bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic correlates of response and resistance to immune checkpoint inhibitors (ICI) in patients with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Pramod Nikhil , Makarov Vladimir , Dawsey Scott , Pavicic Paul G. , Patgunarajah Ubenthira , Nair Monica , Ornstein Moshe Chaim , Gilligan Timothy D. , Wee Christopher Eing , Nizam Amanda , Mian Omar Y. , Nguyen Jane , Diaz-Montero C. Marcela , Gupta Shilpa
Published: January 2024

670

Background: Response rates with ICI are only about 20% in mUC and we lack validated biomarkers to select patients who are most likely to derive benefit from ICI. Programmed cell death ligand 1 (PD-L1) has not proven to be a useful biomarker. We need biomarkers of response and resistance to avoid nonbeneficial treatment (Tx) and spare the majority of pts who will not respond to ICI both physical and financial toxicity. Here we report tumor genomic correlates of response and resistance to ICI in pts with mUC. Methods: We identified 335 adult pts with mUC at the Cleveland Clinic treated who received > / = 2 cycles of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Of the 335 pts, 49 had pre-Tx archival formalin fixed paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as responders (R) (Complete Response (CR), Partial Response (PR), and Stable Disease (SD)) (N = 23) or non-responders (NR) (Progressive Disease (PD)) (N = 26). Whole exome sequencing was performed from macro dissected tumors. Raw data in FASTQ format was aligned to GRCh38 human reference genome, somatic mutations were called by Mutect2 (part of GATK4) and allele-specific copy-number analysis was performed by applying the Facets and Gistic2 package. Results: Comparison of our cohort Tumor Mutation Burden (TMB) with mutation burden of 33 the cancer genome atlas (TCGA) cohorts shows close similarity to TCGA bladder urothelial carcinoma (BCLA). Median TMB in our cohort was 6.46 muts/Mb. In our cohort, TP53 hotspot mutations were found in 52% of the (R) cohort compared to 31% in the (NR) cohort. Additionally, mutations in KMT2C and KMT2A were found in 26% and 22% of the (R) cohort compared to 8% and 12 % of the (NR) cohort. (R) also had increased mutations in the ARID1A (17% vs 4%) and ERBB2 (17% vs 4%) compared to (NR). FGFR3 missense mutations were seen in only 4% of (R) cohort compared to 15% in (NR). In our complete cohort, 49% of patients had ERBB2 copy number amplifications and 92% of patient had CREBP2 deletions. Conclusions: In our real-world cohort of mUC pts treated with ICI, we identified differential genomic alterations between (R) and (NR). High frequency of ERBB2 mutations and alterations in overall cohort and higher frequency in (R) suggests potential role for anti-HER2 therapies alone or in combination with ICI. Ongoing genomic and immunologic correlative studies in our cohort will further help understand biomarkers of response and resistance to ICI in pts with mUC.
Blood-based liquid biopsy: A promising non-invasive test in diagnosis, surveillance, and prognosis of patients with upper tract urothelial carcinoma.
Authors: Ghoreifi Alireza , Shishido Stephanie , Courcoubetis George , Sayeed Salmaan , Huang Amy , Schuckman Anne K. , Aron Monish , Desai Mihir , Daneshmand Siamak , Gill Inderbir , Kuhn Peter , Mason Jeremy , Djaladat Hooman
Published: January 2024

677

Background: Blood-based liquid biopsy has emerged as a novel biomarker to improve the diagnosis and monitoring of urothelial tumors while enabling individualized risk stratification. The aim of this study was to assess the efficacy of these novel biomarkers in the diagnosis, surveillance, and prognosis of patients with primary upper tract urothelial carcinoma (UTUC). Methods: In this prospective study, peripheral blood samples were collected from patients with primary UTUC before surgery with curative intent and follow-up visits between May 2021 and September 2022. The samples were analyzed using the third-generation comprehensive high-definition single-cell assay (HDSCA3.0) to detect rare events, including circulating tumor cells (CTCs) and oncosomes, based on the immunofluorescent signals of DAPI (D), cytokeratin (CK), CD45/CD31 (CD), and vimentin (V). The findings of pre-surgery liquid biopsies were compared to the blood samples of normal donors (NDs) and matched follow-up liquid biopsy samples. The association between liquid biopsy findings and clinical data elements, including progression-free survival (PFS), was also assessed. Results: Twenty-eight patients with a median (range) age of 67.5 (43-88) years were included, of whom 21 had follow-up samples. Pathologic staging revealed 15 pT<2 and 13 pT≥2 tumors, and most cases (23/28) were high-grade.Significant differences in specific rare analytes were detected in pre-op samples as compared to NDs. On the post- vs. pre-surgery matched analysis, a significant decrease was detected in total-, CK-, and CK|V oncosomes as well as D-, D|V-, and D|V|CD cells. Correlation between pre-surgery liquid biopsy findings and clinical data is shown in Table 1. With a median follow-up of 11 months, seven patients had disease recurrence. Survival analysis demonstrated that patients with greater than 1.95 preoperative CK|V oncosomes as well as those with greater than 4.18 D|CK|V cells had worse PFS compared to other patients ( p=0.02 and p=0.05, respectively). Conclusions: This study demonstrates promising initial evidence for biomarker role of CTCs and oncosomes in diagnosis and surveillance of patients with UTUC.[Table: see text]
Describing the genomic landscape of bladder cancer histologic subtypes.
Authors: Talukder Rafee , Berg Rachel , Huang Minxuan , Nepomucino Vanessa M. , Stoppler Melissa Conrad , Makrakis Dimitrios , Yen Aihua Edward , Mims Martha P. , Lerner Seth P. , Woldu Solomon L. , Lotan Yair , Yu Evan Y. , Khaki Ali Raza , Aragon-Ching Jeanny B. , Grivas Petros
Published: January 2024

