bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining molecular features associated with microsatellite instability and response to immune checkpoint blockade in urothelial carcinoma.
Authors: Alam Syed Muneeb , Teo Min Yuen , Woo Jun , Sarfaty Michal , Funt Samuel A , Aggen David H , Lee Chung-Han , Carlo Marie Isabel , Gandhi Jatin , Ratna Neha , Regazzi Ashley M. , Donoghue Mark , Bajorin Dean F. , Coleman Jonathan , Rosenberg Jonathan E. , Al-Ahmadie Hikmat A. , Solit David B. , Iyer Gopa 
Published: January 2024

536 Background: Microsatellite instability (MSI) and deficient mismatch repair (dMMR) are associated with sensitivity to immune checkpoint blockade (ICB) in urothelial carcinoma (UC). MSI status may only partially explain this sensitivity, and the molecular features that distinguish MSI-high (MSI-H) UC are not well described. Methods: Retrospective review of UC patients having undergone targeted exome sequencing of up to 505 genes was performed. Using the previously validated MSIsensor score, we identified MSI-H (score ≥10) and MSI stable (MSS) (score <3) UC tumors. Tumor mutational burden (TMB) was quantified. Gene alterations enriched in MSI-H UC were evaluated using the false discovery method with q<0.05 considered statistically significant. Mutational process signatures (MPS) were characterized using COSMIC v3.3. Survival analysis was performed using the Kaplan-Meier method with Cox proportional-hazards to determine progression-free (PFS) and overall survival (OS) based on molecular features. Results: Targeted exome sequencing data were available for 3,811 UC specimens representing 2,608 patients, of which 471 carried a diagnosis of upper tract UC. Of the total, 60 (1.6%) MSI-H tumors from 55 (2.1%) patients were identified. Germline testing (n=52) revealed dMMR mutations in 24 cases (46.2%) with MSH2 (59.6%) being most common. Median MSIsensor score was 19.8 (IQR 15.5, 27) and median TMB was 52.7 mut/Mb (IQR 39.7, 63.2). Notable gene alterations enriched in MSI-H tumors are summarized in Table 1. Dominant MPS in MSI-H UC included dMMR (85.0%), APOBEC (8.3%), and Aging (6.7%). MSI-H tumors clustered with dMMR mutational signatures SBS6 and SBS44. A total of 21 MSI-H and 160 MSS patients having received ICB for metastatic disease were identified for survival analysis. Median follow-up was 18.4 months (IQR 6.6, 58.5). MSI-H UC demonstrated superior PFS (HR 0.34, 95% CI 0.22-0.55) and OS (HR 0.48, 95% CI 0.28-0.80) following ICB. There was no association between TMB or MPS and survival following ICB in MSI-H UC. In MSS UC, TMB ≥10 mut/mB was associated with improved PFS (HR 0.56, 95% CI 0.40-0.79) and OS (HR 0.71, 95% CI 0.50-1.0). Conclusions: Targeted sequencing reveals distinct genomic features of MSI-H UC. The findings from this relatively large clinical cohort of MSI-H UC patients affirm previous associations between MSI status, TMB, and response to ICB in metastatic UC. [Table: see text]
HER2 and PD-L1 immunohistochemistry (IHC) expression, and HER2 genomic alterations: Associations and clinical outcomes for advanced bladder cancer.
