bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular and molecular determinants of limited anti-tumor immunity in chromophobe renal carcinoma (ChRCC).
Authors: Labaki Chris , Alchoueiry Michel , Bi Kevin , Zhang Long , Hobeika Charbel , Bakouny Ziad , El Ahmar Nourhan , Matar Sayed , Priolo Carmen , Khabibullin Damir , Schindler Nicholas R. , Camp Sabrina Yvonne , Saliby Renee Maria , Saad Eddy , Signoretti Sabina , Van Allen Eliezer Mendel , Shukla Sachet A , Henske Elizabeth , Choueiri Toni K. , Braun David A.
Published: January 2024

476

Background: ChRCC is a rare form of kidney cancer with a poor prognosis in the metastatic setting, in part due to very limited responses to immune checkpoint inhibitors (ICIs), as compared to clear cell RCC (ccRCC). The mechanisms underlying the poor response of ChRCC to ICIs remain largely uncharacterized. We therefore investigated at the single-cell resolution the cellular and molecular determinants of anti-tumor immunity in ChRCC. Methods: ChRCC samples with matched normal kidney specimens were evaluated using single-cell RNA (scRNA-seq) and single-cell T-cell receptor (scTCR-seq) sequencing. Similar data (scRNA-seq and scTCR-seq) was obtained for ccRCC samples (Braun DA. et al., 2021). T cell clonotypes were inferred and classified into their degree of expansion (poorly, moderately and highly expanded). Diversity metrics (normalized Shannon’s entropy) were calculated. Using a previously described methodology (Young M.D. et al., 2018), the cell of origin (COi) of ChRCC was inferred from scRNA-seq data of normal kidney samples, followed by differential gene expression (DGE) and pathway analysis (DPA) between the putative COi and ChRCC cells to identify potential mediators of diminished immune responses. Immunohistochemistry (IHC) of ChRCC and ccRCC samples was used to assess CD8+ and PD-1+ immune cell populations. Results: Analysis of the scTCR-seq data identified a higher proportion of poorly expanded clonotypes in ChRCC as compared to ccRCC (p=0.05), along with a lower proportion of highly expanded clonotypes (p=0.07). Normalized (Shannon’s) entropy was found to be higher in ChRCC versus ccRCC (p<0.05). Analysis of annotated scRNA-seq data identified a lower proportion of CD8+ and CD4+ T-cells among immune cells in ChRCC vs. ccRCC (44.6 vs. 9.6% and 12.3 vs. 3.2%, respectively). DGE between ChRCC and its putative COi (alpha-intercalated cell) showed a lower expression of HLA class I genes in ChRCC (p<0.05). DPA showed a marked downregulation of antigen presentation and protein processing pathways in ChRCC (p<0.05). IHC analysis showed a markedly low infiltration of CD8+ and PD-1+ immune populations in ChRCC, as compared to ccRCC. Conclusions: ChRCC cells have marked downregulation of HLA class I genes and antigen processing pathways related to their COi. Additionally, ChRCC tumors have poor infiltration of T-cells, which show a low degree of clonal expansion. These mechanisms may help to explain the limited anti-tumor immunity and ultimately, the poor response to ICIs seen among patients with ChRCC.
Updated automated PROMISE assessment: Treatment response evaluation based on PSMA PET/CT.
Authors: Benitez Cecil Mayra , Sahlstedt Hannicka , Brynolfsson Johan , Berenji Gholam Reza , Juarez Jesus Eduardo , Kane Nathanael , Tsai Sonny , Rettig Matthew , Nickols Nicholas George , Duriseti Sai
Published: January 2024

48

Background: PSMA PETs can track treatment response in patients with prostate cancer. Recent integration of the RECIP framework with PROMISE v2 allows quantitative assessment of PSMA PETs. While useful for assessing differentially responding lesions, manual measurement and tracking is cumbersome and PSA reliance can be misleading. We evaluated an automated AI-enabled platform, aPROMISE, for longitudinal lesion tracking to evaluate treatment response based solely upon tumor volume. Methods: Patients with castration sensitive or resistant disease undergoing 18F-DCFPyL PET/CTs during workup and at ≥3 months after treatment were included. Tracer-avid lesions were identified using the aPROMISE algorithm. Detected lesions were manually approved by an experienced nuclear medicine physician. After lesion identification and approval, the total tumor volume was calculated. The corresponding low-dose CT was auto-segmented, allowing anatomic compartment (prostate/bed, node, bone, or visceral) annotation of 18F-DCFPyL-avid lesions. Baseline and follow-up PETs were deformably co-registered to automatically match individual lesions if they were in the same anatomic compartment, and had overlap <10 mm center-to-center (<50 mm for rib lesions). Unmatched lesions on follow-up PET were noted as new. Response was assessed as CR (no avidity in follow-up), PR (volume decrease ≥30% without new lesions), SD (volume decrease ≥30% with new lesions), or PD (volume increase ≥20% plus new lesions). Volume changes at the total tumor and individual lesion levels were also assessed independent of RECIP imaging criteria. Results: The automated algorithm assigned the correct RECIP classification in 97% of the 67 cases with 14 as CR, 14 as PR, 20 as SD, and 19 as PD. 1027 of the 1686 lesions identified on baseline PET were seen on follow-up. 673 of the 1700 lesions identified on follow-up PET were new. Conclusions: For response assessment using 18F-DCFPyL PET/CT and RECIP imaging criteria, the automated algorithm and manual detection achieved the same clinical classifications. Automated approaches may allow more granular lesion analysis The precision and accuracy this automated process is being validated in prospective clinical studies.
Evaluating prognostic models for stage I seminoma within the randomised trial of imaging and surveillance in seminoma testis (TRISST).
Authors: Huddart Robert A , Cafferty Fay Helen , Murphy Laura , James Elizabeth , Schiavone Francesca , Rustin Gordon J. S. , Sohaib Syed A , Joffe Johnathan K.
Published: January 2024

