bluuebunny/crossref_metadata_2025 huggingface dataset:
Germline alterations in cancer susceptibility genes in women with high-risk bladder cancer: Implications for germline testing and clinical management.
Authors: Truong Hong , Sheikh Rania , Khurram Aliya , Kemel Yelena , Lenis Andrew Thomas , Reisz Peter , Joseph Vijai , Goh Alvin , Cha Eugene K. , Donahue Timothy F. , Coleman Jonathan , Pietzak Eugene J. , Bochner Bernard H. , Offit Kenneth , Carlo Maria Isabel
Published: March 2021

418

Background: Gender differences exist in bladder cancer incidence, stage at diagnosis, and outcomes. Women have lower incidence of bladder cancer but are diagnosed with more advanced disease at presentation. They also have less favorable outcomes even after adjusting for tumor stage and treatment modality. The biologic mechanisms underlying gender disparities in bladder cancer remain unknown. Methods: We leveraged a prospective matched tumor-normal genomic profiling initiative to determine the prevalence and spectrum of pathogenic/likely pathogenic (P/LP) germline variants in women with bladder cancer. Germline DNA was tested for mutations in ≥77 cancer susceptibility genes using next-generation sequencing in 686 patients with bladder cancer. Mutation frequency and clinical characteristics were assessed by gender. Results: A total of 184 (27%) women and 502 (73%) men with bladder cancer underwent germline testing; median age of diagnosis was 66 ± 11.3 and 65 ± 11.3 years, respectively. Twenty-two women (12%) had bladder cancer diagnosis at age ≤ 50 years. Both groups had similar rate of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.5), and disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 54% vs 54%, MIBC 38% vs 39%, and metastatic disease 8% vs 6%, p = 0.7). Women had more non-urothelial carcinoma histology than men (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001). More P/LP germline variants were found in women than men (38 [21%] vs. 70 [14%], p = 0.04). Twenty-eight women (15%) had P/LP variants in DNA-damage repair (DDR) genes; 23 (13%) carried moderate/high penetrance germline mutations, the most common were BRCA1/ 2, CHEK2, NBN, ATM, and MITF. Current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. Nine women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers ( BRCA1/ 2 [5], ATM [2], MLH1 [1], TP53 [1]). Conclusions: Deleterious germline alterations are commonly present in women with high-risk bladder cancer. The presence of germline variants in some genes, such as BRCA1/2, can guide cancer screening and risk-reducing surgeries for patients and their families. Women with high-risk bladder cancer should be evaluated for suitability of germline testing, especially those who desire preservation of uterus and ovaries at the time of radical cystectomy, to rule out the presence of P/LP variants that increase risk of future gynecologic malignancies.
Efficacy of chemohyperthermia (HIVEC) in patients with high-risk nonmuscle invasive bladder cancer (NMIBC) who fail BCG therapy.
Authors: Pignot Geraldine , Doisy Laure , Walz Jochen , Marquette Thibault , Maubon Thomas , Rybikowski Stanislas , Gravis Gwenaelle
Published: March 2021

456

Background: To evaluate Hyperthermic Intra-Vesical Chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (DFS) rate and bladder preservation rate in patients with high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) who fail BCG therapy or are contraindicated to BCG. Methods: Between June 2016 and October 2019, patients treated with HIVEC for high-risk NMIBC who failed BCG (Fail-BCG) or BCG-naive if BCG contraindicated (N-BCG) have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. Results: Fifty-three patients, median age 72 [39-93] years, were included (n = 29 Fail-BCG and n = 24 N-BCG). The median follow-up was 18 months. The bladder preservation rate was 92.4%. The RFS rate at 12 months was 60.5%. The RFS rate at 12 months for N-BCG and Fail-BCG groups was respectively 70% and 52.2%. Three patients progressed to muscle-invasive disease, all in the Fail-BCG group and all in the very high-risk EORTC group. Two of them experienced metastatic progression and died from bladder cancer. Conclusions: Chemohyperthermia using HIVEC device achieved a RFS rate of 60% at 1 year and enabled a bladder preservation rate of 92%. Given the low risk of progression in the N-BCG group, HIVEC could be a good alternative. Conversely, for patients with very high-risk tumors that fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.
Single-cell DNA targeted sequencing (scDNA-seq) to test therapeutic vulnerabilities in urothelial cancer (UC) patient-derived organoids (PDO).
Authors: Shohdy Kyrillus , Liu Weisi , Alonso Alicia , Xiang Jenny , Martin M. Laura , Elemento Olivier , Faltas Bishoy Morris
Published: March 2021