Authors: Aggen David H , Shah Neil J. , Zheng Junting , Alam Syed Muneeb , Balar Om , Niederhausern Andrew , Regazzi Ashley M. , Ratna Neha , Funt Samuel A , Teo Min Yuen , Pietzak Eugene J. , Solit David B. , Bajorin Dean F. , Ostrovnaya Irina , Rosenberg Jonathan E. , Al-Ahmadie Hikmat A. , Iyer Gopa 
Published: January 2024

538 Background: Bladder cancer (BC) has a relatively high rate of human epidermal growth factor receptor 2 (HER2) alterations. The association between HER2 mutation/amplification, HER2, and PD-L1 immunohistochemistry (IHC) expression and associations with clinical outcomes for advanced bladder cancer (BC) has not been studied. Methods: We retrospectively analyzed BC samples for PD-L1 and HER2 IHC expression and compared HER2 alterations from genomic profiling with the MSK IMPACT platform. HER2 IHC expression was defined as 0, 1+, 2+, 3+, and PD-L1 IHC was the combined tumor and immune cell PD-L1 expression score (CPS). HER2 alteration was defined as either pathogenic mutation and/or amplification. We studied pairwise associations between HER2 alteration, PD-L1, and HER2 IHC expression in all patients and their associations with progression-free survival (PFS) and overall survival (OS) for muscle-invasive bladder cancer (MIBC) pts. Association analyses were performed using the Wilcoxon rank-sum test or Fisher’s exact test. Kaplan-Meier method and Cox proportional hazard models were used for time-to-event analyses. Results: Among 202 pts with HER2 IHC, 188 had MSK IMPACT, and 168 had PD-L1 CPS. The overall incidence of HER2 alteration was 22.3%; 48.2% had CPS ³10, and HER2 IHC distribution was 0:18.8%, 1+:29.7%, 2+:33.7%, and 3+:17.8%. The CPS score was inversely associated with HER2 IHC expression (p<0.001). No association was noted between CPS score and HER2 alteration (p=0.735). HER2 altered tumors were strongly correlated with high-level HER2 IHC expression (p<0.001). However, 41% (n=14/34) of HER2 IHC 3+ samples did not have HER2 alterations, and 17% (n=7/36) of HER2 altered samples had HER2 IHC expression of 0. In patients with MIBC, HER2 alteration and HER2 IHC expression (0/1+ vs. 2+/3+) were not associated with PFS (p=0.5 and p=0.4, respectively) or OS for MIBC pts (p=0.84 and p=0.94, respectively). A higher PD-L1 CPS score (>=10 vs <10) was associated with improved PFS for MIBC pts (p=0.03). Conclusions: Our study is the first to describe an inverse correlation between HER2 IHC expression and PD-L1 CPS score. Furthermore, HER2 IHC overexpression is strongly associated with HER2 amplification, but a subset of patients with high HER2 protein expression are potentially missed by genomic profiling alone. HER2 expression by IHC or HER2 genomic alteration is not a prognostic marker for MIBC pts in this cohort. This data provides the foundation for further HER2-directed advanced BC studies. [Table: see text]
A safety net for safety net hospitals: Affiliation with cancer centers and survival outcomes in patients with metastatic genitourinary cancers.
Authors: Bhanvadia Raj Ramnik , Taylor Jacob , Gaston Kris , Woldu Solomon L. , Lotan Yair , Margulis Vitaly 
Published: January 2024

543 Background: Safety net hospitals (SNH) care for a substantial proportion of medically vulnerable populations (MVP). Addressing health disparities at a hospital level through partnerships with cancer centers is a potential strategy to improve outcomes of MVPs. We thus compared outcomes for metastatic prostate (mPCa), kidney (mKCa), and urothelial cancer (mUCC) among National Cancer Institute centers (NCI), NCI affiliated SNH (NCI-SNH), and non-affiliated SNH using the Texas Cancer Registry (TCR). Methods: The TCR has 98% case ascertainment of all cancers diagnosed in Texas. The TCR can identify each facility where a patient was diagnosed and treated, allowing detailed hospital level comparisons of outcomes. The TCR was queried from 2004-2017 for mPCa, mKCa, and mUCC. Publicly available data identified Texas NCIs. The top quartile of Disproportionate Share Hospital Index values identified SNH. SNH with established relationships to NCI were designated NCI-SNH and remainder were SNH. Non-SNH were hospitals not affiliated with NCI nor SNH. MVPs were defined as age > 75, non-US natives, non-whites, and uninsured or Medicaid patients. Cox multivariable regression was used to assess overall mortality (OM). Results: Of the 1,048,464 