501

Background: Prognosis in stage I seminoma is excellent. Most patients are cured by orchiectomy and, for the 15%-20% that relapse, salvage treatment is generally successful (survival approaching 100%). Relapse risk is reduced with adjuvant carboplatin but may unnecessarily expose young patients to long-term health risks. Effective and reliable risk stratification could guide use of adjuvant treatment and potentially reduce intensity of surveillance for the lowest risk patients. We used data from a UK multicentre, phase III trial to evaluate prognostic factors for relapse in stage I seminoma, including validation of a recently proposed model from the European Association of Urology (EAU)(1). Methods: TRISST used a randomised, factorial design to evaluate imaging schedules (3 vs 7 scans) and modality (MRI vs CT) in surveillance for men who had undergone orchidectomy for stage I seminoma (n=669). In this secondary analysis, model selection was used to fit a multivariable Cox regression to TRISST data to investigate factors predicting time to relapse, including: age, tumour mass size, rete testis invasion (RTI), T stage, lymphovascular invasion (LVI), side of tumour, and tumour markers (LDH, β-HCG). The final model was used to divide the cohort into risk groups. Relapse risk was also estimated according to EAU prognostic groups. Harrell’s C-index was used to measure model fit. Results: Based on TRISST data, tumour size ≥4cm and pT3 disease were associated with the highest risk (multivariable hazard ratio for ≥4cm vs <2cm: HR=4.00, 95% confidence interval 2.00-8.01; pT3 vs pT1: HR=3.89, 1.77-8.57). Patients with one or both of these features (24% of the cohort) had 5-year relapse rate of 22.0%. Medium risk (age<30 years and/or 2-4cm and/or pT2) and low risk (age≥30 years, <2cm and pT1) groups had 5-year relapse rates 12.0% and 2.3% respectively. The EAU model was a good fit to the TRISST data (C-index=0.62); 66%, 33% and 2% fell into the very low, low and high-risk EAU groups respectively with 5-year relapse rates of 10.1%, 16.1% and 45.5%. Conclusions: In stage I seminoma, relapse risk in patients managed with surveillance following orchiectomy is low for the majority of patients. Tumour size is consistently shown to be the best predictor of relapse. The EAU prognostic model, validated here, identifies a small group (>5cm, with RTI and LVI) with particularly high risk who may benefit from adjuvant therapy. Reference: 1. Boormans J, et al. Journal of Clinical Oncology 2023; 41 (6_suppl): 410. Clinical trial information: ISRCTN65987321 .
Excess intermediate risk nonseminoma and regional lymph node metastases at presentation in patients with Hispanic germ cell tumor.
Authors: Kolawa Adam , Iyengar Siddharth , Tiu-lim Justin Wayne Wong , Arizpe Angel , Pan Elizabeth , Chen Irene , Frost Stefani , Daneshmand Siamak , Schuckman Anne K. , Djaladat Hooman , Quinn David I. , Tulpule Varsha , Hu James S. , Cortessis Victoria K. , D'souza Anishka
Published: January 2024

502

Background: Testicular germ cell tumors (TGCTs) is the leading solid-organ malignancy of adolescent/young adult males. Incidence is rising in all racial/ethnic groups, and most rapidly in Hispanics, who tend to be younger than non-Hispanic white (NHW) patients at diagnosis yet have poorer survival. Understanding these disparities is an urgent research priority, but granular prognostic information is inadequate in large population-based registries. We therefore initiated an investigation of a largely Hispanic clinical cohort. Methods: We identified consecutive patients with pathologically confirmed TGCT treated from 2015 to 2020 at two major referral centers in the US, with a large Hispanic population (the Los Angeles General Medical and USC/Norris Comprehensive Cancer Centers) and collected detailed features of demography, clinical presentation, treatment, and outcome into a structured RedCAP database. We used chi-square, Fisher exact, and Mann-Whitney U tests to compare established prognostic features between Hispanic and NHW patients. Results: Among 27 NHW and 75 Hispanic patients, Hispanics were younger at diagnosis (median 27 vs 30 years, p=0.5), diagnosed less frequently with pure seminoma (12% vs 23%, p=0.19), and experienced shorter time to first progression (median 8.5 vs 19 months, p=0.6). Among non-seminoma patients, Hispanics had higher probability of IGCCCG intermediate risk (26% vs 0%, p=0.03) but similar frequency of poor risk disease (Table). Accordingly, Hispanics had more regional lymph node involvement at presentation (48% vs 19%, p=0.03) but comparable frequency of visceral metastasis. Conclusions: Hispanic patients had adverse features already evident in population-based data, and novel findings of higher risk stratification and greater lymph node involvement than NHWs. Expansion of clinical series will be vital to identifying factors and processes that underlie adverse presentation and outcomes of Hispanics with TGCT, and to refining guidelines for care of the growing population of Hispanic patients with TGCT. [Table: see text]
Racial differences and predictors of outcomes in testicular cancer based on the National Cancer Database (NCDB).
Authors: Yu Eun-mi , Wang Hongkun , Aragon-Ching Jeanny B.
Published: January 2024

