bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1 expression and BCG response in nonmuscle invasive bladder cancer.
Authors: Woldu Solomon L. , Gerald Thomas , Margulis Vitaly , Halstuch Daniel , Ber Yaara , Lifshitz Karin , Margel David , Lotan Yair , Jia Liwei 
Published: February 2022

545 Background: Intravesical bacillus Calmette Guerin (BCG) is the standard of care adjuvant therapy for high risk non-muscle invasive bladder cancer (NMIBC), yet many patients experience recurrence or disease progression. The mechanism of action of BCG is believed to be related to stimulation of immune surveillance. Relatedly, systemic immune checkpoint inhibition is currently being utilized in advanced bladder cancer and approved for BCG unresponsive NMIBC. We sought to determine the association between PD-L1 expression and BCG treatment. Methods: We identified 102 BCG-naïve patients with high grade (HG) NMIBC treated with BCG. All patients underwent initial transurethral resection (TUR) for pathologic diagnosis. Dako 22c3 assay was used to determine PD-L1 expression. Patients were defined as PD-L1 positive if the combined positive score (CPS) > 0. BCG unresponsiveness was defined by presence of high grade disease at 6 months following adequate BCG (one induction and maintenance cycle or two induction cycles) for pT1 or 12 months for CIS or presence of pT1 at 3 months following induction. HG relapse was defined as presence of any HG disease after being followed for 6 months after BCG. Results: The median follow-up time was 57 months. Median number of BCG maintenance cycles was 1, and 17 (16.7%) patients underwent immediate reinduction BCG. PD-L1 expression was observed 5.9% of pTa, 30.0% of pT1, and 3.6% of CIS. BCG unresponsiveness and HG relapse were observed in 32 (35.6%) and 29 (34.5%) patients, respectively. On univariate analysis, PD-L1 expression was inversely associated with BCG unresponsiveness (OR = 0.112; 95% CI 0.014-0.898) but not high grade relapse (OR = 0.296; 95% CI 0.061-1.440). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression for BCG responsiveness were 22%, 97%, 93%, and 41%, respectively. The post-test probability of BCG responsiveness was 93% in patients positive for PD-L1 based on a positive likelihood ratio of 7.33 for PD-L1 expression. On multivariate regression, pT1 (OR = 0.159; 95% CI 0.045-0.600), CIS (OR = 0.247; 95% CI 0.071-0.857), and PD-L1 expression (OR = 15.625; 95% CI 1.779-142.857) were independently associated with BCG responsiveness. Conclusions: PD-L1 expression in HG NMIBC was low, and patients with PD-L1 expression at initial TUR were more likely to harbor invasive disease. Patients showing PD-L1 expression were more likely to demonstrate BCG responsiveness. These findings suggest a role of PD-L1 in the immune surveillance mechanism of BCG at initial pathologic diagnosis and may assist in predicting responses to BCG among patients with HG NMIBC. Further investigation is required to determine if additional immune checkpoint markers have strong correlation with BCG response, particularly among patients without PD-L1 expression.
Expanding the use of targeted therapy for urothelial bladder cancer (UBC): Non-FGFR3 receptor tyrosine kinase (RTK) gene rearrangements (ReAr) and fusions (fus).
Authors: Necchi Andrea , Pavlick Dean C. , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Spiess Philippe E. , Grivas Petros , Parini Vamsi , Decker Brennan , Lin Douglas I. , Danziger Natalie , Levy Mia Alyce , Ross Jeffrey S. 