464

Background: Genomic alterations in FGFR3, PIK3CA, and CDKN2A are common actionable targets in urothelial cancer (UC). We aimed to determine the efficacy of alpelisib, a PIK3CA inhibitor, and abemaciclib, a CDK4/6 inhibitor in bladder cancer patient-derived organoid using single-cell targeted DNA sequencing. Methods: We established a patient-derived UC organoid (PDO) harboring the FGFR3 mutation (p.Y375C), the PIK3CA (p. E452K) mutation, and CDKN2A deletion, which we characterized using whole-genome sequencing. We generated dose-response curves of alpelisib, abemaciclib, and erdafitinib (an FGFR3 inhibitor) in PDO cells to determine the IC50 concentrations. The scDNA-seq (Tapsteri) platform was used to measure changes in the variant allele frequencies (VAF) and clonal fractions post-treatment. The Chi-square test for trend was used to test for linear trend across ordered categories. Results: scDNA-seq was performed after treating PDO cells with 3uM erdafitinib or DMSO. A total of 7000 single cells were obtained (4179 cells treated with erdafitinib vs. 2821 cells treated with DMSO). After removing variants mutated in <50% of cells, we identified 94 clonal variants. As expected, cells harboring FGFR3 Y375C have significantly decreased post erdafitinib treatment compared to DMSO-treated cells (66.05% vs. 82.36%, p<0.0001). We identified mutations in two genes ( RAB31 and SMAD4) that were associated with clonal expansion following FGFR3 inhibition (12% vs. 53% and 13% vs. 26%, respectively). We treated PDO cells with 3uM abemaciclib. We identified three genes harboring SNVs ( RB1, GNAQ, and SMAD4). The SNVs harboring cells were significantly decreased after abemaciclib compared to DMSO (p<0.0001). Then, we treated the cells with 1uM alpelisib for 72 hours alone or combined with abemaciclib (0.1uM). We identified that 100% of cells harbored the PIK3CA mutation E452K at pre-treatment, which limited our ability to detect significant changes in VAF post-treatment. Instead, we analyzed the effect on the FGFR3 Y375C clone. Using trend analysis, there was a significant reduction of FGFR3-mutant cells observed across the three conditions, abemaciclib + alpelisib vs. alpelisib alone vs. DMSO (74% vs. 85% vs. 92%, trend test p<0.0001), suggesting in vitro efficacy of alpelisib alone and significant synergism with the addition of abemaciclib. Conclusions: This study established the feasibility of using scDNA-seq as a promising tool to study the clonal evolution patterns in patient-derived UC organoids. Combined pharmacologic inhibition of CDK4/6 and PIK3CA showed more in vitro sensitivity than PIK3CA inhibition alone.
Impact of FGFR2/3 activating genomic alterations on response to enfortumab vedotin in metastatic urothelial carcinoma (mUC).
Authors: Adib Elio , Jain Rohit K. , Skelton William Paul , Freeman Dory , Curran Catherine , Akl Elie W. , Nassar Amin , Ravi Praful , Mantia Charlene , Merchan Jaime R. , Tan Winston , Plastini Trisha M. , Choueiri Toni K. , Sonpavde Guru
Published: March 2021

472

Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved in patients for post-platinum mUC with activating genomic alterations in FGFR2/3, but the activity of EV in this subset is unclear. We investigated the activity of EV in patients (pts) with mUC based on FGFR2/3 genotype to inform management. Methods: In this multi-center, retrospective analysis, we assessed the objective response rate (ORR) to EV in mUC pts with and without FGFR2/3 genomic alterations detected by targeted panel next-generation sequencing. Activating gene fusions and known hotspots mutations in the two genes were considered. Descriptive analysis of ORR and patient characteristics was performed. Fisher’s exact test and binomial test with two-tailed p-value were used. Results: 40 pts were available from 4 institutions. Most pts were male (31/40, 78%) and the median age at start of EV was 74.1 (range 49 – 90) years. Ten patients (25%) had upper tract urothelial carcinoma (UTUC), and 33 (82%) had baseline ECOG performance status of 0-1. 31 of 39 patients had received both platinum-based chemotherapy and PD1/L1 inhibitors. Seven patients had confirmed activating hotspot FGFR3 mutations (p.S249C or p.Y373C). One pt had FGFR2 high-level amplification (HA), and one had FGFR3 HA. Of 36 patients evaluable for ORR, 18 had partial response (PR), 12 had stable disease (SD) and 6 had progressive disease (PD). Patients with FGFR2/3 activating mutations exhibited an ORR that was not statistically different compared to patients without no mutations: 2/7 (29%; 90% CI: 5 – 66%) vs. 16/29 (55%; 90% CI: 38 – 71%) respectively ( p-value = 0.4). 3/7 patients with FGFR3 hotspot mutations received an FGFR2/3 inhibitor and none responded; one of them had a sequential response to EV. Conclusions: In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment.
Prognostic impact of serum cytokeratin 19 fragments in patient with metastatic urothelial cancer (mUC) treated with first-line chemotherapy.
Authors: Endo Yuki , Kimura Go , Akatsuka Jun , Yanagi Masato , Mikami Hikaru , Takeda Hayato , Hasegawa Hiroya , Toyama Yuka , Ikuma Shunsuke , Nishikawa Yoshihiro , Takasaki Suisen , Hayashi Tatsuro , Kondo Yukihiro
Published: March 2021