503

Background: The incidence of testicular cancer in the U.S. is highest in white (W) men and lower in black (B), Hispanic (H) and Asian-American men, with reports of increasing trends in Hispanic men with worse outcomes (Li et al., BMC Cancer 2020). We aim to verify the emerging ethnicity variations in a large database. Methods: Using the NCDB database with patient-level data extraction from 2004 to 2020, we sought to identify the incidence, demographics, regional differences, treatment, and outcomes in men who are Hispanic versus non-Hispanic White (NHW) and other races with testicular cancer diagnoses (non-seminoma, NS; seminoma, S) with differences in treatment patterns from different institution types, insurance across regions. Results: There were 81571 pts in all with 46979 S pts W and 34592 NS pts W vs 1754 S pts B and 1106 NS pts B with 5396 S pts H and 5609 NS pts H with other races/unknown for the rest. More S patients were treated at comprehensive community cancer programs (17%) compared to NS pts (6.1%). The majority of patients had Charlson-Deyo Score of 0 (92.7% of S pts and 93.7% of NS pts), had private insurance (74.1% S pts, 69.1% NS pts), though incidence appeared to be similar except for a slight drop in 2020 at 5.9% compared to 6.6% during years 2018 to 2019. Most were diagnosed with Stage I (29.6%) and Stage II and III (16.3%) though it was unknown/missing for 54%. Overall survival (OS) was better for S compared to NS in all pts (p<0.0001), and in stages II & III (p<0.001). OS was better for W vs B (p<0.0001), NHW vs H (p<0.0001), and with differences in Charlson-Deyo score (p <0.0001), facility type (p=0.008) and insurance status (p <0.0001). OS p-values are from Log-rank tests. Conclusions: Our analysis reveals some differences in survival trends with better survival in seminoma compared to non-seminoma, though Blacks and Hispanics have worse outcomes compared to Whites and Non-Hispanic Whites. This highlights the need for targeted efforts to bridge gaps in care.
Trends and disparities in hospice care utilization in testicular cancer in the United States of America from 2003 to 2020: Analysis of CDC WONDER database.
Authors: Jatwani Karan , Sukaina Mahnoor , Khosla Atulya Aman , Singh Rohit , Garg Tulika , Chahal Rutvi , Patel Archit , Muthusamy Kumarasamy Vasanthan , Gopalakrishnan Dharmesh
Published: January 2024

504

Background: Testicular cancer (TC) is a malignancy with five-year survival reaching up to 95%. It is estimated that 470 deaths from this disease will occur in the United States in 2023. Even with exceptional survival rates, it is important to recognize the need of hospice in these patients. Enrollment in hospice is associated with lower healthcare costs, symptom burden, and psychological distress and improved quality of life. We used publicly available CDC WONDER (Centers for Disease Control and Prevention for Wide-ranging Online Data for Epidemiologic Research) database with the aim to explore the trends of hospice utilization in patients with testicular cancer nationwide in the US. Methods: The search and analysis were conducted using the CDC WONDER database from January 01, 2003, to December 31, 2020. The data for deaths due to TC were pooled using the International Classification of Diseases-10th Revision codes C62, C62.0, C62.1 and C62.9. The inclusion criteria included males aged >15 years. The demographic data was obtained to calculate descriptive statistics using age, census region, and utilization of hospice mortality accordingly over the past two decades. Results: The analysis demonstrated that overall mortality due to TC were 6,969 from 2003-2020. Of these deaths, 520 (7.46%) were recorded in hospice facilities. According to the US census regions, the highest number of hospice deaths were recorded in Census Region 3: South (CENS-R3) 8.99%, followed by Census Region 1: Northeast (CENS-R1) 8.03%, and Census Region 2: Midwest (CENS-R2) 7.23%. While the lowest number of deaths were observed in Census Region 4: West (CENS-R4) at 5.30%. The lowest hospice mortality was 1.9% in 2005 and increased over the years to the highest of 10.4% in 2019, with a slight decline in 2020 which is 7.9%. Moreover, when stratified by age groups, the lowest hospice mortalities are recorded in the age group 15-34 years (6.32%), 35-54 years (7.08%), 55-74 years (10.10%), 75-85+ years (8.72%). Conclusions: To our knowledge this is the first study utilizing CDC WONDER database to demonstrate hospice care utilization in TC related deaths. We observed a steady increase in hospice utilization from 2005-2019 throughout the US with a decline in 2020 possibly related to COVID pandemic. Age stratification further revealed lower utilization in 15-34 years age group compared to 55-74 highlighting the need to improve hospice discussions early in this age group. This study highlights the disparities in end-of-life care in TC and should promote policy-level changes in the states with lower utilization of hospice services to improve access of care in TC patients.
Inconsistency in the assessment of retroperitoneal lymph node metastasis in patients with testicular cancer: Influence on clinical stage, therapy and relapse rate.
Authors: Nestler Tim , Strauch Angelina , Nestler Kai , Schoch Justine , Kubitscheck Laura , Waldeck Stephan , Schmelz Hans
Published: January 2024