Published: February 2022

550 Background: After the regulatory approval of erdafitinib targeting FGFR genomic alterations (GA), molecular profiling and targeted therapy indications may further expand in UBC. We queried a large database of advanced UBC to study the landscape of RTK ReAr and Fus to categorize additional targets beyond FGFR1-3 that have potential to further personalize treatment of this disease. Methods: We analyzed data from 8,233 UBC cases, which underwent hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression in tumor cells was assessed by IHC (Dako 22C3). Results: A total of 1,210 (14.7%) UBC featured known and likely large-scale (LS) internal ReAr with 414 (5%) ReAr in RTK genes. The ReAr/fus were distributed among ABL1 (3), ALK (3), BRAF (29), CDK12 (44), CDK8 (1), EGFR (10 ), ERBB2 (3), FGFR1 (2), FGFR2 (16 ), FGFR3 (231), FLT3 (1), MAO2K4 (4), NTRK1 (7 ), NTRK2 (5), NTRK3 (7), RAF1 (31 ), RET (8) and ROS1 (9). LS ReAr were divided into LS ReAr-associated gene deletions (1%), truncations (1%), rearrangements (61%) and fusions (37%). FGFR3 fus accounted for 81% of RTK fus with BRAF and RAF1 both at 2%. The greatest frequencies of kinase ReAr were in CDK12 (29%), FGFR3 (16%), RAF1 (13%) and BRAF (12%). Additional noteworthy ‘targetable’ RTK ReAR and fus included NTRK1-3 (19 cases), ROS1 (9 cases), RET (8 cases) and ALK (1 case). 407 (98.4%) of the RTK ReAr/fus-positive UBC had only 1 RTK ReAr/fus GA and 7 (1.6%) had 2 ReAr ReAr/fus, 6 (85.7%) of which involved FGFR3. Compared with LS ReAR negative UBC, the LS ReAR UBC cases revealed similar gender and age characteristics, MSI status, similar frequencies of TMB ≥ 10 mut/Mb and PD-L1 expression in tumor cells ≥1% and ≥50%. Conclusions: At a 5% frequency, potentially ‘targetable’ RTK gene rearrangements and fusions are a rare but important opportunity to further personalize treatment selection of UBC, including RTK inhibitors, PARP inhibitors ( CDK12) and immunotherapy. This potential for clinical trials supports broader CGP, compared to targeted FGFR sequencing, in order to uncover additional opportunities for precision therapies that have the potential to improve patient outcomes.[Table: see text]
Integrative analysis of urine cell-free DNA for the detection of residual disease in localized bladder cancer patients.
Authors: Chauhan Pradeep S. , Shiang Alexander , Chen Kevin , Babbra Ramandeep , Feng Wenjia , Szymanski Jeffrey J. , Harris Peter K. , Hatcher Casey , Roussin Jessica , Basarabescu Franco , Brunt Lindsey , Mayer Lindsey R. , Borkowski Ariel , Maguire Lenon , Baumann Brian C. , Reimers Melissa Andrea , Kim Eric H , Arora Vivek K , Smith Zachary L , Chaudhuri Aadel A 
Published: February 2022

559 Background: We previously developed a liquid biopsy assay to measure urine tumor DNA (utDNA) levels based on detection of single nucleotide variants (SNVs) in urine cell-free DNA (cfDNA). Nonsilent SNV detection in urine from muscle-invasive bladder cancer (MIBC) patients prior to radical cystectomy (RC) was associated with pathologic residual disease and worse progression-free survival (Chauhan et al., PLOS Medicine, 2021). Given the multiple types of genomic alterations present in bladder cancer (BC), here we developed a multi-omics approach for estimating utDNA levels without restricting our approach to SNVs. We performed ultra-low pass whole genome sequencing (ULP-WGS) based copy number analysis and urine Cancer Personalized Profiling by deep Sequencing (uCAPP-Seq) of urine cell-free DNA to predict pathologic complete response (pCR) in localized BC patients. Methods: We acquired urine preoperatively from 65 BC patients (69% muscle-invasive) on the day of standard-of-care RC, and after neoadjuvant chemotherapy in 48% of patients. We performed ULP-WGS of urine cfDNA from all 65 BC patients and 11 healthy adults. utDNA levels based on genome-wide copy number alterations (CNAs) in urine cfDNA was estimated using ichorCNA. In order to derive a SNV-based utDNA level as well, uCAPP-Seq was applied to urine cfDNA samples derived from 42 patients using a 145 kb panel of 49 consensus driver genes commonly mutated in MIBC. Results: In our cohort of 65 BC patients, 55% of patients achieved pCR ( n = 36) while 45% had residual disease detected in their surgical sample (no pCR; n = 29). Comparing ULP-WGS-derived utDNA levels between the groups, patients with no pCR had significantly higher CNA-derived tumor fractions in urine compared to patients with pCR (median 8.9% vs 1.8%, p = 0.01) and healthy adults ( n = 11) (median 8.9% vs 0%, p = 0.006). Further analysis with uCAPP-Seq in 42 patients revealed that nonsilent SNV-based utDNA detection correlated significantly with the absence of pCR ( p < 0.001) with a sensitivity of 81% and specificity of 81%. Moreover, utDNA-positive patients exhibited significantly worse progression-free survival compared to utDNA-negative patients (HR = 7.4; 95% CI: 1.4–38.9; p = 0.02). Conclusions: Bladder cancer patients who did not attain a pCR at the time of RC had greater genome-wide copy number alterations and nonsilent single nucleotide variants in their urine cfDNA compared to patients with pCR. These results suggest that integrative multi-omics of urine derived from MIBC patients has potential real-world clinical impact for bladder-sparing approaches in select patients.
Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UBC) genomic alteration (GA) profile.
Authors: Grivas Petros , Necchi Andrea , Spiess Philippe E. , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Lin Douglas I. , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S. 
Published: February 2022

563 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been proposed a companion assay related to the approval of immune checkpoint inhibitors in UBC. We hypothesized that the GA profiles would differ between UBC featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UBC with known PD-L1 expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included with PD-L1 Low (1-49% TC expression) cases excluded from this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UBC featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amp (P =.05). The gender, age was similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p =.02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach statistical significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UBC cases where a mutational signature could be determined, 10/12 (83%) of PD-L1H and 21/29 (72%) of PD-L1N UBC featured APOBEC signature; 2 PD-L1N featured MMR signature and 6 PD-L1N UBC featured no dominant signature. Conclusions: PD-L1H and PD-L1N subtypes of UBC differ in their genomic profiles:PD-L1N UBC features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UBC but also in designing trials that may combine ICPI with targeted therapies. Limitations include small sample size, possible selection bias and lack of clinical annotation.[Table: see text]
Long-term follow-up of intravesical gemcitabine and docetaxel as rescue therapy for nonmuscle-invasive bladder cancer.
Authors: Chevuru Phani T. , McElree Ian Mitchell , Martin Alexander C. , Richards Jordan , Mott Sarah L. , Gellhaus Paul T. , Nepple Kenneth G. , Steinberg Ryan L. , O'Donnell Michael A. , Packiam Vignesh T. 