473

Background: Even today, when several immune checkpoint Inhibitors have been approved for the treatment of metastatic urothelial cancer (mUC), cytotoxic chemotherapy (CTC) still remains the mainstay for first-line treatment. We believe that the prognostic factors for the first-line CTC have become more important again and need to be re-analyzed. Current guidelines do not yet provide recommendations for any serum tumor markers in patients with mUC. Previous studies have shown that serum cytokeratin 19 fragments levels (sCK) were correlated with depth of tumor invasion and metastatic burden in patients with bladder cancer. In this study we evaluated whether sCK, and other clinical parameters could predict overall survival (OS) in patients with mUC treated with CTC. Methods: Two hundreds fifty two patients with mUC received CTC from December 2006 to 2016 at our institution. sCK had been measured in 128 patients at diagnosis of mUC. OS rate were analyzed by Kaplan–Meier curves and log–rank test. Multivariate analysis was carried out using the Cox hazards model. Tumor burden (TB) was measured based on Response Evaluation Criteria In Solid Tumor (version 1.1). Results: Of 128 patients, with median age of 72 (44-93), 36 (28%) had lung metastasis, 11 (9%) had bone metastasis, 10 (8%) had liver metastasis (LM). Ninety five (74%) patients received platinum based chemotherapy as a first-line treatment. During the median follow-up period of 19 (1-89) months, 72 patients (70%) had died. A 1-year (1y) OS was 51% and a 2y-OS was 36%. On univariate analysis, performance status (PS) (HR2.0, p<0.005), sCK (HR3.9, p<0.001), CRP (HR4.0, p<0.001), neutrophil-lymphocyte ratio (HR1.9, p<0.049), LM (HR2.0, p=0.042) and TB (HR2.4, p<0.001) were the significant prognostic factors for OS. On multivariate analysis, PS (HR2.0, 95%CI (1.05-3.85) p=0.036 ), sCK (HR3.1, 95%CI (1.3-8.3), p=0.011), and LM (HR3.0, 95%CI (1.06-6.98), p=0.022) were the independent prognostic factors for OS. Based on these 3 factors we divided patients into three groups, good risk (G, 0 factor), intermediate risk (I, 1 factor) and poor risk (P, 2-3 factors). There was a significant difference between the three groups. (G vs I: p<0.001, I vs P: p=0.001). Conclusions: PS, sCK, and LM were the independent prognostic factors for OS in patients with mUC receiving CTC. For the patients in good or intermediate risk with this score, early exposure of ICIs should be performed after CTCs. Treatment strategy should be changed in patients with poor risk since CTC is primary refractory in such population.
High-throughput global transcriptional profiling to identify the STAT3 signaling pathway as a potential biomarker for immune checkpoint inhibitor resistance in metastatic/advanced urothelial carcinoma.
Authors: Lyou Yung , Dorff Tanya B. , Pal Sumanta K. , Yuan Yate-Ching
Published: March 2021

474

Background: Advanced/metastatic urothelial carcinoma (UC) is a significant public health burden with median overall survival of 15 months. Although, immune checkpoint inhibitors (ICI) have provided an additional second line treatment option, only 15-40% of patients will respond. There has been much effort in determining the mechanisms of immunotherapy resistance and predictive biomarkers to further improve these treatments. Methods: Pre-treatment genomic sequencing data derived from FFPE samples from the IMVIGOR210 clinical trial (n=298) was accessed for analysis. Briefly it was a single arm phase II clinical trial where advanced/metastatic UC patients refractory to platinum chemotherapy treatment received the ICI atezolizumab. This study has been published with detailed methods (PMID: 28950298). The raw sequencing data was pre-processed using standard QC measures and aligned to the human reference genome (hg38). The resulting outputs were then normalized and processed to generate the gene level counts for differential gene expression (DGE). We did DGE analysis comparing patients who had clinical benefit (CR, PR, SD) vs non-clinical benefit (ie. PD) to atezolizumab. The list of differentially expressed genes were then analyzed using various gene ontology, pathway and systems biology tools (IPA, Enrichr, and X2Kweb). Further subset analysis was done using gene-gene correlations (ie. PD-L1 and STAT3) and clinicopathologic features (eg. gender, race, smoking history). Results: Among the 298 patients in this study, there were 25 with CR, 43 with PR, 63 with SD, and 167 with PD based on clinical response to atezolizumab. Subgroup analysis for CR vs PD patients found that approximately 847 genes were differentially expressed with statistical significance (p ≤ 0.05). IPA analysis for this list of differentially expressed genes found among the top signaling pathways were “primary immunodeficiency” and “sirtuin signaling”. Further subset analysis of 39 genes (p ≤ 0.01) enriched in PD patients using Enrichr and X2kweb found that there was an overrepresentation of STAT3 signaling genes (hypergeometric p-val 6.32x104). Conclusions: Our results found that when the transcriptional profiles of CR vs PD there was differential gene expression in STAT3, primary immunodeficiency, and sirtuin signaling pathways. Of note it has been reported that STAT3 signaling can modulate immune activity and its expression is correlated with poor prognosis in urothelial carcinoma patients. These results warrant a larger study to see if STAT3 signaling is a potential biomarker for ICI resistance. If validated this may indicate that the STAT3 pathway is a potential therapeutic target to overcome ICI resistance and improve the efficacy of these agents.
TERT promoter mutation as a prognostic marker in patients with advanced urothelial carcinoma treated with immune checkpoint inhibitors.
Authors: de Kouchkovsky Ivan , Zhang Li , Philip Errol , Wright Francis , Kim Daniel Myung , Natesan Divya , Kwon Daniel , Ho Hansen , Ho Son , Chan Emily , Porten Sima P. , Desai Arpita , Huang Franklin W. , Chou Jonathan , Oh David Yoonsuk , Pruthi Raj , Fong Lawrence , Small Eric Jay , Friedlander Terence W. , Koshkin Vadim S
Published: March 2021