506

Background: In testicular germ cell tumor (GCT) staging, current guidelines lack consensus in the measurement of retroperitoneal lymph node metastasis, including the recommended plane and dimension. Therefore, our objective was to investigate current guideline recommendations for staging of retroperitoneal lymph nodes and their influence on clinical stage (cS), relapse rate and therapy. Methods: In this explorative study we retrospectively analyzed 154 cSI GCT patients who underwent orchiectomy without any adjuvant therapy and had a follow-up of ≥ 24 months. Here, cSI was defined as retroperitoneal lymph nodes <10mm in axial short-axis diameter (SAD). In initial staging imaging the largest retroperitoneal lymph node was measured considering the different dimensions (SAD and long-axis diameter (LAD)) in the three different radiological planes: axial, sagittal and coronal. Results: In the studied cohort overall survival (OS) was 100% and relapse free survival was 82% with a mean follow-up of 95 months. By using axial SAD (RECIST 1.1) all patients were classified as cSI. Based on axial LAD (German S3 guideline) or LAD in any plane (EAU, ESMO, onkopedia and AJCC), significantly more patients would be classified as cSIIA (0% vs. 38% vs. 52%) or even cSIIB (0% vs. 1% vs. 25%; p<0.001). Overtreatment would occur in 0%, 31%, and 61% ( p<0.001) for axial SAD, axial LAD and LAD in any plane, while undertreatment would affect 18%, 10%, and 2% ( p<0.001), respectively. A stage-appropriate therapy would hypothetically require the following number of chemotherapy cycles (BEP or Carboplatin): optionally 34 for axial SAD vs. up to 361 for LAD in any plane. Conclusions: We found a huge variety of clinical stages according to different lymph node staging recommendations in current guidelines. With a 100% OS rate in the entire cohort and considering the balance between the risks of overtreatment and undertreatment, with stage-adapted treatment at relapse, we strongly recommend adopting axial SAD in accordance with RECIST 1.1. Prospective validation is warranted to standardize guideline recommendations.
Real-world comparison of prostate-specific antigen (PSA) response in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or enzalutamide (ENZ).
Authors: Lowentritt Benjamin H. , Du Shawn , Pilon Dominic , Khilfeh Ibrahim , Muser Erik , Rossi Carmine , Kinkead Frederic , Diaz Lilian , Korsiak Jill , Ellis Lorie , Lefebvre Patrick , Brown Gordon Andrew
Published: January 2024

51

Background: APA and ENZ, two androgen receptor synthesis inhibitors (ARSIs), used in combination with androgen deprivation therapy (ADT) are among the recommended treatments for patients with mCSPC. Deep PSA response, evaluated as ≥90% PSA decline (PSA90), is an important outcome after ARSI initiation, with early, deep response associated with longer survival. The primary objective of this study was to compare PSA90 response in ARSI-naïve patients with mCSPC by 6 months after initiating APA or ENZ in real-world clinical practice. Methods: Linked electronic medical record (EMR) data of US community urology practices in the from PPS Analytics and administrative health data from Komodo Health Solutions Research Database were evaluated. Patients with mCSPC were selected into two cohorts, based on the index date, defined as the first paid pharmacy claim or in-office dispensation for APA or ENZ on or after 16 Dec 2019. Patients were required to have ≥12 months of pre-index EMR clinical activity. Pre-index characteristics (i.e., age, race, geographic region, payer type, index year, time from metastasis, time from first prostate cancer [PC] diagnosis, de novo PC, ADT use, first-generation antiandrogen use, chemotherapy use, metastasis locations, most recent PSA level, testosterone level, and Gleason score) were balanced between cohorts with inverse-probability treatment weighting (IPTW). Patients were followed from index date until the earliest of index ARSI discontinuation or switch, radiopharmaceutical initiation, end of open administrative claim or EMR clinical activity, or end of data availability (30 Sep 2022). PSA90 was defined as the earliest ≥90% decline in PSA relative to most recent pre-index PSA. The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: In total 860 APA and 869 ENZ patients were identified. Patient pre-index characteristics were balanced with IPTW (Table). By 6 months post-index, 80.3% of APA and 75.0% of ENZ patients had ≥1 PSA test result. By 6 months, significantly more APA patients attained a PSA90 response, as compared to ENZ patients (p=0.005; Table). The median time to PSA90 response was 3.5 months for APA and 4.9 months for ENZ. Conclusions: This US real-world study of patients with mCSPC demonstrated that treatment with APA produces a deep, early PSA response by 6 months in a greater percentage of patients than treatment with ENZ. [Table: see text]
Survivorship issues beyond 2 years after treatment in testicular germ cell tumors: Experience from a large centre in the United Kingdom.
Authors: Flanders Lucy , Ansell Wendy , Richardson Daniel , Wilson Peter , Ng Kenrick , Shamash Jonathan
Published: January 2024