680

Background: Histologic subtypes of bladder cancer are associated with poor prognosis and therapy resistance; understanding of their biology can help identify therapies to improve outcomes. We aimed to describe the genomic alteration (GA) landscape of pure urothelial (UC) and histologic subtypes: plasmacytoid (PC), micropapillary (MP), sarcomatoid (SA), small cell/neuroendocrine (SC), squamous cell differentiation (SQ), adenocarcinoma (AD). Methods: Approximately 2165 patients (pts) were selected from the Tempus multimodal database. Selection criteria included diagnosis of bladder cancer (UC or histologic subtypes: PC, MP, SA, SC, SQ, AD) and sequencing via the Tempus xT assay. Genomic and immunotherapy biomarkers, including mutations, fusions, copy number variants, tumor mutation burden (TMB-high defined as ≥10 mutations/Mb) and MSI status were determined for each subtype and compared using Fisher’s Exact and Kruskal-Wallis tests. Results: Among 2165 identified pts, 1738 (80%) had UC (84% pure and 16% mixed histology), Table shows genomic alterations per histologic subtype. Median age at diagnosis was 70. The overall cohort included male (73%), white (84%), and ever smokers (71%). Of 1197 pts with staging information available, 71% tumors were stage IV. TMB-H and MSI-high status were noted in 17% and 1.1% of the overall cohort, respectively, and were relatively similar across histologies. PD-L1 positive status by IHC was noted in 30% in the overall cohort, and statistically lower in PC (7.7%), SC (10%) and AD (8.8%) vs UC (32%), SA (46%) and SQ (45%) (p<0.001). Compared to UC, FGFR3 was significantly lower in SC (9% vs 1%, p=0.003) and AD (9% vs 1%, p=0.001). We noted FGFR2/3 fusions in 2.6% of the entire cohort and all cases were UC. Compared to UC, ERBB2 was significantly higher in MP (13% vs 45%, p<0.001) and lower in SQ (13% vs 2%, p<0.001). ERBB2 amplification was more common in MP (16%) vs 8% in PC, 6.2% in UC, and 1.6% in SC. Conclusions: Distinct genomic alteration patterns were found among different histologic subtypes of bladder cancer and conventional UC. Assessing the genomic landscape of bladder cancer can help identify potential ‘actionable’ targets and biomarkers, and better inform clinical trial designs. Limitations include lack of clinical data annotation, tumor heterogeneity and retrospective study nature. [Table: see text]
Identification and characterization of prognostic isoforms associated with bladder cancer outcomes.
Authors: Patsalis Christopher , Bankhead Armand , Palmbos Phillip Lee
Published: January 2024

683

Background: Alternative splicing events can represent driver aberrations in cancer the same way as mutations, copy number changes, and gene fusions. We previously identified TP63 isoforms that were associated with prognosis in patients with bladder cancer and other tumor types. However, little is known about how isoform expression heterogeneity in other genes contributes to outcomes in bladder cancer. We hypothesized that expression of alternative isoforms in bladder cancer would be associated with clinical outcomes in a manner distinct from previously seen gene level associations. Methods: To examine this, we developed a high-throughput approach to identify and characterize prognostic gene isoforms that are associated with worse prognosis using RNA-sequencing data from The Cancer Genome Atlas (TCGA) bladder cancer cohort (BLCA). To identify gene isoforms that associate with bladder cancer outcomes, we aligned patient reads using HISAT2 and quantified expression for 69,272 isoforms using the Refseq isoform definitions from NCBI and the Stringtie algorithm. We filtered our quantifications to isoforms that belong to a gene with two or more isoforms, and those that had >0.1 Log2 TPM expression. The remaining 42,798 isoforms were tested for association with overall survival using cox regression and based on the following criteria: an isoform had to have a Hazard Ratio greater than 1 with a p-value < 0.05, an FDR adjusted p-value < 0.2 for a log-rank survival statistic using 3 quantile expression thresholds (25, 50 and 75th), and no significant gene-level association with disease prognosis. We validated our quantifications by confirming read coverage at the unique splice junctions for each isoform and by RT-PCR. We then performed differential expression and pathway enrichment analyses for tumors with or without expression of each pathogenic isoform. Results: 34 individual isoforms (from 30 genes) fit the criteria for association with survival. Several isoforms identified by our screen, such as FLNB, AXL, and COL6A3 isoforms, were previously shown to be associated with cancer outcomes in other tumor types. Expression of 7 isoforms were confirmed in human bladder cancer (2 isoforms of COL6A1, APLP2, TIAL1, and 1 isoform of FLNB) using RT-PCR. Expression of 21 of these prognostic isoforms were enriched in the aggressive basal squamous molecular subtype. Pathway analysis of TCGA BLCA tumors expressing these isoforms revealed enrichment of gene pathways associated with invasive cancer phenotypes, such as epithelial to mesenchymal transition and MYC targets. Conclusions: Specific isoforms are significantly associated with bladder cancer patient survival and suggest that splicing events in certain genes may act as driver aberrations in bladder cancer. Further work will need to be done to establish the regulatory mechanisms as well as how these isoforms contribute to cancer progression.
Peripheral biomarker analysis in patients with advanced urothelial carcinoma (UC) after platinum chemotherapy treated with cabozantinib (CABO) plus durvalumab (DURVA): Preliminary analysis from the phase 2 ARCADIA trial.
Authors: Giannatempo Patrizia , Sgambelluri Francesco , Stellato Marco , Guadalupi Valentina , Raggi Daniele , Rametta Alessandro , Bottiglieri Achille , Claps Melanie , Walter Ferrari Bravo , Oldani Simone , Zimatore Matteo , Calareso Giuseppina , Alessi Alessandra , Cattaneo Laura , Verzoni Elena , De Braud Filippo G. , Procopio Giuseppe , Necchi Andrea , Anichini Andrea , Mortarini Roberta
Published: January 2024