476

Background: Reliable predictive markers are lacking in patients (pts) with locally advanced or metastatic urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICI). We sought to determine whether specific genomic alterations could be used to predict overall survival (OS) in this patient population. Methods: We undertook a retrospective cohort study of pts with aUC who received ICI and underwent genomic profiling by next-generation sequencing (NGS). All patients underwent NGS using commercially available platforms (e.g. Foundation Medicine, Strata, Invitae), or testing on the CLIA-certified institutional panel UCSF500. Associations between the 20 most frequently altered genes and OS were first examined by Cox regression. Genes with a p <0.1 on univariate analysis and relevant clinical variables were then included in a multivariable analysis. Results: We identified 78 pts treated with ICI for aUC with available genomic profiling results. Median age at ICI initiation was 71; the majority of patients had visceral metastases (70.5%), ECOG performance status ≤1 (62.8%) and received ICI in the post-platinum setting (52.6%). Objective response rate in this cohort was 35.9%, median progression free survival was 4.0 months (95% CI 2.6-10.5) and median OS was 17.5 months (95% CI 14.1-NR) from ICI start. The most commonly altered genes were the TERT promoter (TERTp) (61%), TP53 (52%), RB1 (31%), CDKN2A(29%) and CDKN2B (27%). On univariable analysis there was a trend towards longer OS in pts with TERTp mutations (HR 0.53, 95% CI 0.27-1.06, p = 0.07), and shorter OS in pts with CDKN2B mutations (HR 1.91, 95% CI 0.98-3.73, p = 0.06). Both mutations were included in a multivariable analysis. After adjusting for known prognostic variables (ECOG PS, visceral metastases, albumin, hemoglobin, body mass index [BMI], neutrophil to lymphocyte ratio [NLR], and histology), the presence of a TERTp mutation was significantly associated with improved OS (HR 0.30, 95% CI 0.10-0.93, p = 0.04; Table). Conclusions: The presence of a TERTp mutation was an independent predictor of improved OS in a cohort of aUC pts treated with ICI. Other common mutations and clinical variables were not associated with OS on a multivariable analysis. These findings are hypothesis-generating and prospective validation is needed. [Table: see text]
RNA-seq analysis of non-muscular invasive bladder cancer to reveal different gene expression profiles between smoking and non-smoking patients.
Authors: Fu Zhichao , Liu Shenghua , Wang Jianfei , He Ning , Yang Yadong , Xu Tianyuan , Anil Shrestha , Yan Yang , Li Cheng , Zheng Zongtai , Li Xin , Yao Xudong
Published: March 2021

478

Background: Bladder cancer is the ninth most common malignancy in the world, approximately 75% of patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). Smoking has been established to be a carcinogenic risk factor of bladder cancer. Nevertheless, the detailed relationship between smoking and progression of NMIBC are poorly understood. In this study, we revealed high expressed genes in smoking patients were significantly related to tumor progression in NMIBC patients. Methods: A total of 54 NMIBC patients including 19 never smokers and 35 smokers (current smokers and previous smokers) were enrolled in this study.The gene expression profiles were obtained by RNA-seq and the differentially expressed genes between smoking and non-smoking patients were identified using DESeq2 .The further analysis of the association between genes expression and patient survival in NMIBC cohorts(Jakob et al., 2016)and IMvigor 210 cohorts(Jonathan et al., 2016)by Kaplan-Meier survival estimate. Results: We identified 46 differentially expressed genes (p<0.05) in smoking and non-somking NMIBC patients. IDO1 and KRT14 gene, which related to bladder cancer progression and poor prognosis, was identified significantly higher expressed in somking group compared with non-smoking and they have a logFC of 2.6,3.9 with FDR 1.83E-5,3.40E-5 respectively. The expression of other genes, including KRT6A, CASP14, SERPINA1, MYO3A and IL20RB, were significantly higher in smoking patients compared to non-somking. Notably, survival data analysis from 476 NMIBC cohorts showed that IL20RB had a significant relationship with poor PFS(p = 0.021) and in the Mvigor 210 Cohort including 310 advanced or metastatic urothelial carcinoma patients treated with atezolizumab, we found that the high expression of IL20RB was significantly related to poor OS(p = 0.002). Conclusions: We identified 14 genes related to tumor progression were significantly higher in smoking NMIBC patients than in non-smoking. Among these genes, the expression of IL20RB was related to the poor prognosis of NMIBC, and it may correlates with reduced clinical benefit of immunotherapeutic in patients with urothelial carcinoma.
Characterization of FOXF1 as a novel regulator of nodal metastasis in bladder cancer.
Authors: Mitra Anirban P , Kokorovic Andrea , Miest Tanner , Narayan Vikram M , Sundi Debasish , Lim Amy , Mokkapati Sharada , Dinney Colin P.N.
Published: March 2021