patients in TCR, MVPs accounted for 44.7% of cases. The SNHs and NCI-SNHs accounted for 53.1% of all MVP cancer care statewide. MVPs were the majority of cases within NCI-SNH compared to other SNH or NCI (80% vs 45% vs 37.1%, p<0.01). TCR identified 20,503 metastatic genitourinary (GU) cancers. For mPCa, rates of hormone therapy were similar between NCI-SNH (76.7%) and NCI (76.2%), but greater than SNH (51.5%) or non-SNH (49.7%) ( p<0.01). Receipt of chemotherapy or immunotherapy was greater at NCI-SNH compared to other SNH or non-SNH for both mKCa (36.1% vs 31.1% vs 27.1%, p<0.01) and mUCC (44.0% vs 36.7% vs 33.2%, p<0.01). On multivariable cox analysis, equivalent OM between NCI and NCI-SNH for any metastatic GU cancer (Table). OM was worse at other SNH and non-SNH compared to NCI (Table). Conclusions: Medically vulnerable patients made up almost half of cancer care in Texas and majority were cared for at SNH. NCI-SNHs had equivalent OM to NCI and superior OM compared to other SNH. Future initiatives to improve cancer care should focus on strengthening existing relationships between NCI and SNH, and examine mechanisms to centralize care of MVPs to these facilities.[Table: see text]
Exploration of enfortumab vedotin (EV)–related cutaneous events by race in two real-world cohorts.
Authors: Vlachou Evangelia , Mamtani Ronac , Hahn Noah M. , Johnson Burles Avner , Hoffman-Censits Jean H. , Nimgaonkar Vivek 
Published: January 2024

544 Background: EV is an antibody drug conjugate, approved in advanced urothelial cancer (UC). The Nectin-4 target of EV is present in tumor and normal skin, and EV-related cutaneous events (EVCEs) are common. EVCEs often appear early with variable grade presentation. Continuation of EV is typically safe with supportive management, but rare life-threatening manifestations have occurred. Dermatologic conditions, including medication-related skin events are often underdiagnosed or under-staged in Black patients (pts). Black pts are also frequently under-represented in UC trials, and it is unknown whether EVCE incidence varies by skin tone. We explored whether EVCE frequency varies between Black and White pts in an urban cohort and a large community-based national dataset. Methods: This retrospective cohort analysis used data from Johns Hopkins Hospital (JH) and Flatiron Health (FH), a de-identified electronic health record (EHR)-derived database of community-based oncology clinics across the U.S. Pts treated with EV monotherapy at JH and in the FH database who self-identified as Black or White race were included. In the JH cohort, chart review was used to extract demographics, treatment details, and EVCEs. EVCEs were defined as any grade, new or exacerbated dermatologic event after EV initiation, not attributed to other cause. In the FH cohort, EVCEs were identified through pre-defined skin-related ICD-10 codes identified by the study authors. Odds ratios (OR) with 95% confidence intervals of EVCE incidence between Black and White pts were calculated separately for each cohort. Results: 78 toxicity-evaluable pts were identified in the JH cohort and 316 in the FH cohort. 12 were Black (15.4%) in the JH Cohort vs. 24 Black (7.6%) in the FH cohort. Median age was 71 years (IQR: 64-78), 20 (25.6%) were female, 50 (64.1%) pts had a primary site in the bladder, and 13 (16.7%) had EV as second-line and 49 (62.8%) as third-line treatment in the JH cohort, vs. 71 years (IQR: 65-77), 84 females (26.6%), 226 (71.5%) with bladder primary site, and 122 (38.6%) and 108 (34.2%) receiving EV as second-and-third-line treatment respectively in the FH Cohort. In the JH Cohort 8 of 12 Black pts (66.7%) as compared to 32 of 58 (55.2%) White pts experienced an EVCE (Table, OR 1.63, 95% CI [0.44, 6.0]). In the FH cohort, 6/24 Black pts (25%) compared to 46 /292 White pts (15.8%) experienced an EVCE (Table, OR 1.78, 95% CI [0.67, 4.73]). Conclusions: In this hypothesis-generating analysis of EV treated pts, the largest reported cohort of Black EV treated pts to date, we observed an increased EVCE frequency in Black pts relative to White, though statistical significance was not demonstrated. Future prospective EV studies should aim to recruit Black patients to better characterize this finding. [Table: see text]
Patterns of concurrent chemotherapy selection in US patients undergoing trimodality therapy for muscle-invasive bladder cancer.
