received 30 mg oral tucidinostat twice weekly (BIW) in combination with 200 mg tislelizumab by intravenous drip every three weeks (Q3W). This is a Simon's two-stage design. All pts were treated until progression or unacceptable toxicity in two years. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), the safety and tolerability. Results: From Jan. 2021 to Sep. 2022, 26 pts were enrolled (median age 62 y, range 31-74y), of whom 24 were evaluable for response per RECIST 1.1 criteria. One pt was lost to follow-up and one withdrew the group due to sudden cerebral infarction. Complete response (CR) was observed in 2 pts, while partial response (PR) was observed in 8 pts, with an ORR of 41.7% (10/24). The DCR was 62.5%. The median PFS was 4.6 months. Most adverse events (AEs) were grade 1 or 2. The most common grade 3 AEs were neutropenia 11.5%, thrombocytopenia 11.5%, leukopenia 7.7%, anemia 7.7%, anorexia 7.7%, creatinine increased 3.8%. One pt experienced grade 4 immuno-pneumonia was permanently discontinued. One pt was on maintenance therapy of tucidinostat without immunotherapy because of interstitial pneumonia. Conclusions: The preliminary data indicate that tucidinostat combined with tislelizumab might be a potentially effective regimen with a manageable safety profile in UC. The study remains ongoing and updated results will be presented later. Clinical trial information: NCT04562311 .
Identification of prognostic biomarkers in plasma of patients with metastatic urothelial carcinoma (mUC).
Authors: Palacka Patrik , Svastova Eliska , Csaderova Lucia , Chovanec Michal , Rejlekova Katarina , Obertova Jana , Lesko Peter , Orszaghova Zuzana , De Angelis Valentina , Slopovsky Jan , Holickova Andrea , Roska Jan , Orasova Eveline , Nociar Boris , Mego Michal , Mardiak Jozef , Chovanec Miroslav
Published: June 2023

e16564

Background: Performance status and visceral metastasis before first-line chemotherapy based on cisplatin (CDDP) predict survival of subjects with mUC. The objective of this study was to explore the prognostic value of selected plasma biomarkers. Methods: We have evaluated the samples from 86 mUC subjects (64.0% males). Performance status of ECOG 2 and visceral metastasis were present in 39.5% and 50.0% cases, respectively. The MILLIPLEX panels were used for determination of 51 biomarkers in plasma taken from patients before systemic therapy initiation. Study population was dichotomized into high and low groups by median for each parameter. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was carried out by the Cox regression model. Results: At median follow-up of 8.6 months (6.4-10.1), 95.3% of patients experienced disease progression and died. Better PFS was associated with low levels of nine biomarkers: IL-1RA (HR 0.65, P=0.0425), IL-6 (HR 0.52, P=0.002), IL-8 (HR 0.46, P=0.0002), IL-10 (HR 0.49, P=0.0004), IL-15 (HR 0.61, P=0.0198), IL-22 (HR 0.45, P=0.0043), MCP-1 (HR 0.59, P=0.0147), M-CSF (HR 0.59, P=0.0119), and VEGF-A (HR 0.64, P=0.0392). OS was significantly better in patients with low levels of G-CSF (HR 0.42, P=0.047), IL-1RA (HR 0.63, P=0.0314), IL-2 (HR 0.61, P=0.0249), IL-6 (HR 0.47, P=0.004), IL-8 (HR 0.44, P=0.0001), IL-10 (HR 0.43, P<0.0001), IL-15 (HR 0.53, P=0.0026), IL-22 (HR 0.47, P=0.0065), IL-27 (HR 0.63, P=0.0343), MCP-1 (HR 0.59, P=0.0134), M-CSF (HR 0.55, P=0.0042), TNFα (HR 0.53, P=0.0024), and VEGF-A (HR 0.59, P=0.0124). The independent prognostic values of IL-6, IL-10, MCP-1, M-CSF, and TNFα were confirmed in a multivariate analysis. Conclusions: In this study, we have proved that selected plasma biomarkers may have a prognostic value in mUC patients. Further research is required to understand their role as the biomarkers, but also potentially treatable pathogenic factors for mUC development. This research was funded by grant of the Integrated Infrastructure Operational Program, ITMS: 313011AFG5, co-financed by the European Regional Development Fund & OncoReSearch, Slovakia.
The impact of next generation sequencing on the management of urothelial cell carcinoma.
Authors: Abu-Hashish Hussein , Browne Rasheda , Zhu Xinhua
Published: June 2023

e16576

Background: The urothelial carcinoma is commonly seen in urethra, bladder, ureter and renal pelvis. Targetable mutations included PD-L1, FGFR, PIK3CA, BRCA2, FBXW7, and Tumor mutation burden (TMB) greater than 10 Muts/Mb. Next genome sequencing is widely used to guide treatment of oncology patients; however, the efficacy of this practice is still not clear. Methods: Patients used in this study are from the Northwell Health Zuckerberg Cancer Center. This is a retrospective cohort study of patients with advanced urothelial carcinoma, who underwent next genome sequencing and received treatment based on targetable mutations. The primary objective for this study is to measure the response rate for patients with actionable gene aberrations on targetable treatment. Results: The RECIST 1.1 guidelines were used when identifying measurable lesions. Measurable lesions were identified as lymph nodes with a short axis ≥ 15 mm, or soft tissue lesions with a long axis ≥ 10 mm. Our sample size included 48 patients with urothelial carcinoma, these include bladder, ureter and renal pelvis cancers. Of these 48 patients, 21 received targetable treatment (16 males, 5 females), from those 21 only 20 had imaging before and after treatment. Most common mutations were TMB, PD-L1 and FGFR. 4 patients out of 20 had an overall response rate (20%), 3 had partial response (PR) and 1 had complete response (CR) to their respective targeted treatment. 11 patients had stable disease (SD). Thus disease control rate (DCR) was 15 out of 20 patients (75%) (when including PR, CR and SD out of 20 patients) had no progression of disease. Finally, 5 of the 20 patients had an overall progression of disease (PD). Conclusions: The results of our study indicate that next genome sequencing led to good treatment outcomes for patients previously heavily treated with advanced urothelial malignancy.
Upper tract urothelial cancer (UTUC): Role of sequencing, molecular subtyping and treatment outcomes.
Authors: Belay Sarah , Li Wenping , Aragon-Ching Jeanny B.
Published: June 2023