480

Background: Members of the forkhead transcription factor (FOX) family are important mediators of embryonic development and are known to be altered in a variety of cancers. The functional role of FOXF1 in bladder tumorigenesis and progression has not been clearly characterized thus far. This study investigated the clinical implications of differential FOXF1 expression in bladder cancer, and potential mechanisms by which its alteration can lead to tumor metastasis. Methods: Whole genome expression profiling was performed on paired primary tumors and nodal metastases from a radical cystectomy discovery cohort using Illumina HT12 v3-4 BeadChip arrays to identify FOXF1 as a top differentially expressed gene. Prognostic role of differential FOXF1 expression was validated on two independent cystectomy cohorts. Differential FOXF1 expression was also evaluated in murine orthotopic xenografts. Small interfering RNA was used to knock down FOXF1 in RT112 and UC6 bladder cancer cell lines to develop an in vitro model for assessment of metastatic potential. Next-generation sequencing and hierarchical clustering analysis were used to identify differentially altered genes secondary to FOXF1 knockdown. 186 biologically curated pathways were interrogated with internal validation to elucidate the downstream biologic mechanisms of metastasis. Results: In the discovery cohort, FOXF1 was a top differentially expressed gene with 3.6-fold lower expression in nodal metastases than paired primary tumors (n = 33, p < 0.001). Multivariable analyses in two validation cohorts (total n = 128) indicated that FOXF1 underexpression was associated with worse cancer-specific (p = 0.046) and overall survival (p = 0.006). Murine orthotopic xenografts (n = 13) established from human bladder cancer cell lines (UC3, UC6, UC14) showed FOXF1 underexpression in metastatic deposits compared with primary tumors (p = 0.004). Hierarchical clustering identified 40 differentially expressed genes between FOXF1-knockdown bladder cancer cell lines and their corresponding controls. Biological pathway interrogation showed differential enrichment for genes associated with mitogen-activated protein kinase signaling, focal adhesion and other carcinogenic pathways in FOXF1-knockdown cells compared with controls (normalized enrichment score ≥ 1.3). Conclusions: We identify and characterize FOXF1 as a novel regulatory molecule that potentially drives bladder cancer metastasis. This may be modulated through alterations in intracellular signaling and cellular adhesion. FOXF1 may serve as a prognostic biomarker that can identify patients at impending risk for metastasis who may benefit from more aggressive management.
Patient-centric care in bladder cancer: Virtual simulation to benefit clinical decision-making of oncologists.
Authors: Parikh Kinjal , Topping Donna L. , Dhoble Saee , Cohen Jacob , Kadkhoda Haleh , Kugel Patrick , Van Laar Emily Sherene
Published: March 2021

492

Background: Immunotherapy (IO) utility in bladder cancer (UC) has expanded into multiple stages of disease. Employing IO optimally requires mastery of clinical trial data, patient eligibility criteria, and interpretation of biomarkers and determination of treatment sequencing. Given the nuanced therapeutic decision-making, education was developed in partnership between Medscape Oncology and Society for Immunotherapy of Cancer (SITC) to assist oncologists in improving their performance surrounding the management of patients with advanced UC. Methods: A virtual patient simulation (VPS) continuing medical education (CME)-certified activity depicting 2 advanced UC cases was made available to oncologist members of Medscape. The cases depicted 1) a patient with newly diagnosed metastatic UC with comorbidities and PDL1+ disease and 2) a patient with advanced UC progressing on platinum therapy with no actionable mutations. The VPS platform captures real-life decision making process of oncologists in an EHR-like format supported by an extensive database of diagnostic and treatment possibilities. Learners were able to interact with patients via video, order lab tests, assess patients, make diagnoses, and order treatments matching the scope and depth of actual practice. Tailored clinical guidance (CG) employing up-to-date evidence-based and faculty recommendations was provided after each decision point. Decisions were collected pre- and post-CG and analyzed using McNemar’s test to determine p-values. Data were collected from 4/28/20 to 7/13/20. Results: Analyses from oncologists (n = 51-66) found significant improvement in performance measured pre- to-post CG: Case 1: Ordering appropriate testing to determine patient eligibility for therapy (39% pre; 65% post; p < .001) Prescribing appropriate therapy based on patient- and disease-specific factors (38% pre; 77% post; p < .001) Providing appropriate counseling and follow-up for a patient receiving treatment (65% pre; 80% post; p < .01) Case 2: Ordering appropriate testing to determine patient eligibility for therapy (39% pre; 57% post; p < .01) Prescribing appropriate therapy based on patient- and disease-specific factors (25% pre; 41% post; p < .01) Providing appropriate counseling and follow-up for a patient receiving treatment (71% pre; 82% post; p < .05). Conclusions: This activity demonstrates the value of providing oncologists a simulation platform to practice and master clinical decision-making of the limitless possible diagnostic and therapeutic options in the management of advanced UC. Insights from rationales for each clinical decision point uncover continued gaps for oncologists on guideline recommendations, efficacy outcomes, or molecular implications. They also highlight barriers including limited experience or confidence with IO.
Tumor mutation burden and immune microenvironment analysis of urothelial carcinoma.
Authors: Jia Yuanyuan , He Ning , Yang Yadong , Huang Yuliang , Zhang Xiaoyu , Fu Zhichao , Xu Xiaohong , Cao Jianjun , Wang Jianfei
Published: March 2021