684

Background: Preliminary results of the interim analysis of the ARCADIA trial have shown that combining multitargeted receptor tyrosine kinase inhibitor CABO with the checkpoint inhibitor DURVA has promising activity and a manageable safety profile in patients (pts) affected by UC recurred or progressed after failure of at least one line of platinum-based chemotherapy for metastatic disease in a phase II study (NCT03824691). To identify peripheral blood biomarkers potentially associated with clinical response, we carried out a quantitative profiling of innate and adaptive immune subsets from a subset of treated pts. Methods: From 09/2019 and 08/2023 blood samples from 65 pts were collected at baseline and before the third treatment cycle. Absolute cell counts for 29 innate and adaptive immune subsets were determined by multiparametric flow cytometry. Results: In pre-therapy samples a significant higher counts for all CD45+ leukocytes were found in non-responders compared to responders (p=0.0053, Mann Whitney test, n= 27 patients). This was, explained by higher counts for CD16+CD15+ neutrophils (p=0.0005), classical CD14+CD16- (p=0.0119) and CD14++CD16+ intermediate (p=0.0186) monocytes, CD56dim CD16+ NK cells (p=0.0365) and Lin-HLA-DR-/LoCD33+CD14+CD15- M-MDSCs (p=0.0281). At baseline, higher neutrophils counts were associated with worse PFS (p=0.0117, log rank test), while higher eosinophils counts were associated with improved PFS (p=0.0158). Compared to responders, non-responders underwent a significant reduction in post-treatment counts for all CD45+ leukocytes (p=0,0024, Wilcoxon matched pair test), due to reduction of neutrophils (p=0.0068), CD15+CD16- eosinophils (p=0.0068), CD3+ T cells (p=0.0425) CD19+ B cells (p=0.0068), classical monocytes (p=0.0034), activated (HLA-DR+) CD56dim CD16- NK cells (p=0.0068), M-MDSCs (p=0.0161), Lin- HLA-DR-/Lo CD33+ CD14- CD15+ PMN-MDSCs (p=0.001), Lin- HLA-DR+ CD33- pDCs (p=0.0269) and Lin- HLA-DR+ CD33+ mDCs (p=0.0005). Conclusions: These preliminary findings suggest that high baseline counts for granulocytes, monocytes and MDSCs may negatively impact on response in pts treated with CABO+DURVA. Moreover, baseline neutrophils and eosinophils counts show opposite impact on PFS. Grant support: NET-2016-02361632 from Italian Health Ministry to A. Anichini. Clinical trial information: NCT03824691 .
EIF2S1 as a novel diagnostic marker for bladder cancer in urinary extracellular vesicles.
Authors: Tomiyama Eisuke , Fujita Kazutoshi , Kato Taigo , Hatano Koji , Kawashima Atsunari , Nonomura Norio
Published: January 2024

692

Background: Urinary extracellular vesicles (uEVs) secreted directly from BCa are considered a promising tool for diagnosing BCa, as they contain cancer-specific molecules. Among them, proteins in uEVs have attracted considerable attention, and several membrane EV proteins have been reported as urinary markers for BCa. However, few studies have focused on non-membranous (cytoplasmic) EV proteins. This study aimed to explore and validate a uEV-based diagnostic marker for BCa, focusing on cytoplasmic EV proteins. In addition, the functions of the identified protein were assessed. Methods: uEVs were isolated by ultracentrifugation with a sucrose cushion. Shotgun proteomics (TMT-labeled LC-MS/MS) was performed on uEVs from seven patients with BCa and four healthy individuals. Diagnostic marker candidates were selected from the identified cytoplasmic EV proteins and validated with targeted proteomics (SRM/MRM) of uEVs from 49 patients with BCa and 48 individuals without BCa, including patients with hematuria. The functional analysis of the identified EV protein was conducted in vitro. Results: Shotgun proteomics identified 1960 proteins, of which 17 cytoplasmic EV proteins were significantly elevated in the uEVs from patients with BCa (Fold change >1.5, p-value < 0.05). Of these, all ten measurable EV proteins were confirmed to be significantly elevated in urine from patients with BCa, of which EV-EIF2S1 showed the best diagnostic performance (ROCAUC: 0.83, sensitivity: 80%, specificity: 77%) in the validation cohort. Additionally, EV-EIF2S1 distinguished patients with BCa from non-BCa hematuria patients in a suitable manner (ROCAUC: 0.92, sensitivity: 82%, specificity: 83%). In the functional analysis of EIF2S1 in BCa cell lines T24 and 5637, the knockdown of EIF2S1 markedly inhibited cell proliferation. Cell cycle studies showed that the knockdown of EIF2S1 resulted in cell cycle arrest and induction of apoptosis. Therefore, EIF2S1 was considered an essential protein for the growth and survival of BCa cells. Conclusions: We identified EIF2S1 in uEVs as a novel diagnostic marker for BCa, enabling accurate and non-invasive diagnosis for BCa in a hematuria setting.
ABC transporter expression to predict therapeutic effect of enfortumab vedotin in urothelial cancer.
Authors: Shimoda Hiroki , Takada-Owada Atsuko , Kijima Toshiki , Kokubun Hidetoshi , Uematsu Toshitaka , Takei Kohei , Nakazato Yoshimasa , Yashi Masahiro , Ishida Kazuyuki , Kamai Takao
Published: January 2024

693

Background: Enfortumab vedotin (EV) is an antibody-drug conjugate consisting of anti-Nectin-4 antibody and is approved for metastatic urothelial cancer. Predictors of therapeutic benefit of EV have not been established since nectin-4 expression varies widely with the course of treatment. ATP Binding Cassette (ABC) transporters which export the administered anti-cancer drugs out of the cells have been postulated as one of the mechanisms of therapeutic resistance to EV. In this study, we evaluated the expression of Nectin-4 and ABC transporters in primary biopsy tissues, primary radical resection tissues, and metastatic sites from urothelial cancer patients and evaluated their association with prognosis after EV therapy. Methods: We studied 16 patients who received enfortumab vedotin for metastatic urothelial cancer. Biopsy of primary tissue, radical surgery of primary tumor, and resection of metastatic sites was performed in 16, 7, and 4 patients, respectively. In these specimens, the expression of nectin-4 and ABC transporters was evaluated by immunostaining. Among ABC transporters, we evaluated MDR1 (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2) since they have been reported to be associated with anticancer drug resistance. Staining intensity on the cell membrane was classified into 0 to 3 according to the evaluation criteria of HER2. We investigated the relationship between the expression of nectin-4 and ABC transporters and survival after EV therapy. Results: Nectin-4 was positive in all patients (score 3 in 12 patients, score 1 in 4 patients) in primary biopsy. All patients tested negative for MDR1. MRP1 was positive in 11 (score 2 in 2 patients and score 1 in 9 patients), and BCRP was positive in 14 (score 2 in 10 patients, score 1 in 4 patients). Nectin-4 expression decreased in radical surgery tissues and metastatic sites. On the other hand, ABC transporter expression remained unchanged or rather increased in radical surgery tissues and metastatic sites (Table). Patients with both MRP1 and BCRP expression in the primary biopsy specimen (n=8) had significantly worse PFS and OS after EV therapy while nectin-4 expression in the primary biopsy specimen was not associated with survival. Conclusions: Patients with ABC transporter expression had a poor prognosis after EV therapy, although nectin-4 expression in primary biopsies was not associated with prognosis. Nectin-4 expression tended to decrease, while the ABC transporter remained unchanged or enhanced as the disease progressed. [Table: see text]
Population based trends in intravesical gemcitabine use among patients with high-risk non-muscle invasive bladder cancer.
Authors: Williams Stephen B. , He Jinghua , Jackson Aeja , Ireland Andrea , Balaji Hiremagalur Parthasarathy , Huang Wenxi , Shi Qian , Ellis Lorie , Singhal Mukul
Published: January 2024