e16578

Background: Upper tract urothelial cancers (UTUCs) are rare forms of urothelial cancer that behave in a more aggressive manner. Treatment response to immunotherapy may be less impactful in the adjuvant setting. Studies suggest molecular subtyping might predict survival outcomes. We seek to determine whether genomic sequencing, molecular subtype signatures can be used to predict patient response to chemotherapy in upper tract urothelial cancers. Methods: UTUC patients seen consecutively at a single institution during a 4-year period were evaluated with IRB approval. Analyses of NGS (next-generation sequencing) using Foundation Medicine or TEMPUS platforms were compiled. Decipher Bladder assay (research use only for UTUC) using a transcriptome microarray to characterize tumor specimens as luminal vs. non-luminal and 4 non-luminal subtypes. Retrospective and descriptive analyses were used to identify predictors of response and survival and therapeutic options patients (pts) underwent. Additional phenotypic factors such as initial staging, tumor location, response to neoadjuvant chemotherapy (NAC), and responses to treatment for localized or metastatic disease were determined. Results: UTUC patients whose clinical and demographic features were available for 23 patients (Male = 7; Female = 16); locally advanced = 9; metastatic = 14. Tumor samples were obtained with Decipher bladder assay (n=4); next-generation sequencing assay (n = 9). Neoadjuvant chemotherapy (NAC) was given in all pts with localized disease and for metastatic disease (n=11 pts). Platinum-based chemotherapy (PBC) resulted in median overall survival (mOS) of 36.6 mos compared to no chemotherapy 22.8 mos at the time of data cut-off. Decipher bladder assay showed basal subtype and mixed basal/claudin-low in 4 patients of whom one achieved stable disease though residual ypT3 after NAC and the 3 achieved progressive disease as best response, all with metastatic disease. NGS showed LOH - 21.01% and ATM truncation in 2 patients with prolonged responses to avelumab maintenance immunotherapy and 2 patients with CDK2A/2B loss with prolonged survival (mOS = 16.8 mos). Additionally, 5 patients were identified as having a TERT promoter variant, though this does not appear to have a significant relationship with survival or disease progression when compared to those without the variant. Conclusions: Results do not identify a specific NGS signature or subtype signature that predicts response to chemotherapy in the neoadjuvant or metastatic setting though receipt of chemotherapy appears to clinically affect outcomes in this small sample of UTUC patients. Further studies are needed to identify specific molecular signatures that would predict responses to therapy.
AI-based identification of FGFR3 mutation status from routine histology slides of muscle-invasive bladder cancer.
Authors: Saillard Charlie , Bannier Pierre-Antoine , Mann Philipp , Maussion Charles , Matek Christian , Hartmann Arndt , Eckstein Markus
Published: June 2023

e16580

Background: Gain of function mutations of the FGFR3 gene have been reported to be important driver mutations in a subset of muscle-invasive bladder urothelial cancer (MIBC). Subsequently, gene specific kinase inhibitors (e.g., erdafitinib) have been developed to target FGFR3 mutant metastasized MIBC with promising clinical activity. FGFR3 mutational status testing is required for erdafitinib treatment, but FGFR3 mutations are rare in metastatic MIBC (10-15%). Thus, cheap and fast pre-screening tools such as artificial intelligence (AI) based image classifiers could help to reduce turnover times of FGFR3 mutational testing and save costs arising from universal mutational testing. Herein, we propose an AI-based approach to identify MIBC FGFR3 mutated patients on routine histological slides. Methods: Slides from 612 patients with MIBC from two different sources (CCC-EMN Erlangen cohort n = 239, mutant = 20; TCGA-BLCA n = 373, mutant = 50) were used. The CCC-EMN cohort was used as a discovery set while TCGA-BLCA was used as an independent validation set. A two-step AI model was used to 1) extract features from each slide and 2) predict FGFR3 status from these features. The AUC, sensitivity and specificity were used as metrics to assess the performance of our model. Most predictive regions of FGFR3 mutation were reviewed by an expert pathologist. Results: The model reached an AUC/Sensitivity/Specificity of 0.82 [0.76-0.87] / 0.90 [0.82-0.97] / 0.57 [0.53-0.62] on TCGA-BLCA, substantially improving upon results previously reported on the same cohort (Loeffler et al. 2021: AUC = 0.70). Most predictive regions of FGFR3 mutation revealed monomorphous conventional urothelial tumor morphology and low desmoplastic tumor stroma content, while least predictive regions contained pleomorphic tumor morphology and high amounts of desmoplastic tumor content. Conclusions: By ruling out 57% of MIBC FGFR3 wild type tumors with high sensitivity, our model is the first to reach valuable performance for clinical use. Consequently, this study paves the way for the development of FGFR3 pre-screening tools to ease the management of patients with MIBC.
Association of enfortumab vedotin (EV) toxicity with baseline parameters and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Semaan Karl , El Zarif Talal , Saliby Renee Maria , Eid Marc , Saad Eddy , Labaki Chris , Kwak Lucia , Kaymakcalan Marina D. , Baca Sylvan , Berg Stephanie A. , Xie Wanling , Mantia Charlene , Choueiri Toni K. , McGregor Bradley Alexander , Bellmunt Joaquim
Published: June 2023