494

Background: Tumor mutation burden (TMB) has been established as a biomarker for response to immune therapy and prognosis in various cancers. However, the correlation between TMB and immune microenvironment remains unwell studied, especially in urothelial carcinoma. This study was aimed to investigate the relationship between TMB and other immunotherapy related biomarkers, including genetic alterations, APOBEC signature, microsatellite instability (MSI), PD-L1 expression and immune cell infiltration in urothelial carcinoma. Methods: 131 patients with urothelial carcinoma admitted from October 2018 to May 2020 were included. Total DNA was isolated from FFPE or fresh tissues. Mutation profiles, APOBEC signature and MSI scores were obtained by next-generation sequencing based a 642 cancer genes panel assay. PD-L1 expression, CD8+ T-cells and tumor-infiltrating lymphocytes density were evaluated by immunohistochemistry. The correlation was analyzed by Wilcoxon signed-rank test. Results: The mutation landscape showed that TP53 mutation is the most common alterations (n = 64/131, 48.9%), followed by KMT2D alterations (n = 49/131, 37.4%), KDM6A mutations (n = 42/131, 32.1%), MUC17 mutations (n = 42/131, 32.1%). The median TMB was 5.06 Muts/Mb (0-118 Muts/Mb). 2 of 131 patients showed MSI-H, who exhibited a much higher TMB (41, 118 Muts/Mb). Further analysis showed that TMB in the patients with certain gene mutations (such as TP53, KMT2D, KDM6A and MUC17) was significantly higher than those wild type ones (p < 0.05). Meanwhile, the high APOBEC-enrichment group has a higher TMB than the low APOBEC-enrichment group (p = 0.045). Furthermore,we observed that the patients with a higher PD-L1 expression (n = 28/131, 21.4%, at a combined positive score cut-off value of 10) also showed a significantly higher TMB (p = 0.016), and TMB in the patients with higher density of CD8+ T-cells (n = 42/131, 32.1%, at a cut-off value of 5%) was also significantly higher than that of the group with lower density of CD8+ T-cells (p = 0.039). Conclusions: This study provides new insights into the correlation between the TMB and the immune microenvironment in urothelial carcinoma. The result may be a reference to immunotherapy.
The impact of adjuvant chemotherapy on oncologic outcomes of patients with locally advanced bladder adenocarcinoma: An analysis of the National Cancer Database.
Authors: Reddy Akshay G , Sparks Andrew D , Helbig Michael , Whalen Michael Joseph
Published: March 2021

495

Background: The relatively poor prognosis associated with locally advanced bladder adenocarcinoma necessitates investigation of the utility of adjuvant chemotherapy (AC) and risk stratification of those who would benefit from such systemic therapy. This study seeks to evaluate the oncologic and surgical outcomes of those with locally advanced disease treated with and without AC. Methods: A retrospective cohort analysis was performed using the National Cancer Database from 2006 to 2016. Patients with non-metastatic locally advanced pT3-4 or pT(any)N1-3 primary bladder adenocarcinoma who received AC only or did not receive AC after radical (RC) or partial cystectomy (PC) were included. The AC cohort was further sub-stratified by surgery type (PC versus RC) and disease origin (urachal versus non-urachal subtypes). Survival, oncologic, and surgical outcomes were compared between cohorts. Results: Inclusion criteria identified 79 AC patients and 251 no AC patients. Of the 79 patients who received AC, 23 had PC procedure, 56 had RC procedure, 10 had urachal origin and 69 had non-urachal origin. Receipt of AC was significantly higher in RC relative to PC (27.6% vs 18.1%; p = 0.049). Urachal vs. non-urachal subtype did not impact receipt of AC (25.3% vs 17.5%; p = 0.214), but urachal subtype was associated with improved overall survival compared to non-urachal (47% vs 18%; HR = 0.37; p = 0.04). Although receipt of AC was significantly associated with higher odds of positive margins (46% vs 23%; odds ratio = 2.85; p < 0.01), no difference in overall survival was detected between the AC and no AC cohorts (23% vs 19%; hazards ratio [HR] = 0.98; p = 0.91). Of note, independent of AC, PC was associated with improved survival compared to RC (51% vs 12%; HR = 0.25; p < 0.01). Conclusions: There is no detected survival benefit to the use of a non-standardized AC regimen in locally advanced bladder adenocarcinoma. Within the AC treated population, survival outcomes suggest that urachal subtype may confer survival advantage and that those patients selected for PC tend to have improved survival. Although employing a national dataset, statistical power was limited given the rarity of this disease. Further investigation is warranted on a larger scale in order to assess the impact of AC regimen, afford proper patient selection, and enhance risk stratification for oncologic outcomes.
Cognitive status of prostate cancer (PCa) patients aged 60 years and older after a six-month gonadotropin-releasing hormone agonist (GnRHa) therapy, according to age groups: Secondary analysis of PRISME study.
Authors: Roupret Morgan , Rozet Francois , Hennequin Christophe , Pello Leprince Ringuet Nathalie , Grandoulier Anne-Sophie , Mongiat-Artus Pierre
Published: March 2021