Authors: Callihan Eryn , Molina Kuna Elizabeth , Robin Tyler P. , Eule Corbin J. , Kim Simon P. , Flaig Thomas W. 
Published: January 2024

554 Background: Trimodality therapy (TMT) consists of concurrent chemoradiation following maximal transurethral resection of the bladder tumor for muscle-invasive bladder cancer (MIBC). Current TMT treatment guidelines allow for several different radiosensitizing chemotherapy regimens, however there is limited data on existing use patterns. Methods: Using data from CancerLinQ Discovery, 71,499 patients with a bladder tumor diagnosed between 2000-2022 were included. Patients with documented radiation to “bladder” or “pelvis” with no known metastatic disease and a documented chemotherapy regimen started within a 30-day window of radiation, were included in the final analyses (n=233). Chemotherapy regimens included cisplatin, gemcitabine, 5FU+ mitomycin, taxanes, and other. Through bivariate analyses, patient characteristics and TMT treatment patterns were characterized. Results: The most commonly utilized TMT chemotherapy regimen was cisplatin alone (42.5%) followed by gemcitabine (19.3%), 5FU+ mitomycin (15.8%), taxanes (12.5%) and other (9.9%). These data demonstrated a significant relationship between age at diagnosis and chosen TMT regimen (p=0.017). Patients <65 were more likely to receive cisplatin (27.3%), 5FU mitomycin (29.7%) or other (30.4%) while patients 85+ were more likely to receive gemcitabine (28.9%). Patients more frequently received cisplatin alone prior to 2017 (before 2011: 28.3% vs. 2011-2016: 53.5% vs. 2017-2022:18.2%, p-value <.001), with a trend towards more gemcitabine use in the most recent period between 2017-2022 (51.1% vs. before 2011: 20.0% vs 2011-2016: 28.9%, p-value <.001). Additionally, there was less taxane use over time (before 2011: 37.9% vs. 2011-2016: 55.2% vs 2017-2022: 6.9%, p-value <.001). Finally, the association between TMT regimen and Charlson Comorbidity Index (CCI) trended toward significance—those treated with cisplatin alone were most likely to have a CCI of 0 (62.6%, p-value = 0.081) while patients receiving gemcitabine alone or 5FU + mitomycin were more likely to have a CCI of 1+ (gemcitabine alone: 51.1%, 5FU + mitomycin 51.4%, p-value = 0.081). Conclusions: There remains wide variation in the use of chemotherapy regimens in TMT with cisplatin monotherapy as the most utilized radiosensitizing agent overall. Since 2000, there has been a shift away from taxane therapy and increased gemcitabine use. Patients with lower CCI had a trend to more frequently receive cisplatin and older patients more frequently received gemcitabine. Further investigations are needed to better characterize patient characteristics as well as toxicity and survival by drug regimen to better help inform treatment guidelines.
Geriatric assessment (GA) in elderly patients with urothelial cancer (UC): Can GA select frail patients and avoid toxic treatment? Multidisciplinary single center experience.