512

Background: Testicular germ cell tumors (tGCTs) are rare but are highly curable, resulting in a large cohort of long-term survivors. The primary aim of most follow-up programs after initial treatment is to detect recurrence, which emphasizes regular imaging and measurement of serum tumor markers. Most relapses occur in the first two years after treatment. However, many of these patients also experience survivorship issues beyond the two-year timepoint which are underrecognized in the clinical setting and underreported in clinical literature. Methods: We retrospectively reviewed clinical documentation across a cohort of tGCT patients in St Bartholomew’s Hospital who received adjuvant treatment (n=171), treatment for metastatic cancer (n=325) and those who underwent surveillance only (n=225) from 2011 and 2021. Only patients with a minimum follow-up of 5 years were included. Data was collected between Year 3 to Year 10 after initial treatment, ie only after two years of surveillance were completed. The frequency in which the following terminology/symptoms appeared in clinical documentation was recorded: relapse, endocrinology (a hormone problem including, but not included to hypogonadism/diabetes/thyroid dysfunction), lifestyle advice (eg weight management), blood pressure, cholesterol, psychology, fertility and other problems. Each reported issue was only recorded once per patient for this study. Results: Relapse rates were 0-0.75% annually (0% adjuvant, 0.7% metastatic, 0.75% surveillance). Total relapse rates beyond the two year time point, per group, were 0% in the adjuvant group, 5.8% in the metastatic group, and 6.0% in the surveillance group. Of the patient group who received treatment, significantly more reported endocrinological issues (7.0% average annually in the adjuvant group vs 4.2% metastatic vs 0.1% surveillance). Issues relating to blood pressure were equally reported (5.5% average annually in adjuvant vs 2.95% in metastatic vs 2.60% in surveillance) as were cholesterol (4.7% average annually in adjuvant vs 2.2% in metastatic vs 2.2% in surveillance). Fertility issues were more commonly reported in the group of patients who received treatment for metastatic cancer (2.4%) as opposed to those who received adjuvant treatment(0.5%) and surveillance only (0.7%). Conclusions: Relapse rates in our cohort of patients are low and consistent with previous studies. However, we highlight multiple survivorship issues for patients who have received treatment – particularly issues pertaining to endocrinological issues and fertility. These results suggest the need to incorporate monitoring of survivorship issues into our routine follow-up to improve patient experiences and outcomes. We suggest that a specialist clinic focused on long-term survivorship issues be established to better address the needs of this patient population.
Outcomes after primary retroperitoneal lymph node dissection in men with stage 2 non-seminomatous germ cell tumour: A multicenter retrospective cohort study.
Authors: Antonelli Luca , Heidenreich Axel , Bagrodia Aditya , Branger Nicolas , Clinton Timothy , Daneshmand Siamak , Djaladat Hooman , Hamilton Robert James , Ho Matthew , Sexton Wade J. , Nicol David , Nicolai Nicola , Olson Kathleen , Porter James , Singla Nirmish , Stroup Sean P. , Terbuch Angelika , Cary Clint , Fankhauser Christian Daniel
Published: January 2024

516

Background: Based on only smaller retrospective cohort studies, current guidelines recommend primary retroperitoneal lymph node dissection (RPLND) for men with marker-negative stage 2a non-seminomatous germ cell tumor (NSGCT). We aimed to reassess the role of primary RPLND in marker negative stage 2a, explore results in stages 2b/c and/or marker-positive disease, and evaluate surgical methods, recurrence, and adjuvant chemotherapy indications. Methods: Data from 17 institutions were collected, comprising 305 men who underwent primary RPLND for stage 2 NSGCT. Regression analyses were conducted to predict histology in the RPLND specimen and progression-free survival (PFS). Results: A larger retroperitoneal lymph node diameter was associated with pure teratoma in the RPLND specimen (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.09, p-value = 0.02), but it did not correlate with PFS. The 5-year PFS rates were 85% for men with pure teratoma, 94% for men with viable cancer who received adjuvant chemotherapy, and 72% for men with viable cancer who did not receive adjuvant chemotherapy. The number of adjuvant chemotherapy cycles did not significantly affect PFS. Conclusions: Our study suggests considering primary RPLND not only in marker negative clinical stage 2a but also marker negative clinical stage 2b. Further research should identify the efficacy in men in other stages (2C or marker positive) and which patients may benefit from adjuvant chemotherapy and the optimal cycle number.
FGFR3 mutated (FGFR3mut+) urothelial carcinoma of bladder (UCB) or upper tract (UTUC): A comparative genomic landscape study.
Authors: Basin Michael , Sager Rebecca A , Pavlick Dean C. , Necchi Andrea , Spiess Philippe E. , Li Roger , Kamat Ashish M. , Grivas Petros , Cheng Liang , Lin Douglas I. , Ross Jeffrey S. , Basnet Alina , Bratslavsky Gennady , Jacob Joseph M
Published: January 2024

540

Background: Activating DNA sequence genomic alterations (GA) in the FGFR3 gene including short variant (SV) mutations and kinase domain activating gene rearrangements/fusions (RE-FUS) are known drivers and relevant precision treatment targets for pts with UC. THOR trial showed a significant overall survival benefit with erdafitinib (FGFR inhibitor) vs (taxane or vinflunine) in patients (pts) with advanced UCB or UTUC. PROOF-302 trial showed higher frequency of FGFR3 GA in UTUC (30%) vs UCB (13%). We sought to explore differences in frequency of FGFR3 alterations and the genomic landscapes of FGFR3-altered UCB and UTUC. Methods: 10,402 UCB and 2,325 UTUC (combined ureter and renal pelvis) underwent hybrid capture-based comprehensive genomic profiling (CGP) using a hybrid capture-based to assess all classes of GA and measure MSI status, TMB level, genomic ancestry, genomic signature, germline mutations and HRD score. PD-L1 was determined by IHC (Dako 22C3 using the TPS system. Results were compared using the Fisher Exact method with the Benjamini-Hochberg adjustment. Results: FGFR3mut+ status was significantly more frequent in UTUC than in UBC (24.9% vs 17.7%; p<.0001) (Table). UCB pts were more often male than UTUC (P=.0003). Age (71-72 yrs), EUR ancestry (85%) and GA/tumor (8.9-9.0) were similar. The number of GA/case and the frequency of EUR ancestry were similar. Targetable GA in ERBB2 and PIK3CA were more frequent in FGFR3mut+ UBC vs FGFR3mut+ UTUC. GA in PTEN, TSC1 and MTAP currently associated with clinical trials were similar in UBC and UTUC. The KEGG ERBB and VEGF signaling pathways were more frequently identified in UCB (p=0.036) and the MMR pathway more frequently identified in UTUC (p=0.014). The HRD signature was similar in both groups (2.3-3.1%). Anti-PD(L)1 putative biomarkers included a significantly higher frequency of MSI-high status in UTUC vs UCB but no significant difference in TMB or PD-L1 expression levels. Conclusions: Although histologically similar, the genomic landscape of FGFR3mut+ UTUC has notable differences with FGFR3mut+ UCB. Limitations include lack of clinical data annotation. The findings may impact of clinical trial designs for UCB and UTUC, including evaluating combinations of anti-FGFR3 with other agents. [Table: see text]
Real-world treatment (Tx) sequences and time to discontinuation (rwTTD) in the first-line (1L) metastatic castration-resistant prostate cancer (mCRPC) setting.
Authors: Nash Smyth Emily , Whipple Samuel , Guinter Mark , Haddad Nadine , Piao Wenxian , Cui Zhanglin Lin , Balar Arjun Vasant
Published: January 2024