56

Background: Age is a risk factor for both PCa and cognitive impairment. Moreover, androgen deprivation therapy (ADT) is suspected to alter cognition, but little is known about the cognitive status of men starting ADT. Our purpose was to analyze cognitive status in 3 groups of age ([60-70[, [70-75[ and ≥ 75 years), before and after a 6-month GnRHa therapy. Methods: Between March 2018 and February 2020, a prospective, multicenter, longitudinal, non-interventional study was conducted in France (PRISME, NCT03516110). Urologists, radiation oncologists and medical oncologists recruited patients aged 60 years and older, with PCa, initiating a GnRHa therapy. 1000 patients were planned to be included 1:2:1 in prespecified age groups ([60-70[, [70-75[, ≥ 75 years). Cognitive status was evaluated through Mini Mental State Evaluation (MMSE) questionnaire (scores 0-30). Significant differences between groups were concluded in case of non-overlapping of the means 95% CIs, and significant changes in case of means 95% CIs not including 0. An analysis of covariance (ANCOVA) was performed to compare evolution of MMSE global score in subgroups of ages, adjusted on baseline scores (secondary effectiveness analysis). Post-hoc analyses of subgroups of level of education were also provided. Results: The final analysis included 652 patients (full analysis set population). Mean (±SD) age was 72.5±6.2 years. There were 193, 269 and 190 patients, in the [60-70[, [70-75[ and ≥75y age groups, respectively. 95.5% of patients had a Karnofsky score ≥ 80%; 71.6% had at least one comorbidity at baseline,65.0% were receiving at least one concomitant systemic treatment. Main reasons for GnRHa initiation were high risk PCa (65.3%), metastatic stage (18.4%), biochemical recurrence (13.3%). Mean [95% CI] baseline MMSE score was significantly lower in the ≥75y age group (26.2 [25.6-26.8]) than in the [60-70[ (27.9 [27.5-28.3]) and [70-75[ (27.6 [27.3-28.0]) age groups, with significantly more patients with cognitive impairment (MMSE < 26) in the ≥75y (30.9%) than in the [60-70[ (15.3%) and [70-75[ (14.7%) age groups. Baseline MMSE scores were significantly different between all level of education groups: 28.4 [28.0-28.7] in high, 27.2 [26.8-27.7] in middle and 24.7 [23.5-25.9] in low level groups. No significant changes in MMSE scores were observed after a 6-month GnRHa therapy inside age groups or inside level of education groups. Planned ANCOVA analyses found no statistically significant changes of MMSE global score from baseline between age groups. Conclusions: In this large observational cohort of PCa patients aged 60 years and older with prespecified age groups, cognitive status did not change after a 6-month GnRHa therapy, whatever the age group. Clinical trial information: NCT03516110.
Clinically significant events associated with metastatic castration-resistant prostate cancer (mCRPC) treatments.
Authors: Moses Kelvin A. , Wallace Katrine L , Landsteiner Adrienne , Bunner Scott H , Engel-Nitz Nicole , Lal Lincy S. , Golsorkhi Tony
Published: March 2021

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Background: We describe the association between clinically significant events (CSEs) and mCRPC treatments in US-insured patients using an administrative claims database. Methods: Adult men in a large administrative claims database from Jan 2008 to Mar 2019 with ≥1 claim for prostate cancer, codes for pharmacologic or surgical castration, and incident metastatic disease during the identification period were included in the study. Patients who had ≥6 months of continuous enrollment before and after the index date (first metastatic claim) were included. Patients were followed until death, end of study, or disenrollment. Claims-based algorithms were used to identify patients with mCRPC, lines of therapy (LOTs), and CSEs of interest. CSEs were assessed in the first LOT in which an mCRPC regimen was used. Time on treatment was used as a person-time denominator to assess rates of CSEs per 365 days (treatment year) to control for differing times on treatment regimens. Results: Overall, we identified 3690 patients with mCRPC, of which 3150 (85%) received ≥1 LOT, among whom 1680/3150 (53%) received a regimen indicated for mCRPC. Average follow-up time was 705 days. CSEs occurred in 664/1680 (40%) patients, an average of 1.15 CSE per treatment year (Table). Patients had an average of 2 CSEs. The most common CSEs were anemia (14%), fatigue (15%), and back pain (10%). CSE rates per treatment year were highest among patients who received a taxane (1.7 per treatment year), taxane + gonadotropin-releasing hormone (GnRH) modulator (1.6 per treatment year), and other chemotherapy (1.6 per treatment year). Conclusions: Among treatments for patients with mCRPC, chemotherapy-based regimens showed the highest CSE rates per treatment year. These data indicate the burden of treatment for patients and can inform treatment decisions. [Table: see text]
Comparative cardiotoxicity of the novel hormonal agents abiraterone and enzalutamide in metastatic castration-resistant prostate cancer using real-world data.
Authors: Hu Jason , Aprikian Armen G. , Vanhuyse Marie , Dragomir Alice
Published: March 2021