Authors: Girones Sarrio Maria Regina , Arnal Rondán Maria , Berenguer Francés Miguel Angel , Torres Martínez Alba Girones , Conde Moreno Antonio Jose , Pontones José Luis , Delgado Francisco , Bonastre Cristina , Ramos David , Gómez Sepúlveda Nuria , Lorente Estelles David , Forcano Silvia 
Published: January 2024

564 Background: UC is a disease of the elderly. Median age at UC diagnosis is olderthan for other major tumours (73 years old). The correct management of UC in the elderly remains controversial. Treatment-decisions should be based on biological age, not in chronological one. The role of geriatric assessment (GA) evolution is potentially beneficial. It has been detected between 10% to 25% frailty patients aged over 65 years are characterised as frail on GA on other tumors. GA has not been studied prospectively in UC patients. Objective: to assess the paper of GA in elderly patients with UC patients attended in an outpatient medical oncology consultation. To confirm that GA can detect at least 25% of frailty patients unsuitable for active treatment. Methods: Prospective interventional study. GA was done by a Geriatrician at patient’s home. Treatment-decisions were based on GA results, physician choice and patients/caregivers goals. Population: patients ≥ 70 years old sent from January 2019 to September 2023 diagnosed with UC. Patients unsuitable to be ambulatory (Performance status PS ≥ 3) were excluded. Ethics review board approved the analysis. All participants signed informed consent. Results: 82 patients were aged ≥ 70 years old (57% of all patients attended). Table shows patient’s information. GA detected 24 (30%) of frailty patients. They were elder, former smokers, had worse PS and worse overall survival in all stages. Non frail patient received active treatment. Comorbid and polypharmacy population was found in all three GA groups. More fit and vulnerable patients were treated with cisplatin by GA assessment than if we have applied Galsky criteria. This suggests than the strict use of a CrcL < 60 ml/min is still controversial. Conclusions: In a very selected population, GA can still find 30% of frail patients unsuitable for treatment. Frailty seems to be a predictive and prognostic factor in elderly patients with UC. Treatment selection based on GA increase the number of patients suitable for platinum treatment. Defining “platinum-ineligible” patients with metastatic urothelial cancer should be reviewed. Selection bias cannot be excluded from our analysis.
Characteristics of patients (pts) with muscle-invasive urothelial carcinoma (MIUC) who received adjuvant nivolumab (NIVO) or adjuvant platinum-based chemotherapy (CHEMO) in the real-world (RW) setting.
Authors: Chehrazi-Raffle Alex , Feinberg Bruce A. , John William S. , Miller Taavy A. , Bland Emily , Gordon Sarah , Laney Jalyna R. , Klink Andrew J. , Ebrahimi Hedyeh , Patel Miraj Y. , Rosenblatt Lisa , Alonso Carmelo , Singh Nisha , Yin Xin 
Published: January 2024

565 Background: NIVO has shown promise as an adjuvant treatment for MIUC. In the CheckMate 274 trial, NIVO achieved a significant improvement in disease-free survival compared to placebo in MIUC pts at high risk of recurrence following radical surgery. However, it is unclear how treatment decisions are made in the RW setting and what factors drive providers in selecting either NIVO or CHEMO as adjuvant treatment. We compared the baseline demographic and clinical characteristics of pts with MIUC who received adjuvant NIVO to those who received adjuvant platinum-based CHEMO in the RW setting. Methods: This retrospective medical chart review included pts diagnosed with stage II-IIIB MIUC who initiated treatment with NIVO or CHEMO within 120 days of radical resection between 9/1/2021 and 11/25/2022. Treating oncologists from a US nationally representative network abstracted pts’ data from electronic medical charts. Pts’ demographic