e16585

Background: EV is an antibody-drug conjugate approved for the treatment of mUC. Toxicities of special interest with EV are neuropathy, rash, and hyperglycemia. While it has been reported that EV-related skin toxicity may be associated with better responses to EV, the relationship of EV-related adverse events (AEs) with clinical outcomes is still unclear. The aim of this study is to investigate the association of EV-related toxicity and clinical outcomes among pts with mUC. Methods: We retrospectively reviewed demographic, clinical and laboratory data from pts with mUC who were treated with > 1 dose of EV at Dana-Farber Cancer Institute. AEs were graded per the CTCAE V5.0. A multivariable Cox regression analysis was performed to analyze overall survival (OS) and the occurrence of AEs while accounting for age, sex, and baseline peripheral neuropathy (BPN). A landmark analysis was performed to evaluate the association of toxicity occurrence and clinical outcomes, accounting for guarantee-time bias. Results: Our cohort included 54 pts with a median age of 72 years, of which 72.2% (n = 39) were male. Median follow-up was 18.6 months. Neuropathy was the most common AE occurring in 66.7% (n = 36) pts with 7.4% (n = 4) grade 3-4. Skin toxicity occurred in 57.4% (n = 31) pts with 3.7% (n = 2) grade 3-4. There were no recorded grade 5 AEs. Worse baseline Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was associated with the development of more AEs (HR = 2.8; 95% CI = 1.2-6.3; p = 0.01). Decreased baseline hemoglobin (Hb) was associated with more EV-related neuropathy (1/HR = 1.25; 95% CI = 1.1-1.4; p = 0.01) and higher neuropathy grade (1/HR = 1.7; 95% CI = 1.1-2.5; p = 0.01). Moreover, pts who have previously received immune checkpoint inhibitors (ICI) were more likely to develop EV-related rash (HR = 5.4; 95% CI = 1.1-26.2; p = 0.03; Table 1). Overall, 30 deaths were observed, and median OS was 13.3 months (95% CI = 9.5-NA). A landmark analysis at 2 weeks of therapy (marking the final infusion of the 1st cycle of EV therapy) showed that in 16 pts who developed early skin toxicity, OS was improved vs. 38 pts who did not develop early skin toxicity (HR = 0.4; 95% CI = 0.2-0.9; p = 0.04). Conclusions: To our knowledge, this is the first study to investigate the association of EV-related AEs and clinical outcomes of pts with mUC using a landmark analysis. ECOG-PS and baseline Hb may be predictors of EV-related AEs. The incidence of early skin toxicity may be associated with improved OS. [Table: see text]
Neutrophil-to-lymphocyte ratio as a predictor of immune checkpoint inhibitor therapy response in advanced bladder cancer.
Authors: Nair Monica , Dawsey Scott , Pramod Nikhil , Clemenceau Jean Rene , Gilligan Timothy D. , Ornstein Moshe Chaim , Wee Christopher Eing , Nizam Amanda , Almassi Nima , Weight Christopher J. , Gray Michi , Echle Jessica , Ciezki Jay P. , Stephans Kevin L. , Tendulkar Rahul D. , Scott Jacob , Gupta Shilpa , Mian Omar Y.
Published: June 2023

e16586

Background: Immune checkpoint inhibitor (ICI) therapy is a novel and promising agent for treating muscle invasive bladder cancer (MIBC). However, there is a need for further understanding of which patient factors or biological markers can be used to help identify patients who will have a successful response to ICI therapy. We hypothesized that Neutrophil-to-Lymphocyte Ratio (NLR) could be predictive of response to ICI therapy as this ratio has previously been reported to correlate with a higher number of myeloid derived suppressor cells. Methods: A retrospective cohort analysis was performed on patients with advanced or metastatic bladder cancer who were treated with ICI therapy at a single institution between 2015-2020. Information on survival, disease recurrence, and patient characteristics was gathered. Neutrophil and lymphocyte numbers were recorded at time of ICI administration and a ratio of neutrophils to lymphocytes was calculated. The median of these values was calculated and used to divide the cohort into low NLR and high NLR. Tissue samples from a subset of these patients were collected and sent for multiplex immunohistochemistry with a myeloid and T cell staining panel. Results: In a cohort of 115 patients with advanced bladder cancer treated with ICI, the mean time to last follow up or event (death or disease progression) was 375.78 days (SD 41). 35 patients (30%) had either a complete or partial response to ICI therapy. A Kaplan Meier survival analysis shows a significant difference in survival between the low and high NLR group, with lower NLR having a longer event free survival (Wilcoxon rank p = 0.0156). Multiplex IHC showed variable tumor and adjacent microenvironmental distributions of myeloid and lymphoid marker positive populations in ICI responders and non-responders. Conclusions: In an effort to better predict which patients may benefit from ICI therapy, we have studied NLR at the time of ICI administration and its association with event free survival. Our results suggest that a lower NLR could be associated with a longer event free survival. Further research is being conducted to study the immune microenvironment as it relates to bladder cancer response to ICI therapy.
Real world outcome of neuroendocrine carcinomas of the bladder compared to conventional tumors of the bladder.
Authors: Unlu Serhan , Ogbue Olisaemeka , Nanah Abdel Rahman , Sorathia Sharmeen , Almassi Nima , Lapinski James , Haddad Abdo S. , Daw Hamed
Published: June 2023