699

Background: Intravesical gemcitabine (iGEM) use among patients with high-risk non-muscle invasive bladder cancer (HR NMIBC) has shown effectiveness towards preventing or delaying tumor recurrence, although Bacillus Calmette-Guérin (BCG) remains the standard of care for newly diagnosed HR NMIBC. This retrospective cohort study investigated iGEM users and reported their treatment patterns among SEER-Medicare enrollees newly diagnosed with HR NMIBC patients naïve (BCG-N) or exposed (BCG-Exp) to BCG therapy. Methods: Patients enrolled inMedicare Part A & B fee-for-service enrolled, with HR NMIBC, defined by Tis, Ta, T1, N0, M0 and ≥65 years with iGEM use between 2008-2020 were evaluated. Patients with missing TNM stage, low/ intermediate risk NMIBC, or other primary cancers were excluded. Index date was defined as the first claim of iGEM after HR NMIBC diagnosis, regardless of their prior BCG use. Patients were followed until the earliest event of death, end of Medicare advantage enrollment, or data availability end (12/31/2020). Demographic and clinical characteristics were reported in the baseline period (12-month pre-index) and treatment patterns were reported calendar year post-index date for BCG-N and BCG-Exp cohorts. Results: The analysis included 277 BCG-N and 402 BCG-Exp patients receiving iGEM. In both cohorts, mean age was >75 years, ≥80% were male, and >90% were White. The mean (SD) national cancer index comorbidity index score was 0.85 (0.7) for BCG-N and 0.63 (0.7) for BCG-Exp. Intravesical therapy use beyond a perioperative instillation during the baseline period was observed in 27% of BCG-N and 14% of BCG-Exp patients; docetaxel (17% BCG-N, <1% BCG-Exp) and mitomycin (12% BCG-N, 14% BCG-Exp) were most common. The median number of iGEM doses in the BCG-N group was 6 (IQR 1,8) with mean (SD) of 28 (43) days of retreatment interval. In BCG-Exp, the median number of iGEM doses was 6 (IQR 2,9) with mean (SD) of 23 (26) days of retreatment interval. The table shows increasing iGEM use in both BCG-N and BCG-Exp groups, with 70% of BCG-N in years 2019 through 2020, and 22-30% of BCG-Exp patients receiving iGEM in years 2017 through 2020. Conclusions: Recent BCG shortages may have played a significant role in recent increased uptake of iGEM in both BCG-N and BCG-Exp cohort among HR NMIBC patients. Further information on the efficacy and safety outcomes of iGEM vs BCG in various HR NMIBC populations are needed. [Table: see text]
Clinical outcomes with systemic therapy given after progression on prostate specific membrane antigen radioligand therapy (PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Labidi Soumaya , Salehi Aida , Fallah Parvaneh , Morin Vincent G. , Li Meredith , Probst Stephan , Ferrario Cristiano , Rose April A. N.
Published: January 2024

78

Background: PSMA-RLT is a novel therapeutic modality that improves overall survival in mCRPC. However, outcomes for systemic therapy given after progression on PSMA-RLT are not well described. We investigated treatment choices and outcomes in patients (pts) with mCRPC who experienced disease progression after PSMA-RLT. Methods: We performed a single center retrospective cohort study of pts with mCRPC, who received PSMA-RLT at the Jewish General Hospital between 2020 and 2023. Clinical characteristics, PSA50, further lines of therapy post PSMA-RLT and survival were abstracted from chart review. A log-rank test was used to assess overall survival (OS). Post-PSMA-RLT specific OS (Post-RLT-OS) was defined from the date of first systemic treatment after PSMA-RLT failure to death or last follow up. Results: We identified 42 pts who received PSMA-RLT for mCRPC. The median age was 63 years (47-89) and the majority (56.1%) of pts received PSMA-RLT as a 3rd or later line of therapy in mCRPC setting. Amongst these pts, 15/42 (35.7%) achieved a PSA50 response to PSMA-RLT; 36 pts experienced disease progression, and 25/36 with disease progression (69.4%) received subsequent active systemic therapy. Post-PSMA-RLT systemic therapy included chemotherapy (n=17), PARP inhibitors (PARPi) (n=3), bipolar androgen therapy (BAT) followed by androgen receptor-axis targeted agent (ARAT) (BAT+ARAT) (n=2), Radium (n=2), BAT (n=1), and different PSMA-RLT agent (n=1). Amongst the pts who received post-PSMA-RLT therapy, 5/25 (20%) achieved a PSA50 response. PSA50 responses were observed in pts who received chemotherapy (n=2), BAT+ARAT (n=2) and PARPi (n=1). After a median follow-up of 10 months, the median Post-RLT-OS in the entire cohort was 11.7 months. Post-RLT-OS was significantly associated with PSA levels at the time of post-PSMA-RLT systemic therapy. The median Post-RLT-OS for pts with PSA < 100 (n=11), 100 ≤ PSA < 1000 (n=5) PSA ≥ 1000 (n=5) was 15, 15.7, and 8.6 months respectively (P = 0.014). Conclusions: Some pts derive benefit from post-PSMA-RLT systemic therapy; however, the overall response rate is low and therapeutic options are limited. More research is needed to define mechanisms of resistance to PSMA-RLT, and to identify novel therapeutic opportunities in this patient population.
HRR testing and PARPi utilization among patients with metastatic castration resistant prostate cancer treated in the real-world setting.
Authors: Vasudevan Anupama , Katzen Harvey I. , Gart Mike , Blanc Simon
Published: January 2024