55

Background: There is limited real-world data on tx sequencing in metastatic prostate cancer. Additionally, while guidelines support adding novel hormonal agents (NHA) to androgen deprivation tx (ADT) for metastatic hormone-sensitive prostate cancer, use is limited because of clinical and/or pt-driven factors. We evaluated tx patterns, rwTTD, and time-to-chemotherapy (rwTTC) for 1L mCRPC pts, including Black/African Americans (BAA) treated predominantly in a community oncology setting. Additionally, we analyzed systemic treatments prior to 1L mCRPC as well as progression to 2L mCRPC. Methods: This retrospective study included pts with mCRPC from the nationwide Flatiron Health EHR-derived, deidentified database who initiated 1L tx between 1/2013 and 1/2023. Study end was 4/2023. Tx patterns were described by time period (TP) of 1L initiation: TP1 - 01/2013–12/2017 and TP2 - 01/2018–01/2023; Kaplan-Meier analyses were conducted for rwTTD/TTC and a Cox proportional hazards regression model was used to determine the association between pt characteristics and rwTTD/TTC for 1L mCRPC. Subgroup analyses were performed for BAAs. Results: Of the 8915 1L-tx pts (median age 74 yrs), 871 (10%) were BAA (median age 70 yrs) and 5870 (66%) were NHA-naïve at 1L mCRPC. Overall, the percent of pts who were NHA-naïve decreased from 2018 (72%) to 2023 (39%) and a similar trend was observed for BAA (74% [2018] to 25% [2023]). 1L NHA use in mCRPC increased from TP1 to TP2 (overall: 70% to 80%; BAA: 73% to 83%), primarily driven by enzalutamide (Enz) (overall: 30% to 39%; BAA: 33% to 38%) and decrease in chemotherapy (overall: 16% to 12%; BAA: 17% to 13%). The top 3 1L mCRPC regimens for the overall population and BAA were abiraterone (Abi) (35%; 38%), Enz (32%; 33%), and docetaxel (10%; 11%). Among pts who progressed to 2L mCRPC, the most common sequences for patients tx with Abi or Enz for 1L mCRPC were ADT monotherapy in the prior line of tx and a switch to Abi (19%) or Enz (24%) upon progression from 1L to 2L. 1L rwTTD for the overall cohort is in the Table. Age ≥80 years, ECOG PS ≥1, socioeconomic status = 5 (highest), and median time ≤39.8 months from initial dx to mCRPC were associated with a higher hazard of discontinuation (all p ≤0.05). Conclusions: Overall, most pts received their first NHA in 1L mCRPC; NHA use increased and chemotherapy use decreased from TP1 to TP2. There was heterogeneity in tx sequences in patients treated with an NHA in 1L mCRPC; some pts were rechallenged with a different NHA in 2L despite lack of robust prospective data to support use. Overall, 1L rwTTD was short with a small numerical increase in TP2. Factors contributing to discontinuation, such as treatment resistance, need to be better understood to further improve real-world outcomes. [Table: see text]
Real-world treatment (tx) patterns and clinical outcomes in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) in Germany: Results of a retrospective observational study (CONVINCE).
Authors: Machtens Stefan , Schlack Katrin , Kubin Thomas , Ruhnke Markus , Schulte Clemens , Eisen Anna , Osowski Ulrike , Guenther Silke , Kearney Mairead , Lipp Rainer , Schmitz Stephan H.
Published: January 2024