e16591

Background: Platinum based neoadjuvant chemotherapy (NAC) has been shown to be a beneficial treatment strategy that increases overall survival (OS) in bladder cancer (BC) when compared to radical cystectomy (RC) alone, and the benefit was observed in multiple histologies associated with BC. Neuroendocrine carcinomas (NEC) of the bladder are a rare and aggressive BC subtype known to be chemotherapy sensitive, with improvement in oncological outcomes after NAC. However, due to inherent differences in natural progression of different BC histologies, higher chemosensitivity does not necessarily mean NEC has better outcomes compared to other BC histologies after NAC. We analyzed the outcomes of NEC patients and non-NEC BC patients to investigate the differences in benefit observed from NAC, and in oncological outcomes. Methods: Patients with BC that underwent cystectomy from 2000 to 2022 at the Cleveland Clinic Foundation were identified. Patients with NEC at transurethral resection (TUR) or cystectomy, and patients with BC with other pathologies (non-NEC) were selected. pCR was defined as downstaging from tumor presence in diagnostic resection to no residual tumor (pT0N0) after NAC. Survival outcomes of interest included recurrence-free survival (RFS) and OS. Results: A total of 562 cases of BC that underwent RC were identified. Of these, 50 patients included a diagnosis of NEC in their pathology report, either in TUR (n=42), or in RC (n=8) with 36% (18/50) of them with NEC without an associated conventional urothelial cell carcinoma (UCC), while 502 patients were diagnosed with UCC, with or without variant histologies and 10 patients with other histologies without UCC. Among patients with NEC, median age was 69 and M:F-45:5. When NEC patients were compared to non-NEC BC patients, they were more likely to present with muscle invasive bladder cancer (MIBC), (83% vs 60%; p=0.003) and receive NAC (86% vs 35%; p<0.001) Most common chemotherapy regimen used in NEC patients was combination platinum and etoposide (26/36), compared to platinum and gemcitabine in non-NEC BC patients (141/184). pCR rate was 36% (13/36) in NEC, compared to 20% (36/184) in non-NEC cohort. (p=0.046). In terms of survival outcomes, RFS and OS were similar between the two groups (log-rank p-values 0.08 and 0.14, respectively). Conclusions: NAC prior to RC is beneficial in NEC of the bladder as a higher proportion achieve pCR when compared to non-NEC BC. In our cohort, despite presenting with more advanced disease, oncologic outcomes after NAC with RC were similar between the two groups. [Table: see text]
Urine DNA model to predict response to neoadjuvant immune checkpoint inhibitors combined with chemotherapy in muscle-invasive bladder cancer.
Authors: Hu Hailong , Liu Huanhuan , Zhao Gangjian , Zhang Zhe , Shen Chong , Qin Jiayue , Cao Shanbo
Published: June 2023

e16594

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy show promise in the treatment of muscle-invasive bladder cancer (MIBC). However, not all patients benefit from the treatment. Urine can overcome shortcomings of tissue-based biomarkers to guide treatment decisions. Methods: Thirty-Three patients were recruited in this study and they received three cycles of tislelizumab 200 mg intravenously on day 1 plus nab-paclitaxel 200 mg intravenously on day 2 every three weeks, followed by surgical treatment. Acornmed 808 panel and shallow whole-genome sequencing were performed to predict the efficacy based on the urine DNA. Results: The urine ctDNA levels (highest variant allele fraction) were significantly lower in responder (CR and PR ) patients than this in non-responder (SD and PD) patients (p < 0.001). In addition, a decrease in chromosomal instability number (CIN) occurred in responding tumors (p = 0.028). Furthermore, ROC curves were used to compare the sensitivity and specificity of efficacy prediction, including the urine ctDNA level and CIN. In the ROC analysis, urine ctDNA level setting with an area under the ROC curve (AUROC) of 0.781 (95% CI 0.603 - 0.905, p = 0.005), achieving 100% sensitivity and 54.6% specificity in efficacy prediction. The ROC curve for CIN achieved a sensitivity of 68.2% and specificity of 72.7% (AUC = 0.731; 95% CI: 0.549-0.870, p = 0.013). Combination urine ctDNA level and CIN achieved a sensitivity of 100%, specificity of 63.6% (AUC = 0.806; 95% CI: 0.631-0.922, p = 0.002), positive predictive value (PPV) of 0.846, and negative predictive value (NPV) of 1.000. Conclusions: The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Cell-free urinary tumor DNA to detect minimal residual disease prior to repeat-transurethral resection of bladder tumor in non-muscle invasive bladder cancer: A prospective study.
Authors: Rose Kyle M. , Murthy Prithvi , Gould Billie , Huelster Heather L. , Davaro Facundo , Camperlengo Lucia P. , Du Pan , Jia Shidong , Vosoughi Aram , Grass G. Daniel , Spiess Philippe E. , Gilbert Scott Michael , Sexton Wade J. , Li Roger
Published: June 2023