91

Background: HRR mutations (HRRm) have prognostic value in metastatic castration-resistant prostate cancer (mCRPC). Treatment with poly (ADP-ribose) polymerase inhibitors (PARPi) has shown better outcomes among patients with HRR mutations. This study aimed to understand the HRR testing rates among mCRPC patients and utilization of PARPi(s) among HRRm mCRPC patients treated in the real world. Methods: A random sample of 480 mCRPC patients from the Integra Connect PrecisionQ de-identified database were included in this retrospective observational analysis with additional information supplemented by curation. The database contains ~80% community oncology and ~20% academic practices with over 2 million cancer patients across 500 sites of care. Eligible male patients were those aged ≥18 years, diagnosed with mCRPC, and who received treatment between 2020 and 2023. HRR testing rates and utilization of PARPi use were assessed and presented for this study. Results: The mean (SD) age of 480 mCRPC patients was 76.9 (8.3) years; 78.3 % reported being White, 7.9% as African American, 1% as Asian, and 12.7% as Other. Most of the patients reported a payer type of Medicare/Medicaid (69.2%) followed by 15.6% Commercial and 15.2% as Self-Pay/Other. Testing for HRR was reported in 235 (48.9%) of the mCRPC patients and 59 (25.1%) of those patients were HRRm. The mean (SD) age of 59 HRRm mCRPC patients was 77.1 (7.2) years; 88.1% were white, 6.8% African/American, and 5.1% Other. Payer type was reported as being Medicare/Medicaid in 72.9% followed by 18.6% Commercial and 8.5% as Self-Pay/Other. BRCA and ATM mutations were reported among 22/59 (37.2%) and 15/59 (25.4%) patients, respectively. Among the 59 HRRm mCRPC patients, 53 (90%) were noted to have received prior NHA (novel hormone agents) while only 36/53 (67.9%) were noted to have received PARPi. Conclusions: Fewer than half of those patients with mCRPC were tested for HRR. This highlights the lack of testing among those receiving care in a real-world setting. The underutilization of PARPi in these patients is a missed potential opportunity for improving their outcomes.
Secondary primary malignancies among patients with GU cancer.
Authors: Tripathi Nikita , Ayaz Ahsan , Naqvi Syed Arsalan Ahmed , Khan Muhammad Ali , Saxena Akshat , Bibi Arifa , Channar Aneeta , Tyson Mark , Riaz Irbaz Bin , Cobran Ewan Kemar , Bryce Alan Haruo , Abdul-Muhsin Haidar , Singh Parminder
Published: January 2024

98

Background: The risk of secondary primary malignancies (SPM) among the survivors of GU cancer is not well-established. In this study, we attempt to describe the patterns of SPMs in patients diagnosed with GU cancers. Methods: The Surveillance, Epidemiology, and End Results (SEER) database (SEER*Stat 8.4.2) was searched to obtain data on the incidence of SPM in adult patients (age >18 years) diagnosed with GU cancers, including prostate, renal, and bladder cancer. Standardized incidence ratios (SIRs) with a 95% confidence interval (CI) were calculated. SIR was defined as the observed SPMS from each category divided by the expected number of SPMs in the age-matched US population for the same period. The data was further stratified by age (<50y, 50-70y, >70y), race (White, Black, Asian/Pacific Islander), ethnicity (Hispanic, non-Hispanic), chemotherapy, and radiotherapy exposure. Results: A total of 1,041,217 patients were included in this analysis. In patients diagnosed with GU cancer, the incidence of overall SPM was 11%. Particularly, patients with GU cancers were observed to have a high incidence of Endocrine system SPM (1.52; 1.45-1.59), and urinary system SPM (1.51; 1.49-1.53) These results were consistent by different sociodemographic groups. In patients diagnosed with prostate cancer, the incidence of thyroid SPM was increased (1.31; 1.23-1.39). Particularly, prostate cancer patients treated with radiation therapy had increased incidence rates of SPM in the peritoneum, omentum and mesentery (1.57; 0.79-2.81) and urinary bladder (1.36;1.32-1.40) was higher as compared to those with no exposure to radiation therapy (1.11;1.08-1.13 and 1.03;1-1.06 respectively). Bladder cancer patients had an overall increased incidence of SPM in the esophagus (1.21; 1.08-1.35), lung, bronchus, trachea, and other respiratory organs (1.97;1.92-2.01), prostate (3.50;3.4-3.6) and kidney (1.86;1.76-1.97). A higher incidence of renal pelvis, ureter and other urinary organ SPM (11.08;10.48-11.07) was also notable in this population. Similarly, kidney cancer patients had a higher incidence of the endocrine system (3.00;2.74-3.27), prostate (1.24;1.2-1.29) and bladder 1.78;1.68-1.79 SPMs. Conclusions: This population-based study shows an increased risk of SPM development in GU cancer survivors compared to the general population. Clinicians should keep a high index of suspicion for SPMs and initiate appropriate workups at early warning signs.
COMBAT: A study of 64Cu-SAR-BBN and 67Cu-SAR-BBN for identification and treatment of GRPr-expressing metastatic castrate-resistant prostate cancer.
Authors: Nordquist Luke T. , Lengyelova Eva , Almaguel Frankis , Mancini Brandon Robert , Song Hong , Armstrong Andrew J. , Zurita Amado J. , Anderson Monique , Parker Michelle , Miller Robert M. , Iagaru Andrei
Published: January 2024