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Background: Novel hormonal agents (NHAs) such abiraterone (ABI) and enzalutamide (ENZA) have demonstrated similar survival benefits against placebo groups in their respective clinical trials leading to their regulatory approval in both the pre- and post-chemotherapy settings in metastatic castration-resistant prostate cancer (mCRPC). Despite the overall tolerable risk profile, certain signals of cardiovascular toxicity were reported for these agents in clinical trials but little is known about their incidence in clinical practice. The objective was to assess the comparative cardiovascular safety of ABI and ENZA in patients with mCRPC in the real-world. Methods: A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. Patients were selected on the basis of having received androgen deprivation therapy prior to initiating a novel hormonal agent (ABI or ENZA) between 2012 and 2016. The primary outcome of interest was cardiovascular-related hospitalization (composite outcome that included acute coronary disease, cerebrovascular disease, heart failure, arrhythmia and other cardiovascular causes). Inverse probability of treatment weighting (IPTW) with the propensity score was used to adjust for measured baseline confounders including pre-existing cardiovascular disease. Results: The cohort comprises 2,183 patients, with 1,773 (81.2%) in the ABI group and 410 (18.8%) in the ENZA group. Before IPTW, mean age of the ENZA group was higher than the ABI group (78 vs 76). There were more ENZA patients with pre-existing arrythmia (ABI: 10.7%, ENZA: 15.1%) and diabetes (ABI: 21.5%, ENZA: 25.1%). Crude incidence rates of cardiovascular-related hospitalization were of 10 events per 100 person-years (PYs) and of 7 events per 100 PYs for the ABI and ENZA groups, respectively. After applying IPTW, all baseline variables were well balanced across both groups with standardized differences < 0.05. The ABI group was at greater risk of cardiovascular-related hospitalization compared to the ENZA group (IPTW-hazard ratio (HR): 1.79, 95% confidence interval (95%CI): 1.04-3.09). The risk of hospitalization for heart failure was greater in ABI (IPTW-HR: 3.02, 95%CI: 1.17-7.78). Conclusions: In our study population, there was a greater risk of cardiovascular-related hospitalizations for ABI users relative to ENZA users, in particular for hospitalization for heart failure. Given the lack of evidence from randomized head-to-head comparisons of both agents, these results provide clinicians with additional insight on the cardiovascular risks of mCRPC patients treated with NHAs in the real-world and further large studies are required to corroborate these findings.
Health-related quality-of-life (HRQoL) analysis from a randomized phase II trial of androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.
Authors: Soares Andrey , Bastos Diogo Assed , Schutz Fabio A. B. , Cronemberger Eduardo , Luz Murilo , Martins Suelen P. S. , Muniz David Queiroz Borges , Carcano Flavio Mavignier , Smaletz Oren , Peixoto Fábio A , Gomes Andrea Juliana , Cruz Felipe Melo , Franke Fabio Andre , Herchenhorn Daniel , Gidekel Rosemarie , Rebelatto Taiane Francieli , Gomes Rafaela , Souza Vinicius Carrera , Fay Andre P. , Maluf Fernando C.
Published: March 2021

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Background: LACOG0415 is a 3-arm randomized trial evaluating ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA) or apalutamide with AAP (APA+AAP) for patients with locally-advanced, high-risk biochemical recurrence or metastatic castration-sensitive prostate cancer (ASCO 2020). In this trial, ADT+AAP and APA+AAP achieved the primary endpoint of percentage of patients with PSA ≤ 0.2 ng/mL at week 25. Apalutamide alone showed a high PSA decline > 50% rate, but did not achieve the pre-specified PSA threshold. Here we report patient-reported outcome data using Functional Assessment of Cancer Therapy-Prostate (FACT-P). Methods: HRQoL was measured in the overall population using the FACT-P questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing (EWB), social/family wellbeing (SFWB), and prostate cancer subscale (PCS). Scores for each patient were measured at baseline and every four weeks until week 25. Questionnaire completion was defined as ≥ 1 question answered at an assessment time point. Analysis of HRQoL change from baseline and deterioration included only patients with baseline and ≥ 1 postbaseline score. Differences greater than 10-points in FACT-P total score and differences greater than 3-points in PWB, FWB, EWB, SFWB, and PCS scores were considered clinically significant. The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were included in LACOG0415 trial and 122 of them completed the HRQoL assessments (ranging from 95.3% at baseline to 79.7% at week 25). FACT-P and all subscales scores were similar for all three arms at baseline. There were no meaningful differences in FACT-P scores at baseline and at week 25 between the 3 arms. The subscales scores also showed no statistically differences at baseline and at week 25. Time to FACT-P deterioration did not show any statistically difference between three arms ( P=0.3371). Conclusions: ADT free alternatives with APA alone or APA+AAP did not show meaningful differences in HRQoL in patients with advanced castration-sensitive prostate cancer compared to ADT+AAP. The short follow-up period limited the ability to explore differences in HRQoL after 25 weeks. Larger studies with longer follow-up are needed to further evaluate HRQoL with ADT-free strategies. Clinical trial information: NCT02867020. [Table: see text]
Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men.
Authors: Huynh-Le Minh-Phuong , Karunamuni Roshan , Fan Chun Chieh , Thompson Wesley K , Muir Kenneth , Lophatananon Artitaya , Tye Karen , Wolk Alicja , Niclas Hakansson , Mills Ian G. , Andreassen Ole A , Dale Anders M , Seibert Tyler M , Consortium The PRACTICAL
Published: March 2021

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Background: Clinical variables (age, family history, and genetics) are commonly used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores, including PHS, are associated with all prostate cancer and are not specific for fatal cancers, PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to available clinical variables improves associations with prostate cancer death. Methods: Genotype and phenotype data were obtained from a nested case-control subset (n=3,279; 2,163 were diagnosed with prostate cancer, 278 died of prostate cancer) of the longitudinal, population-based Cohort of Swedish Men. PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes history, and body mass index) were independently tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models were constructed with clinical variables and PHS. Log-likelihood tests compared models. Results: Median age at last follow-up and at prostate cancer death were 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol intake (HR 1.74 [1.40-2.15]), and diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. A multivariable clinical model including PHS46 improved associations for fatal disease ( p<10−15). On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol intake (HR 1.45 [1.19-1.76]), and diabetes (HR 0.62 [0.42-0.90]) all remained associated with prostate cancer death. Similar results were found using the newer PHS166. Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common clinical risk factors, including family history. Adding PHS to clinical variables may improve individualized prostate cancer risk stratification strategies.