e16598

Background: Cell-free urinary tumor DNA (utDNA) generated from tumor genomic sequencing is an emerging biomarker showing tremendous potential for detecting minimal residual disease (MRD) in muscle-invasive and metastatic bladder cancer. We performed a prospective study to assess utDNA’s ability to measure MRD at the time of standard-of-care repeat transurethral resection of bladder tumor (rTURBT) in non-muscle invasive bladder cancer (NMIBC). Methods: Patients with high-risk NMIBC were enrolled prior to rTURBT. Index tumor and rTURBT mutational profile was performed via PredicineWES whole exome sequencing across 20,000 genes. Genes with non-synonymous (NS) mutations observed in index and rTURBT specimens identified in a minimum of two samples are reported. Urine samples were taken immediately prior to r-TURBT. utDNA detection was performed by ultra-deep sequencing of urinary cfDNA using a custom panel of up to 50-baseline mutations per patient together with a fixed core panel covering hotspot regions and actionable variants via PredicineBEACON Urinary tumor fraction was used to call utDNA positivity. The primary endpoint was the detection of utDNA to predict MRD at the time of repeat-TURBT. Results: Eleven patients underwent rTURBT for high risk NMIBC. Residual tumor was detected at rTURBT in 8/11 (73%) patients. Fifty genes with NS mutations found in at least two samples were identified including TP53, PIK3CA, RB1, MYC, CDKN1A and ARID1A. A median of 146 (range 39-418) and 91 NS (range 2-312) mutations were identified in the index and re-TUR specimens, respectively. Concordance rates were 83% on average between primary and rTURBT, highest for patients upstaged to T2 disease, and lowest for patients harboring CIS. Genomic alterations in urinary tumor DNA were detected in ten patients. The tumor fraction of utDNA was higher in patients with residual disease (mean 2.5% vs. 0.2%, p=0.10). Using tumor-fraction to predict MRD, the area under the receiver-operator curve (AUC) for this test was 0.85. Using an optimal threshold of ≥3.3% tumor-fraction to define utDNA positivity, the test had a sensitivity of 75% at 100% specificity. Conclusions: Urinary tumor DNA shows promise as a surrogate for minimal residual disease and may predict TURBT pathology for NMIBC. Genomic alterations between index and rTURBT tumors are highly concordant in papillary tumors even in the setting of upstaging, which may aid in targeted intravesical or systemic therapy selection. Larger cohorts and long-term follow up is needed to determine if utDNA can risk-stratify patients prior to rTURBT and predict long-term recurrence.
Tislelizumab in combination with gemcitabine plus cisplatin as neoadjuvant therapy for lymph node‐positive bladder cancer.
Authors: Yang Xiao , Cao Qiang , Li Pengchao , Cai Lingkai , Zhuang Juntao , Lyu Qiang
Published: June 2023

e16599

Background: Although multiple single-arm clinical trials have shown promising pathologic complete response (pCR) rates with neoadjuvant ICIs combined with gemcitabine plus cisplatin in MIBC, lymph node‐positive bladder cancer is generally excluded. Our specific aim was to compare the efficacy and prognosis of neoadjuvant tislelizumab combined with gemcitabine plus cisplatin in patients with lymph node‐positive bladder cancer. Methods: In this single arm phase II study, eligible patients had cT2-T4a N+ M0 MIBC, cisplatin-eligible, and to be planned radical cystectomy (RC). Patients received tislelizumab 200 mg in day D8, cisplatin 70 mg/m2 D2, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for 3 or 4 cycles. RC was performed within 6 weeks after last dose treatment. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging ( < ypT2), EFS, OS and safety. Results: By Jan 2023, 17 eligible pts (2cT2, 10 cT3, 5 cT4) were enrolled. 14 pts have completed neoadjuvant therapy, with median age of 67 (60-81) years, among whom 10 pts underwent RC and two declined RC. According to RECIST 1.1, 6 pts achieved a clinical complete response (cCR)(6/14,42.8%). Pathological results revealed 5 pCR (ypT0N0, 50%), 3 ypT1N0, and 2 ypT2/T3N0. A complete nodal response (pN0) occurred in 10 (100%) pts post- tislelizumab +chemotherapy and 8 ( < ypT2N0,80%) pts achieved pathologic downstaging. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (11/14,78.5%), nausea (9/14,64.2%), vomiting (8/14,57.1%), decreased appetite (6/14,42.8%), fatigue (4/14,28.5%), pruritus (3/14,21.4%) and ALT/AST increased (4/14,28.5%). Grade ≥3 neoadjuvant therapy related AEs were neutropenia (n = 3), thrombocytopenia (n = 2), anemia (n = 2). One patient discontinued GC plus tislelizumab due to AEs. Conclusions: Patients with clinically lymph node‐positive bladder cancer have significant pN0 after neoadjuvant therapy. Neoadjuvant tislelizumab plus gemcitabine/cisplatin was feasible and provided meaningful pathologic responses in lymph node‐positive bladder cancer. Clinical trial information: NCT04570410 .
ANTICIPATE phase I: Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).
Authors: Galsky Matt D. , Sfakianos John P. , Ye Ding-Wei , Song Xiaodong , Hu Hailong , Shore Neal D. , Zhang Xiaoping , Zhang Mingming
Published: June 2023