TPS247

Background: Metastatic castrate resistant prostate cancer (mCRPC) is an advanced and lethal form of prostate cancer. Prostate-specific membrane antigen (PSMA)-targeted theranostic agents, 68Ga-PSMA-11 and 177Lu-PSMA-617, have been approved by the FDA for patient selection and therapy for patients with mCRPC, respectively. Approximately 25% of patients with mCRPC show low or no PSMA expression. Consequently, these patients are unlikely to benefit from PSMA-targeted agents and represent a significant unmet need for both imaging and therapy. The Gastrin Releasing Peptide receptor (GRPr) is a transmembrane G-protein coupled receptor that is upregulated in many human cancers, including PC. A promising new theranostic pair, consisting of 64Cu-SAR-BBN (imaging) and 67Cu-SAR-BBN (therapy), targets the GRPr. This may offer a potential imaging and treatment option for patients with low or no PSMA expression. Methods: COMBAT is a multi-center, open-label, phase I/IIa dose-escalation and cohort expansion study of 64Cu-SAR-BBN and 67Cu-SAR-BBN administered to patients with mCRPC. Eligible patients will have progressive mCRPC, prior exposure to at least one androgen receptor pathway inhibitor, will be ineligible for 177Lu-PSMA-617 therapy, and show a positive 64Cu-SAR-BBN PET. This study is being conducted in 2 phases: a Dose Escalation Phase (n=up to 24) and a Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of safety of 64Cu- and 67Cu-SAR-BBN, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-BBN. The 67Cu-SAR-BBN dose levels investigated in the escalation phase include: 6 GBq (cohort 1, single dose with dosimetry assessment), 10 GBq (cohort 2, single dose), 14 GBq (cohort 3, single dose), and up to 28 GBq across two doses (cohort 4, two doses at MTD/MFD). Additional doses may be administered during the Dose Escalation Phase (maximum of 4 doses in each cohort). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-BBN at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response, and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 1 is open for enrollment. Clinical trial information: NCT05633160 .
A randomized phase I/II study of neoadjuvant treatment with 177-Lutetium-PSMA-617 with or without ipilimumab in patients with very high-risk prostate cancer who are candidates for radical prostatectomy (NEPI trial).
Authors: Krafft Ulrich , Grünwald Viktor , Fendler Wolfgang P. , Herrmann Ken , Reis Henning , Roghmann Florian , Rahbar Kambiz , Heidenreich Axel , Giesel Frederik , Niegisch Guenter , Hadaschik Boris A.
Published: January 2024

TPS352

Background: High-risk prostate cancer accounts for approximately 15% of newly diagnosed prostate cancers. For patients with high-risk, locally advanced prostate cancer, prostatectomy alone may be insufficient therapy. Cure rates from radical prostatectomy alone are less than 25%. Ipilimumab increases overall survival in men with post-docetaxel mCRPC who received radiotherapy to bone metastases followed by ipilimumab in comparison to placebo. Final results of the VISION trial (NCT03511664), a phase III study designed to assess the efficacy of [177Lu]Lu-PSMA-617 in patients with PSMA-positive mCRPC, show a significant prolongation of survival in a setting without established therapy. Since both ipilimumab combined with radiation and [177Lu]Lu-PSMA-617 have been proven to be effective in the treatment of mCRPC, we hypothesize, that CTLA-4-inhibitors exert synergistic effects on [177Lu]Lu-PSMA-617 RLT-induced tumor damage and immune priming. Methods: Patients diagnosed with highest risk prostate cancer (ISUP-GG 4+5 and cT3 plus cN+ or PSA > 20ng/ml) who are candidates for radical prostatectomy receive 12 weeks of neoadjuvant treatment with ADT plus [177Lu]Lu-PSMA-617 (LuPSMA) with randomized allocation with or without ipilimumab. Prior to initiation of the randomized set, we will conduct a Safety-Run-In-Phase. The initial 3-6 patients will receive a reduced dose of 3.7 Gb [177Lu]Lu-PSMA-617 and 3 mg/kg Ipilimumab, which will be increased to the target dose of 7.4Gb [177Lu]Lu-PSMA-617 and 3 mg/kg Ipilimumab in the following 3-6 patients if sufficiently well tolerated. The safety and feasibility of the combination will be assessed after 6-12 patients based on toxicity or delay of prostatectomy (max. 3 weeks). In the absence of serious toxicity signals a total of 46 patients will be randomized 1:1 (ipilimumab + ADT + LuPSMA vs. ADT + LuPSMA) to receive 2 cycles of 7.4 GBq LuPSMA with or without 4 cycles of ipilimumab 3mg/kg prior to prostatectomy. Scheduled Imaging with mpMRI and PSMA PET CT is performed prior to neoadjuvant therapy and prior to radical prostatectomy. Co-primary endpoints of the study are feasibility of radical prostatectomy after neoadjuvant therapy, and complete pathologic response. Secondary endpoints are evaluation of the safety profile of neoadjuvant treatment according to "National Cancer Institute Common Terminology Criteria for Adverse Events" (NCI CTCAE) v5.0 and disease-free survival. Enrollment of the first patient in NEPI Trial is expected to be completed in late September 2023. A total of up to 3 German centers will participate. Clinical trial information: EudraCT-Nr.: 2021-004894-30.
SWOG S2210: A phase II study of neoadjuvant carboplatin for localized, high-risk prostate cancer with germline BRCA1/2 mutations.
Authors: Cheng Heather H. , Callis Samuel , Lin Daniel W. , Yu Evan Y. , Dorff Tanya B. , Kase Adam McLain , Tangen Catherine , Petrylak Daniel P. , Lerner Seth P.
Published: January 2024