and clinical characteristics were assessed. Results: Age, sex, and race were similar across cohorts (Table). Pts who received adjuvant NIVO (n = 158) vs CHEMO (n = 88) were more likely to have ECOG-PS≥ 2 at treatment initiation (24.1% vs 17.1%; P = 0.02), and more likely to receive PD-L1 testing (Not tested: 36.1% vs. 47.7%; P < 0.0001) and have PD-L1 expression levels ≥ 50% (13.9% vs 1.1%; P < 0.0001). A higher proportion of pts who received NIVO vs CHEMO had diabetes with chronic complications (15.8% vs 5.7%; P = 0.02) and hypertension (20.9% vs 6.8%; P = 0.004), and were determined to be cisplatin-ineligible (41.8% vs 25%; P = 0.007), predominately based on creatinine clearance (< 60 mL/min: 48.7% vs. 34.1%; P = 0.002) and poor PS (13.9% vs. 4.6%; P = 0.07); rheumatologic disease was less common among the NIVO cohort (1.9% vs 11.4%; P = 0.002). Conclusions: This RW analysis demonstrated that pts with MIUC who received adjuvant NIVO had greater baseline disease severity and comorbidities than those who received adjuvant CHEMO. These findings suggest that patient characteristics influence treatment selection of adjuvant therapy in this patient population, highlighting the need to adjust for baseline characteristics in future comparative analyses.[Table: see text]
Pathologic and survival outcomes following radical cystectomy for “progressive” and “de novo” muscle-invasive bladder cancer: A meta-analysis stratified by neoadjuvant chemotherapy status.
Authors: Xia Leilei , Dadabhoy Anosh , Wood Erika L. , Roberson Daniel , Guzzo Thomas J. , Bivalacqua Trinity , Daneshmand Siamak 
Published: January 2024

566 Background: Muscle-invasive bladder cancer (MIBC) can present as de novo MIBC (dnMIBC) or progressive MIBC (pgMIBC), the latter occurring in patients with a history of non-muscle-invasive bladder cancer (NMIBC). Retrospective cohort studies have reported varied survival outcomes following RC for pgMIBC versus dnMIBC.Here we aim to pool previous studies and compare survival and pathologic outcomes in patients with pgMIBC and dnMIBC following radical cystectomy (RC), with an investigation of the impact of neoadjuvant chemotherapy (NAC). Methods: A comprehensive literature search was conducted on PubMed and EMBASE databases to identify studies comparing pgMIBC to dnMIBC. Survival outcomes, including cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS), as well as pathologic outcomes following surgery (rates of ≤pT1, pT0, pT3/T4, and pN+ disease) were compared between pgMIBC and dnMIBC. Results: The analysis included 19 cohorts from 16 studies, categorized into three groups based on NAC status: 1. patients who underwent RC following completion of NAC (RC + NAC only group); 2. patients who underwent RC, with or without NAC (RC +/- NAC group); 3. patients who only underwent RC without NAC (RC only group). Compared to dnMIBC, pgMIBC demonstrated worse outcomes for CSS, OS, and RFS. In the RC + NAC only group (3 cohorts), the hazard ratio (HR) for CSS was 1.52 (95% confidence interval [CI] = 1.05-2.2), the HR for OS was 1.46 (95%CI = 1.05-2.02). Similarly, in the RC +/- NAC group (6 cohorts for CSS and 3 cohorts for OS), the HR for CSS was 1.27 (95%CI = 1.05-1.55), and the HR for OS was 1.27 (95%CI = 1.08-1.51). There were no significant differences observed in pathologic outcomes, including rates of ≤pT1, pT0, and pT3/T4 disease, across all subgroups. However, pgMIBC was associated with a higher risk of nodal metastatic (pN+) disease in the RC + NAC only group (4 cohorts, relative risk [RR] = 1.43, 95%CI = 1.12-1.84). Conclusions: The findings highlight the potentially worse prognosis in patients with pgMIBC compared to dnMIBC, even with the modern use of NAC. The study emphasizes the importance of careful patient counseling, further classification of patients for treatment selection, and the consideration of additional or innovative systemic therapies for pgMIBC.