e16607

Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: ANTICIPATE Phase I was a dose escalation study to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of APL-1202. Eligible patients had newly diagnosed MIBC, were cisplatin-ineligible or refused cisplatin-based neoadjuvant chemotherapy, and were planned for radical cystectomy (RC). A standard 3+3 dose-escalation design was employed. On day 1 of each cycle, a single dose of 200 mg tislelizumab was administered intravenously. APL-1202 was administered orally 3 times daily and with the dose escalated in 3 successive cohorts (375 mg, 750 mg, and 1,125 mg). Intra-patient dose escalation was not allowed. Blood samples were collected for pharmacokinetics and other translational studies. Results: Nine patients have been enrolled in phase I: 3 patients each at 375 mg, 750 mg, and 1125 mg of APL-1202. All patients had predominant urothelial cancer with cT2 (6/9) and cT3 (3/9); PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay and 1/9 (11.1%) patients was positive. No dose-limiting toxicities were observed at either 375 mg, 750 mg, or 1125 mg daily dose of APL-1202. Treatment-related adverse events (TRAE) were observed in 6 patients. All AEs were grade 1, except 1 grade 2 T wave abnormality on ECG and 1 grade 3 liver dysfunction. No grade 4 or 5 related AEs were observed. The patient with grade 3 liver dysfunction recovered to baseline within 2 weeks and underwent RC. Pathologic downstaging to < pT2 was observed in 5/8 (62.5%) and 1/8 (12.5%) with pT0 in 8 evaluable patients; 1 patient refused RC. Conclusions: APL-1202 plus tislelizumab was well tolerated. The RP2D of APL-1202 was identified as 1125 mg daily dose. Early efficacy signals were observed including pathologic downstaging to < pT2 (5/8, 62.5%) and pT0 (1/8, 12.5%). Phase 2 trial was ongoing. (NCT04813107). Clinical trial information: NCT04813107 .
Preoperative oral antibiotic bowel preparation regimens in radical cystectomies with continent diversion.
Authors: Simhal Rishabh , Wang Kerith Ruoyao , Poluch Maria L. , Shah Yash , Leong Joon Yau , Shah Mihir S. , Gomella Leonard G. , Chandrasekar Thenappan , Lallas Costas D.
Published: June 2023

e16610

Background: Bowel preparation regimens (BRs) were historically standard before radical cystectomy (RC) with urinary diversion to decrease infection and anastomotic breakdown. However, the Enhanced Recovery After Surgery protocol (ERAS) no longer includes BRs. Recent data show that BRs may exacerbate frailty, worsen surgical outcomes, and prolong recovery. Importantly, however, previous studies did not stratify by diversion type. We performed a population-based analysis of preoperative oral antibiotic BRs (OABRs) with RC, alongside subgroup analyses to compare outcomes by diversion type. Methods: RCs performed from 2019-2020 were identified using the new NSQIP Cystectomy-Targeted PUF. Captured variables included OABR, diversion type, demographics, comorbidities, and perioperative outcomes. Univariate analysis with two tailed chi square and t tests was performed to compare baseline characteristics, 30-day mortality, and complications. Multivariable logistic regression with stepwise-backward-elimination (p > 0.25) adjusted for mechanical BRs, operative approach, comorbidities, functional status, demographics, ASA class, labs, and staging. Results: In total, 3,894 RCs were performed, of which 357 (9.2%) included OABR. There were no significant baseline differences between the OABR and the non-OABR cohorts. On univariate analysis, OABR patients had increased operative time, length of stay (LOS), minor complications, and bleeds. On subgroup analysis, ileal conduit patients experienced higher rates of the 4 aforementioned outcomes plus deep wound infections and NGT use. However, the continent diversion subgroup was not associated with increased operative time, LOS, or any complications. Continent diversion had significantly lower rates of sepsis and ureteral fistula formation. Upon multivariable adjustment, OABR was not associated with increased rates of any complications across any subgroup. OABR did confer significantly decreased odds of sepsis in continent diversion patients. Conclusions: Supporting ERAS recommendations, this study showed that pre-RC OABRs do not improve outcomes and increase LOS for ileal conduits. However, this study uniquely included continent diversions, such as neobladders and Indiana pouches. Importantly, in continent diversion patients, OABR did not increase LOS or complications while decreasing sepsis rates. These findings suggest possible utility of OABR before RC with continent diversion.
Clinical efficacy analysis of patients (pts) with HER-2 expressing metastatic urothelial carcinoma (mUC) treated with enfortumab vedotin (EV).
Authors: Jiang Cindy , Alhalabi Omar , Haro-Silerio Jaime , Qiao Wei , Shah Amishi Yogesh , Siefker-Radtke Arlene O. , Gao Jianjun , Goswami Sangeeta , Alva Ajjai Shivaram , Koshkin Vadim S. , Guo Charles , Campbell Matthew T.
Published: June 2023