TPS354

Background: Carriers of germline pathogenic variants or mutations in BRCA2 and BRCA1 (referred to here as gBRCA1/2m) are enriched in metastatic prostate cancer (PrCa), and now have FDA-approved options for PARP inhibitors in late-stage disease. The NCCN guidelines recommends germline genetic testing for PrCa patients with metastatic, node positive and high risk localized prostate cancer. Prior studies have shown that gBRCA1/2m carriers with PrCa are more likely to have high-risk disease (6,7) and to develop lethal disease even after curative intent treatment (8,9). In other gBRCA1/2m-related cancers (breast, ovarian and pancreas), platinum-based regimens are part of neoadjuvant and front-line metastatic therapy options. Carboplatin is a well-tolerated, widely available and inexpensive DNA-damaging alkylating agent that is familiar to oncologists. The study hypothesis is that 4 cycles of neoadjuvant carboplatin, followed by radical prostatectomy for patients with localized high/very high risk PrCa and g BRCA1/2m will result in a meaningful pathologic complete response (pCR) rate. Methods: S2210 is a single-arm, open label study of 12 wks neoadjuvant carboplatin (4 cycles of AUC 5 every 21 days), followed by radical prostatectomy. Key eligibility criteria include people with high/very high-risk disease: cT3a or Grade Group 4-5 PrCa and/or PSA>20 ng/mL, have no evidence of distant metastases by conventional imaging (PSMA-PET-detected mets permitted if conventional imaging is negative and surgeon deems PSMA-detected sites resectable), who are candidates for radical prostatectomy and carboplatin, and have documented evidence of gBRCA1/2m through testing in a CLIA-certified lab. ADT prior to registration is permitted but must be discontinued on study. The study hypothesis is that the study treatment will result in ³30% rate of pathologic complete response (pCR, primary endpoint). A two-stage design will be used such that if ³1 of first 20 eligible patients achieves pCR, 20 further evaluable patients will be enrolled. This design has a significance level of 4.7%, and a power of 99%. Secondary endpoints include biochemical recurrence-free (at 2-, 3-, 5-yrs), metastasis-free and overall survival. Translational/correlative studies include analysis of 2nd allele inactivation in tumor, HRD signature, and ctDNA signature for monitoring of recurrence. S2210 was activated in August 2023. Clinical trial information: NCT05806515 .
A phase 1, first-in-human, dose-escalation and expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma.
Authors: Iyer Gopa , Gao Xin , Rasco Drew W. , Milowsky Matthew I. , Garmezy Benjamin , Rodriguez Rivera Ildefonso I , Tepper Jennifer , Moles Melissa Ann , Gjini Evisa , Bowden Michaela , Meyers Michael L. , Bellmunt Joaquim , Galsky Matt D.
Published: January 2024

TPS709

Background: High Expression of Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor-family transcription factor, drives the initiation and development of UC in luminal molecular subtype tumors. Genetic profiling of UC has identified recurrent oncogenic alterations in the PPARG transcriptional complex, including focal amplification, missense mutations, and fusions in the heterodimeric partner of PPARG, the retinoid X receptor alpha (RXRA). High levels of PPARG expression and recurrent oncogenic alterations are observed in other solid malignancies including colorectal, gastroesophageal, pancreatic and lung cancers. FX-909 is an oral, first-in-class, new molecular agent that specifically, potently, and covalently modifies PPARG to mediate basal and ligand-activated transcription. Treatment of genetically defined UC xenografts with FX-909 has shown an 84% tumor growth inhibition (TGI) at a dose expected to be equivalent to 50 mg dose in humans, which is the starting dose in this clinical study. Methods: FX-909-CLINPRO-1 (NCT05929235) is a first-in-human, multicenter, open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of FX-909 given orally in patients with advanced solid malignancies. Patients enrolled in the trial must have ECOG performance status ≤2 and must be ≥ 18 years of age. Initially, FX-909 will be given once daily to patients with any advanced solid malignancy in a dose-escalation phase (Part A) utilizing a 3+3 design. Five dose cohorts of 3 to 6 patients are planned. At the time of submission, three patients are enrolled in Part A- cohort one, 50mg. Additional patients will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or evidence of clinical activity. Once a RP2D has been determined, a monotherapy expansion phase (Part B) will proceed in a Simon 2-stage design in patients with locally advanced (unresectable) or metastatic UC with measurable disease and tumors harboring defined genetic alterations in PPARG, RXRA and FGFR3 (Motley et al, 2022). In stage 1, up to 19 evaluable patients will be enrolled. If ≥4 objective responses are observed, enrollment will continue into Stage 2 with an additional 14 evaluable patients. One treatment cycle is 28 days. Dose expansion will evaluate the safety, PK/PD profile, and antitumor activity of FX-909 at the RP2D. Exploratory objectives include the evaluation patient selection biomarkers from tissue and blood samples. FX-909 clinical activity will be assessed using RECIST v1.1 criteria. The study is currently enrolling patients in the US. Clinical trial information: NCT05929235 .
Using hierarchical risk parity in the Brazilian market: An out-of-sample analysis
Authors: Reis Felipe , Sobreira Anderson , Trucios Carlos , Asrilhant Boris
Published: January 2024

Portfolio allocation is an important tool for portfolio managers and investors interested in diversification as well as improvements in out-of-sample portfolio performance. Recently, new portfolio allocation strategies based on unsupervised machine learning have been proposed in the literature, with hierarchical risk parity being one of the most popular. This article uses assets from the Brazilian financial market to perform an extensive out-of-sample comparison of hierarchical risk parity against widely-known, traditional portfolio allocation techniques. The results suggest that, in general, hierarchical risk parity does not report the best performance but, in some performance measures, performs equally well to other approaches. Overall, hierarchical risk parity outperforms the market index.
Evolution of cellular energetics
Authors: Τσιπουρλιάνος Ανδρέας
Published: January 2024