551

Background: Platinum-based chemotherapy (PBC) is the standard-of-care first-line (1L) tx for pts with la/mUC (followed by avelumab 1L maintenance in pts without progressive disease since its approval in Germany in Jan 2021). This study describes demographics, tx patterns, and clinical outcomes for pts with la/mUC treated in routine clinical practice in Germany between 2019 and 2021. Methods: CONVINCE, a retrospective, multicenter medical chart review study, was initiated in Dec 2021 and included adult pts who received 1L tx for la/mUC between 2019 and 2021. All pts were required to have ≥6 months of follow-up data available after end/start of 1L, depending on the type of tx received. Fully anonymized data were obtained from 27 oncology or urology institutions (8 hospitals and 19 office-based practices) across Germany. Descriptive statistics were used to analyze the results, and Kaplan-Meier methods were used to compute time-to-event outcomes. Pts were classified into 3 groups: (A) PBC with end of tx between Jan 2019 and Sep 2021 and (B) immuno-oncology (IO) therapy and (C) other non-PBC tx, both with start of tx between Jan 2019 and Sep 2021. Results: Of 188 pts included, median age at start of 1L was 70 years, 72.3% were male, most had ECOG PS 0/1 (92.5%), and the majority (60.1%) were treated by medical oncologists. A total of 143 pts (group A) received PBC (PBC + gemcitabine, 88.1%; PBC + non-gemcitabine agents, 8.4%; and cisplatin monotherapy, 3.5%). Cisplatin + gemcitabine (82.5%) was used more often than carboplatin + gemcitabine (17.5%). Six pts were treated with avelumab 1L maintenance following PBC. In group B, 36 pts (19.1%) received IO monotherapy (atezolizumab, 44.4%; pembrolizumab, 41.7%). In group C, 9 pts (4.8%) received non-PBC tx. Clinical outcomes in groups A and B are shown in the Table. Results for group C are not shown due to small sample size. Conclusions: CONVINCE describes characteristics, tx patterns, and outcomes in pts with la/mUC in routine clinical practice in Germany. In adherence with tx guidelines, most pts received PBC in 1L. New IO approvals, including avelumab 1L maintenance and other novel agents, could improve outcomes in pts with la/mUC. Further real-world studies should be performed to evaluate the uptake of these options within routine care. [Table: see text]
Safety and efficacy of enfortumab vedotin in patients with metastatic/locally advanced urothelial cancer: Real-world evidence from a European database.
Authors: Zschaebitz Stefanie , Klümper Niklas , Büttner Thomas , Holzwarth Nina , Biernath Nadine , Höllein Alexander , Niegisch Guenter , Seidl Daniel , Aydogdu Can , Handke Analena , Paffenholz Pia , Schlack Katrin , Cathomas Richard , Erne Eva , Banek Severine , Tauber Robert , Casuscelli Jozefina , Seitz Anna Katharina , Grünwald Viktor , Darr Christopher ,   GUARDIAN Study Group
Published: January 2024

553

Background: Enfortumab vedotin (EV) is an antibody drug conjugate targeting Nectin-4. It was approved by EMA/FDA in patients (pts) with metastatic/ locally advanced urothelial cancer post platinum and immune check point inhibitors following the results of the EV-301 trial. We report updated efficacy and safety data of EV in a large European cohort of real-world pts (GUARDIANS consortium) treated in hospitals and private practices. Methods: Retrospective data were collected from 25 German and Swiss hospitals and private practices for pts who received EV. Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated by local investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Weidentified 188 pts (32.4% female) with a median age of 66 yrs (range 31-89; 22.3% >/= 75 yrs). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0/1/2/3-4/unknown in 36/39/11/3/11%. EV was administered in the fourth or later line in 43% of pts. Overall response rate (ORR) was 46.3% (partial remission: 42.0%, complete response 4.3%), disease control rate was 58.0%. Median OS (mOS) was 12.0 months (mo) (95% confidence interval 9.65-14.35) and median PFS (mPFS) was 7.0 mo (95% confidence interval 5.43-8.57). Any-grade AEs were observed in 71% and CTCAE grade ≥3 AEs in 32% of pts. Most common AEs were peripheral sensory neuropathy (33.5% any grade), skin toxicity (24.5%) and fatigue (22.9%). In pts >/= 75 yrs, females, and pts treated in >/=4th line mOS, mPFS, ORR, and toxicities were comparable to younger and male counterparts and pts treated in <4th line, respectively. Limitations are retrospective design and short follow-up. Conclusions: Anti-tumor activity of EV in real-world pts including difficult-to-treat subgroups is comparable to the results of the pivotal EV-301 trial. No new safety signals were observed.
Avelumab first-line maintenance (1LM) in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) in the Czech Republic: Interim real-world results from a national reimbursement registry.
Authors: Zemankova Anezka , Studentova Hana , Melichar Bohuslav , Eid Michal , Poprach Alexandr , Kopecky Jindrich , Spacek Jan , Stuhlova Sarka , Dvorak Jan , Vlcek Pavel , Zychackova Katerina , Katolicka Jana , Blazek Tomas , Vrana David , Majkova Petra , Cepa Adam , Fiala Ondrej
Published: January 2024

557

Background: Avelumab 1LM treatment is recommended by international guidelines as the standard of care for pts with la/mUC that has not progressed with 1L platinum-based chemotherapy (PBC) and has been approved in the EU since Jan 2021. In the Czech Republic, following EU approval, there is a requirement to provide real-world data for “highly innovative medicinal products” such as avelumab 1LM when reimbursement decisions are temporary. Obtaining reimbursement therefore requires the creation of a registry to collect real-world data. We report interim results from a retrospective analysis of a national reimbursement registry for avelumab 1LM in the Czech Republic. Methods: Registry data were collected by the Office of Health Insurance (KZP) for pts with la/mUC receiving avelumab 1LM in the Czech Republic between Oct 2021 and Jan 2023. The primary endpoint was overall survival (OS) from the start of avelumab 1LM (index date); secondary endpoints included progression-free survival (PFS) from the start of avelumab 1LM and safety. Descriptive statistics were used to analyze the data. OS and PFS were estimated using the Kaplan-Meier method. Results: 59 eligible pts with la/mUC were treated and documented. At data cutoff (Jan 3, 2023), median follow-up was 6.1 mo (range, 0-16.5). All pts were White; 43 were male and 16 were female. At the start of avelumab 1LM, median age was 71 y (range, 49-84) and 22 pts (37.3%) had visceral metastases. 1L PBC was cisplatin-based in 30 pts (50.8%), carboplatin-based in 24 (40.7%), and both (switched from cisplatin to carboplatin) in 5 (8.5%). Best response to 1L PBC was complete response in 5 pts (8.5%), partial response in 30 (50.8%), and stable disease in 24 (40.7%). Median time from the end of PBC to the start of avelumab was 4.1 wk (range, 1.0-44.0). Effectiveness data for avelumab 1LM are shown in the Table. OS and PFS data are immature, with only 14 pts (23.7%) having died or had disease progression at the time of analysis. 10 adverse events were reported in 9 pts (15.3%), including grade 3 infusion-related reaction (1 pt), grade 2 diarrhea (2 pts), and grade 2 nephritis, pneumonitis, and Addison disease (1 pt each). At last evaluation, 53 pts were alive, of whom 5 pts had started subsequent treatment. Conclusions: This is the first study of pts with la/mUC treated with avelumab 1LM in a real-world setting in the Czech Republic. These preliminary data agree with the results of the phase 3 JAVELIN Bladder 100 trial and other real-world studies, confirming the effectiveness and manageable safety profile of avelumab 1LM in la/mUC. Follow-up for OS is ongoing. [Table: see text]
Identifying patient profiles and mapping treatment journeys of ARPI-treated, taxane-naive patients with metastatic prostate cancer across three countries in a digital patient survey.
Authors: O'Sullivan Joe M. , Lehmann Reiner , Sievert Henning , Allen Stephen , Carl Ernst-Günther , Wolinsky Howard , Poschenrieder Andreas , Mirante Osvaldo , Morgans Alicia K.
Published: January 2024