e16618

Background: EV, an antibody drug conjugate (ADC) targeting NECTIN-4, is an approved salvage treatment for unselected pts with mUC. ADCs targeting the human epidermal growth factor receptor-2 (HER-2) have also shown robust activity in clinical trials for mUC with tumor HER-2 expression. We investigated the interaction between HER-2 expression and clinical outcomes of pts treated with EV, which are currently unknown. Methods: We conducted a retrospective, single institution study analyzing pts with mUC who received EV. Immunohistochemistry (IHC) staining for HER-2 was completed with PATHWAY anti-HER2 (4B5) Antibody (Ventana Medical Systems, Tucson, AZ) using established breast cancer scoring algorithm. Wilcoxon rank sum and Fisher exact tests were used to compare continuous and categorical variables, respectively. Cox proportional hazards regression model was used to evaluate a variable’s ability to predict overall survival (OS). Variables with p-value ≤0.1 were included in the multivariate analysis (MVA). Results: We identified 158 pts with mUC who received EV. Median age at EV start was 70 (IQR 66-76), most pts were Caucasian (144, 91%), male (108, 68%), primary bladder tumors (113, 72%), and pure urothelial histology (95, 60%). 96 pts (61%) received prior platinum therapy and 117 pts (74%) had prior immunotherapy. ECOG scores ≥2 was seen in 54 pts (39%) while 75 pts (54%) had Bellmunt scores ≥2 (54%). Median follow up time was 12.5 months and median OS from EV start was 13 months. 94 pts (60%) had HER2 IHC staining. There was no association between HER2 intensity and any of the clinical variables. On univariate analysis (UVA): HER2 3 vs HER2 ≤2 HR was 0.38 (0.14, 0.98), male vs female HR=1.56 (0.94, 2.58), ECOG ≤1 vs ≥2 HR=0.6 (0.38,0.95), Bellmunt score 0-1 vs 2-3 HR=0.49 (0.3, 0.78), and hemoglobin (Hgb) HR=0.75 (0.67, 0.85). MVA showed HER2 3 vs HER2 ≤2 HR was 0.42 (0.16, 1.12), male vs female HR=2.3 (1.17, 4.42), ECOG ≤1 vs ≥2 HR=0.56 (0.30, 1.05), and Hgb HR=0.77 (0.65, 0.92). Conclusions: MVA of this single-site retrospective cohort did not show any association between HER2 expression and survival outcomes in pts with mUC who received EV. Further studies are needed to continue assessing the role of HER2 as a potential prognostic and predictive biomarker in UC, especially if HER-2 directed therapies become incorporated in the mUC treatment paradigm. [Table: see text]
Preclinical development of RAG1-40-31L: A novel small activating RNA-lipid conjugate targeting tumor suppressor gene p21 for treatment of non-muscle invasive bladder cancer.
Authors: Jarvelainen Harri , Lin Wei-Hsiang , Kang Moorim , Zhou Xiaojie , Place Robert F. , Li Long-Cheng
Published: June 2023

e16620

Background: Loss-of-function of tumor suppressor genes are the dominant driving force in tumorigenesis. Restoration in function and/or expression of these genes holds tremendous therapeutic potential in cancer treatment. Bladder cancer is the 9th leading cause of cancer-related deaths in the United States in which ~75% of all newly diagnosed cases are non-muscle invasive bladder cancer (NMIBC). Standard-of-care includes intravesical installation of Bacillus Calmette-Guerin following tumor resection with an expected failure rate of ~50% within 6 months for patients with high-grade tumors. RNA activation (RNAa) is a mechanism in which short RNA duplexes termed small activating RNA (saRNA) induce gene transcription by targeting non-coding regulatory sequence ( i.e., promoters) embedded in chromatin. Thus, saRNA-induced overexpression of p21WAF1/CIP1 (p21) – a tumor suppressor of several anti-growth pathways – may hold therapeutic potential in bladder cancer. Through conjugation of a novel lipid ( i.e., C5X5), we have created a p21-targeting saRNA drug candidate referred to as RAG01-40-31L for delivery to bladder cancer cells in vivo. The aim of this work was to characterize the intravesical administration of RAG01-40-31L on p21 induction and its anti-tumor potential in NMBIC models. Methods: In vitro expression analyses were performed to investigate p21 induction via saRNA in KU7 and T24 bladder cancer cell lines by RT-qPCR and immunoblot analysis. Cell cycle analysis and tumorigenicity assays examined impact of RAG1-40-31L on cancer cell growth. Orthotopic human bladder tumors were established in female BALB/c nude mice using the recombinant cell line KU7 engineered to overexpress luciferase reporter. Tumor growth was monitored in live animals via luciferase bioluminescence using an in vivo imaging system. Plasma and tissue were harvested for drug exposure and expression analytics. Results: In vitro analyses indicated RAG1-40-31L activated p21 expression by approximately 6-fold and inhibited bladder cancer cell growth ( i.e., cell cycle arrest, apoptosis, and senescence) in a dose-dependent manner with low nanomolar potency. Intravesical administration of RAG1-40-31L (3 times per week for 2 weeks) inhibited growth of orthotopic tumors by 65% in mouse bladder models. Single-dose pharmacokinetics demonstrated a half-life (t1/2) of ~114 h with minimal systemic exposure (~0.05% of that of bladder tissue). Conclusions: These data constitute a preclinical proof-of-concept for saRNA as a novel p21-targeting modality in the treatment of cancer. The C5X5 lipid conjugate appears to be a viable approach to enhance oligonucleotide delivery and activity in bladder cancer. Preclinical safety assessment studies to enable clinical trials of RAG01-40-31L are currently underway.
Baseline endogenous serum testosterone levels and all-cause mortality in men with prostate cancer treated by radical radiotherapy: 11-year follow-up data.
Authors: Sundar Santhanam , Shawcroft Ewan , Jones Lauren , O'Cathail Micheal , Hosni Shaymaa Usama , Little Jessica , Walker Georgina , Cox Ashley , Fergusson Eamonn
Published: June 2023