Published: February 2022

573 Background: Intravesical bacillus Calmette-Guérin (BCG) is the first-line treatment for high-risk non-muscle invasive bladder cancer (NMIBC). Unfortunately, disease recurrence/progression is common and associated with increased risk of death from bladder cancer. While radical cystectomy remains the preferred treatment for BCG unresponsive NMIBC, many patients are either unwilling or unfit to undergo surgery. Previous retrospective studies have demonstrated the efficacy of intravesical gemcitabine and docetaxel (Gem/Doce) for treating NMIBC after BCG failure. However, the long-term outcomes of this cohort are unknown. We report 5-year survival outcomes of patients treated with intravesical Gem/Doce after BCG failure. Methods: We retrospectively identified patients at our institution who were treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Initial responders received monthly maintenance instillations for 2 years. Surveillance was performed according to American Urological Association guidelines. Survival time was measured from start of Gem/Doce induction. Outcomes included high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS) and overall survival (OS). Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as recurrence of disease with stage T2 or greater, cystectomy or death due to bladder cancer. Survival probabilities were calculated with the Kaplan-Meier method. Results: A total of 97 patients with a median age of 73 years were treated with Gem/Doce after BCG failure. Median follow-up was 49 months. BCG failure was further stratified as BCG unresponsive (35%), BCG relapsing (38%), BCG intolerant (11%) or unspecified (16%). 71% and 21% of patients had carcinoma in-situ and high-grade T1 disease, respectively. Complete response at initial surveillance was 74% and median duration of response was 26 months. Overall HG-RFS at 1, 2 and 5 years was 60%, 51% and 31%, respectively. HG-RFS was similar among BCG unresponsive patients and the overall cohort (see table). During follow-up, 18 patients (19%) underwent radical cystectomy and 28 patients (29%) experienced disease progression. PFS, CFS, CSS and OS at 5 years was 68%, 75%, 91% and 64%, respectively. Conclusions: Intravesical Gem/Doce for high-risk NMIBC after BCG failure offers long-term efficacy and substantial durability of response with a high likelihood of bladder preservation at five years after induction. Future prospective trials assessing Gem/Doce are warranted.[Table: see text]
Phase 1b study of tarlatamab, a half-life extended bispecific T-cell engager (HLE BiTEimmune therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).
Authors: Aggarwal Rahul Raj , Rottey Sylvie , Aparicio Ana , Greil Richard , Reimers Melissa Andrea , Sandhu Shahneen Kaur , Zhang Yiran , Salvati Mark , Hashemi Sadraei Nooshin 
Published: February 2022

TPS197 Background: NEPC is an aggressive cancer with no standard treatment approach and poor prognosis. It is usually treatment-emergent, occurring in 15%–20% of patients (pts) with metastatic castration-resistant prostate cancer following treatment with androgen signaling inhibitors (ASI) and is characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor.1 The tumor associated antigen delta-like ligand 3 (DLL3) has been identified as a promising target in both NEPC and small cell lung cancer (SCLC), as it is highly expressed in these tumors and minimally expressed on normal tissue. Tarlatamab is a DLL3-targeting HLE BiTE® immune therapy designed to bind DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In preclinical studies, tarlatamab induced T-cell dependent lysis of DLL3-expressing neuroendocrine tumor cell lines, including NEPC cells.2 Interim results of an ongoing first-in-human study in pts with SCLC (NCT03319940) show evidence for tarlatamab efficacy with an acceptable safety profile.3 Together, these findings support a clinical study of tarlatamab in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating tarlatamab infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with metastatic NEPC whose disease progressed/recurred after ≥1 prior line of systemic therapy (platinum-based regimen for de novo NEPC or an ASI if treatment-emergent), measurable disease per RECIST 1.1 with Prostate Cancer Working Group 3 modifications, and ECOG performance status ≤2. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of tarlatamab. Secondary objectives are to evaluate antitumor activity (as assessed by objective response, duration of response, progression-free survival, overall survival, and disease control rate) and characterize pharmacokinetics. Four US and international study sites have been activated with two enrolled pts. References: Aggarwal R, et al. J Clin Oncol. 2018;36:2492-2503. Cooke K, et al. Abstract 627. Presented at: SITC Annual Meeting, Nov 9–14, 2020; Virtual. Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4–8, 2021; Virtual. Clinical trial information: NCT04702737.
Salvage radiotherapy (SRT) in combination with pembrolizumab in patients with PSA persistence or biochemical recurrence after radical prostatectomy due to prostate cancer.