56

Background: A fully digital survey of patients with prostate cancer (PCa) was conducted in Germany (DE), the US and the UK to map characteristics, experiences and attitudes. Real-world profiles and treatment journeys, as well as intercountry differences, of taxane-naive patients with metastatic PCa (mPCa) are relatively unknown; data from the survey were leveraged to gain insights into these. Methods: From February 9 to April 10, 2021, DontBePatient Intelligence conducted a survey of patients with PCa. We identified responses from patients with mPCa who were taxane-naive and received at least one androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide. Demographics, disease characteristics, diagnostic trends and treatments journeys were analyzed, using descriptive and inductive statistics. Results: In total, 458 taxane-naive patients (mean age 68.9 years) had received one ARPI, while 36 had received two. There were differences in time since, mode of, and disease stage at diagnosis between countries (Table). Notably, more US patients were diagnosed through routine screening, yet more had been diagnosed with metastases vs UK/DE. UK patients more frequently reported hospital urologists and oncologists being involved in diagnosis vs DE/US patients. In DE, practice urologists were more frequently reported as being involved vs other specialties throughout the patient journey and these were more involved than in the UK/US. UK patients were more satisfied with radio/brachytherapy and hormone therapy and less satisfied with surgery vs DE/US patients. We uncovered considerable differences in treatment journeys between countries. UK patients had received less surgery vs DE/US patients (9.8% vs 41.5/33.1% patients), driven by less use in 1L. Radio/brachytherapy use was highest in the US (69.4%) and lowest in DE (37.3%), driven by infrequent 1L use in DE. Treatment with bone strengthening agents was less common in the UK (16.4%) vs DE/US (37.3/33.8%). Conclusions: In different countries, taxane-naive patients who received one ARPI have different characteristics at diagnosis and distinct patterns of care. It is important to understand how these differences may affect diagnostic and therapeutic trends to maximally improve patient care in this treatment setting. [Table: see text]
Evaluation of provider preferences in first-line metastatic cisplatin-ineligible urothelial carcinoma in the setting of platinum shortages.
Authors: Weinfeld Michael Seth , Chablani Priyanka Vinod , Reizine Natalie Marie , Stadler Walter Michael , Tawagi Karine
Published: January 2024

576

Background: Standard of care for patients with metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin has been gemcitabine and carboplatin (gem/carbo), and more recently followed by maintenance therapy with avelumab. Combination pembrolizumab (pembro) and the antibody-drug conjugate enfortumab vedotin (EV) has shown very promising results and is now approved for first-line therapy in cisplatin-ineligible patients based on the phase Ib/II EV-103 trial. We were interested in assessing providers’ decision-making between gem/carbo and EV/pembro based on perceived comparative response rates and toxicity profiles, as well as the nationwide platinum chemotherapy shortage in 2023. Methods: We sent a 10-question encrypted electronic survey centered on a scenario of a mUC case to 150 oncologists via email listservs and social media. Results: We received 45 responses: 7 oncologists (15.6%) chose gem/carbo, 15 (33.3%) chose EV/pembro, and a majority, 23 (51.5%) chose to discuss both options with patients. 40 (88.9%) were academic or disease focused and 5 (11.1%) described their practice as general oncology. Of oncologists who chose gem/carbo, the most common reasons were: gem/carbo has more long-term data (86.6%) and lack of phase 3 data for EV/pembro (71.4%). Of oncologists who chose EV/pembro, the most common reasons were: higher response rates (86.7%) followed by the carboplatin shortage (40%). Only 6.7% chose the carboplatin shortage as the main reason while 73.3% chose higher response rates as the main reason. Of oncologists who chose to discuss both, the most common reasons why they would consider EV/pembro were: higher response rates (82.6%), followed by patient preference (56.5%), followed by the carboplatin shortage (43.5%). 60.9% chose higher response rates as the main reason why they would consider EV/pembro. Conclusions: This questionnaire-based study of predominantly academic genitourinary oncologists suggests that the majority would consider EV/pembro as a first-line treatment for cisplatin-ineligible patients with mUC. The primary reason for this choice was the belief that it has higher response rates, as opposed to the national shortage of carboplatin or concerns regarding toxicity. We anticipate that the awaited results of the EV-302 trial in the coming months will also change the treatment landscape of mUC. However, similar issues may be relevant in the future for other treatment decisions in which incomplete information is available or with ongoing chemotherapy shortages.