e17003

Background: Low levels of serum testosterone are associated with higher all-cause mortality and cardiovascular mortality in some studies.(PMID: 18040028). But men with low levels of serum testosterone at reduced risk of developing prostate cancer. (PMID: 30077399). In middle-aged and elderly men, single point testosterone measurements have been shown to reliably reflect long term androgen exposure. [PMID: 1548361]. We assessed the interaction of pre-treatment serum testosterone levels and long term all-cause mortality in men with newly diagnosed prostate cancer. Methods: Prostate cancer pts enrolled in an ethics approved, prospective study evaluating a rating scale. Baseline serum testosterone levels were measured before the pts were commenced on androgen deprivation therapy and radical radiotherapy. Patient characteristics: Mean age 68.2yrs (median 69yrs); Age range category < 60yrs:14.9% , 61-70yrs:47.3% and > 71 yrs: 37.8%. Charlson Comorbidity Index (CCI) prevalence at baseline as follows CCI- Low risk : 39.9%; CCI-medium risk : 51.4%; CCI-high risk: 8.8%. PSA median level was 10.85 ug/L. Tumour was localised in a majority of pts- stage T1/T2 in 72% . Pts with M1 disease were not enrolled. Histology grade: Gleeson grade 6 in 7.4% and Gleeson grade 7 in 53.4% . Serum testosterone: Median 11.9 nmol/l; Mean 12.4 (Min-Max 2.6 to 26.7). Cox proportional hazards regression used to analyze the effect of baseline Serum Testosterone on long term overall survival, while controlling for covariates (age, cancer T stage, PSA category, Gleeson Category and Charlson Comorbidity index). Results: Lower levels of serum testosterone at baseline were associated with decreased all-cause mortality. There was no significant correlation between testosterone levels and age in our study sample of relatively elderly population (Pearson Correlation p = 0.362); There was no correlation testosterone levels and PSA levels(P = 0.821); no association between serum Testosterone levels and Gleeson Grade as well as T stage. (F = 0.78 ; P = 0.46 and F = 1.34 ; P = 0.26 respectively). There was also no significant variation in testosterone levels according to Comorbidity categorised by Charlson Comorbidity Index. (F = 1.31 P = 0 .26). Conclusions: Lower Serum testosterone levels were associated with decreased all-cause mortality in this prospectively collected survival data of non-metastatic Prostate cancer patients. [Table: see text]
Real-world evidence analysis of early-stage prostate cancer using natural language processing.
Authors: Juárez Álvaro , Carles Joan , Conde-Moreno Antonio José , Maroto-Rey Pablo , Puente Javier , Muñoz Del Toro Jacobo , Calderon Jose M , Lopez Maria , Valdivieso Juan , Casadevall David , Taberna Miren , Alcaraz Antonio
Published: June 2023

e17007

Background: Real-world evidence (RWE) on the epidemiology and management of localized/locally advanced prostate cancer (LPC) is lacking. Here we used EHRead, a natural language processing framework based on SNOMED CT terminology, to extract clinical information from electronic health records (EHRs) to perform a comprehensive description of a real-world cohort of LPC patients. Here we present a follow-up of the project already communicated at ESMO 2020. Methods: This is an observational, multicenter, retrospective study based on the secondary analysis of free-text and structured clinical information found in EHRs from all observed adult patients with LPC between January 2014 and December 2018 in 12 Spanish hospitals. A total of 375 variables were extracted using EHRead to assess patient clinical characteristics, treatment patterns and journey across different prostate cancer stages. Event-free survival (EFS) was analyzed in incident LPC patients with presence of Gleason or PSA and follow-up greater than 0 days. A multivariable Cox-proportional hazards model was applied to obtain adjusted hazard ratios (aHR). Results: We observed 19788 patients with LPC during a median of 3.5 (interquartile range 1.4-7.4) years of follow-up. 52% of patients had low- (LR), 21% intermediate- (IR) and 27% high-risk (HR) disease. 3938 (18%) patients transitioned to other disease stages, leading to castration-resistant prostate cancer (mCRPC) in 4%, 7%, 16% of patients with LR, IR, and HR LPC, respectively. 7884 (42%) patients received radiotherapy (RT), 7021 (38%) prostatectomy (PT), 6061 (31%) androgen deprivation therapy (ADT), and 1034 (6%) active surveillance. Local recurrence was observed in 3% and distant metastasis in 11% (57% bone, 37% visceral). Distant metastases were observed in 7%, 12% and 21% of HR, IR and LR; 8% vs. 9% of PT vs. RT; and 16% vs 6% of ADT vs. no ADT, respectively. EFS was assessed in 7465 (38%) patients, with a 4-year EFS rate of 18%. Median EFS was 22, 13, and 8 months for LR, IR, HR; 23 vs. 12 months for PT vs. RT; and 8 vs. 21 months for ADT vs. no ADT, respectively. A multivariable cox proportional hazards model is presented in the following Table. Conclusions: During the study period, 11% of all LPC patients developed metastatic disease, with only 18% remaining event-free at 4 years. Transition to mCRPC was 4- and 2-fold higher in HR vs. IR and LR disease, respectively. Disease risk, treatment with RT and/or addition of ADT were independently associated with shorter EFS. Our findings suggest that, despite adjuvant treatment, LPC local extension and histopathological characteristics at diagnosis remain critical determinants of patient prognosis. A more detailed analysis in patients with available Gleason and PSA is underway. [Table: see text]