Authors: Grabbert Markus , Zamboglou Constantinos , Josef Annika , Sigle August , Spohn Simon K.B. , Grosu Anca L. , Gratzke Christian 
Published: February 2022

TPS212 Background: Goal of our study is to evaluate the efficacy and safety of immunotherapy in combination with standard salvage radiation therapy (SRT) in patients with biochemical recurrence (BCR) or prostate-specific antigen (PSA) persistence after radical prostatectomy (RP). The combination of immunotherapy (IO) with radiation therapy might provide a clinical benefit to patients with recurrent prostate cancer due to an induction of increased activity of the immune system against cancerous tissue (abscopal effect). Primary endpoint is complete biochemical response (PSA level below detection level) 60 weeks after start of trial treatment, which further defines prognosis of patients. Further explorative endpoints like radiographic progression-free survival, PSA-nadir level and time to PSA-nadir, time to initiation of subsequent therapy (secondary ADT or NHA) and quality of life as well as adverse events will be evaluated. Methods: The trial is as a phase II, open-label, single arm monocenter trial which evaluates the combination of pembrolizumab as study medication in combination with SRT. Pembrolizumab will be administered in a three-weekly scheme up to one year of treatment. A concomitant ADT is administered in high-risk patients only (PSA > 0.7ng/ml or cN+ in imaging studies). All patients will be staged with PSMA PET-CT, if applicable. Additionally, blood and urine samples will be collected for correlative biomarker studies. A total of 49 patients are planned to be enrolled in this explorative study within 2 years. INCLUSION CRITERIA (excerpt) Histologically confirmed diagnosis of an adenocarcinoma of the prostate and a BCR or PSA persistence after RP. Histology of the RP specimen needs to fulfill the following criteria: adenocarcinoma of the prostate, Gleason score 7-10; pNX or pN0 or pN1 (max. 2 lymph nodes involved). Imaging within 30 days prior to study inclusion is mandatory (([68Ga] or [18F] PSMA PET-CT as standard imaging modality, alternatively CT abdomen and full-body bone scan). PSA value between ≥0.2 and ≤1.0 ng/ml, measured at least six weeks postoperatively. EXCLUSION CRITERIA (excerpt) Prior-therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to registration (like neo-adjuvant androgen deprivation therapy (ADT), secondary hormone ablation or taxan-based chemotherapy). Distant metastases or suspicious lymph nodes outside the lower pelvis in imaging with PSMA PET-CT (patients with PET positive bone lesions that are morphologically not clearly suspicious of metastases and would not change clinical practice can be included). Clinical trial information: NCT04931979.
A phase 2 study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Einstein David Johnson , Choudhury Atish Dipankar , Saylor Philip James , Patterson Jesse Christopher , Croucher Peter , Ridinger Maya , Erlander Mark G. , Yaffe Michael B. , Bubley Glenn 
Published: February 2022

TPS219 Background: Metastatic CRPC is a leading cause of cancer death worldwide. Although abiraterone (abi) + prednisone in either castration-sensitive or castration-resistant disease increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic function and is upregulated in prostate cancer following androgen-deprivation therapy (ADT). Onvansertib is an oral and highly-selective PLK1 inhibitor that demonstrated safety and tolerability as a single agent in a Ph1 trial. Preclinical studies showed that PLK1 inhibition enhanced abi anti-tumor effect in cell line models and in patient-derived tumor xenografts via an AR-independent mechanism. Transcriptomic analyses revealed that abi induced mitosis-related gene sets in cells synergistic for abi + onvansertib, and identified an abi-onvansertib synergy gene signature. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib + abi on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients are enrolled at time of PSA progression while on standard abi. Prior treatment with enzalutamide or apalutamide is not permitted. Three onvansertib dosing schedules are tested in noncomparative arms: arm A (24 mg/m2 on days 1-5 of a 21-day cycle), arm B (18 mg/m2 on days 1-5 of a 14-day cycle), and arm C (12 mg/m2 on days 1-14 of a 21-day cycle). To-date, 24 patients were enrolled in Arm A, and 20 patients each in Arms B and C. With 32 patients in each arm, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if < 2 of the first 13 patients in each arm achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) in circulating tumor cells and targeted genomic profiling of circulating tumor DNA to assess associations between genomic alterations and response to treatment. Additionally, transcriptomic analysis of archived tumor tissue will be performed to identify gene expression signatures associated with clinical responses. Clinical trial information: NCT03414034.