Η οξειδωτική φωσφορυλίωση (OXPHOS) καλύπτει πάνω από το 90% των κυτταρικών απαιτήσεων σε ΑΤΡ μέσω της ενορχηστρωμένης λειτουργίας πέντε πολυπρωτεϊνικών συμπλόκων που βρίσκονται στην εσωτερική μιτοχονδριακή μεμβράνη. Η διατριβή διερευνά πώς οι εξελικτικοί περιορισμοί που επιβάλλονται από την απαραίτητη λειτουργία της OXPHOS καθοδηγούν την έκβαση των γεγονότων διπλασιασμού ολόκληρου του γονιδιώματος (WGD). Δύο τελεόστεοι, η τσιπούρα (Sparus aurata, GSB) και το ευρωπαϊκό λαβράκι (Dicentrarchus labrax, ESB), τα οποία έχουν υποστεί τρεις γύρους WGD χρησιμοποιήθηκαν ως μοντέλα κατά τη διάρκεια της ιδιαίτερα πλαστικής και απαιτητικής σε ενέργεια περιόδου της πρώιμης ανάπτυξης. Η οντογένεση των ψαριών είναι μια μοναδική περίοδος στη ζωή των ψαριών που χαρακτηρίζεται από δραματικές αλλαγές στη μορφολογία, τη φυσιολογία, το μεταβολισμό και τη συμπεριφορά. Το αυστηρά ρυθμιζόμενο τοπίο των κυτταρικών διαιρέσεων, των μεταναστεύσεων και της διαφοροποίησης που οδηγούν σε αυτές τις δραματικές αλλαγές απαιτεί υψηλές ποσότητες ενέργειας. Η ανακάλυψη 24 και 22 οικογενειών γονιδίων OXPHOS στο γονιδίωμα των GSB και ESB, αντίστοιχα, και η επακόλουθη φυλογενετική ανάλυση έδειξαν στις περισσότερες περιπτώσεις προέλευση από έναν κοινό πρόγονο στη βάση της γενεαλογίας των τελεόστεων, μια διαδικασία που αποδίδεται στο ειδικό για τους τελεόστεους WGD. Συνολικά τα αποτελέσματα δείχνουν ότι τα γεγονότα WGD είχαν ως αποτέλεσμα την πρώιμη διατήρηση των παράλογων γονιδίων OXPHOS και τις επακόλουθες απώλειες να είναι ειδικές για το είδος ή την γενεαλογία. Τα επίπεδα έκφρασης των παράλογων γονιδίων OXPHOS συγκρίθηκαν μετά από αλληλούχιση RNA εντός και μεταξύ διαφορετικών αναπτυξιακών σταδίων στα GSB και ESB. Αποκαλύφθηκαν διαφορετικά πρότυπα έκφρασης μεταξύ των παραλόγων γονιδίων∙ ορισμένα από τα οποία βρίσκονταν σε ισορροπία δόσης, άλλα εκφράζονταν μόνο σε συγκεκριμένα στάδια και πολλά από αυτά εκφράζονταν διαφορικά μεταξύ των σταδίων. Τα αποτελέσματα επιβεβαιώθηκαν σε μια εστιασμένη μελέτη που συνέκρινε την έκφραση των παραλόγων του OXPHOS στο ESB, σε διαφορετικά αναπτυξιακά στάδια και ιστούς. Αποκαλύφθηκαν διαφορές τόσο στον αριθμό όσο και στη θέση των SNPs μεταξύ των παραλόγων, μετά τη συγχώνευση των δεδομένων αλληλούχισης RNA με δεδομένα αλληλούχισης ολόκληρου του γονιδιώματος. Οι μεταλλάξεις χαρτογραφήθηκαν ως επί το πλείστον στης UTR’s και λιγότερες στα CDS. Η αναλογία των μη συνώνυμων προς τις συνώνυμες υποκαταστάσεις κατά τη σύγκριση των παραλλαγών του CDS αποκάλυψε την Σταθεροποιούσα (Purifing) και Ουδέτερη (Neutral) επιλογή σε δράση, διασφαλίζοντας τη δομική ακεραιότητα ή/και τη λειτουργία των πρωτεϊνών. Συνολικά, η ρυθμιστική Neo/Subfunctionalization των παραλόγων γονιδίων της OXPHOS εμφανίστηκε ως ο εξελικτικός μηχανισμός πίσω από τη διατήρηση των παραλόγων γονιδίων στα γονιδιώματα των GSB και ESB. Πράγματι, τα παράλογα γονίδια της OXPHOS παρουσίασαν διαφορετική θερμική πλαστικότητα στο GSB, η οποία έγινε εμφανής υπό συνθήκες υψηλών ενεργειακών απαιτήσεων.
Το Ημερολόγιο της Άννας Φρανκ
Authors: Σεβεντεκίδου Κυριακή
Published: January 2024

Στην παρούσα διδακτορική διατριβή εξετάζεται η μεταγραφή του Ημερολογίου της Άννας Φρανκ στην αφηγηματική και εικαστική φόρμα των graphic novels. Πιο συγκεκριμένα, η μελέτη έχει σκοπό να αναδείξει τη διακειμενική σχέση που αναπτύσσεται ανάμεσα στο αφετηριακό έργο και στην προσαρμογή του (adaptation) σε graphic diary από τους A.Folman και D.Polonsky (Εκδόσεις Πατάκη 2017). Στο θεωρητικό μέρος της εργασίας διερευνώνται οι θεωρητικοί όροι που άπτονται του θέματος, όπως ημερολόγιο, graphic novels, καθώς και το ιστορικό συγκείμενό τους. Ενδεικτικά, ορισμένα θέματα που θίγονται και εξετάζονται είναι το χρονικό έκδοσης του Ημερολογίου της Άννας Φρανκ, οι πολυτροπικές απεικονίσεις του Ημερολογίου (κινηματογράφος, όπερα, τηλεόραση), η διαλογική σχέση που αναπτύσσεται ανάμεσα στη λογοτεχνία και τα κόμικς, ζητήματα γλώσσας και τεχνικής - η μεταφορά του λόγου και των αφηγηματικών δομών του Ημερολογίου στο graphic diary. Επίσης, επιχειρείται η ανάδειξη άγνωστων πτυχών και κεκαλυμμένων νοημάτων του λογοτεχνικού έργου μέσω της εικόνας στο graphic diary και μελετώνται ζητήματα, όπως η πιστότητα της εικονογράφησης στην ιστορική εποχή του λογοτεχνικού έργου, η επιρροή που ασκεί το ποιόν των δημιουργών και το κοινωνικοπολιτικό γίγνεσθαι της εποχής δημιουργίας του graphic diary, καθώς και ζητήματα μετάφρασης του αφετηριακού έργου στην ελληνική γλώσσα. Στο ερευνητικό μέρος, επιχειρείται συγκριτική μελέτη του αφετηριακού και του διασκευασμένου έργου. Ουσιαστικά, ερευνάται η διακειμενική σχέση της λογοτεχνίας -συγκεκριμένα του ημερολογιακού είδους- και των κόμικς, μία σχέση που καταδεικνύει την αλληλεπίδραση και τον αμφίδρομο δανεισμό στοιχείων μεταξύ των δύο μορφών τέχνης. Ταυτόχρονα, διερευνώνται οι συγκλίσεις και οι αποκλίσεις που διαπιστώνονται ανάμεσα στο πρωτότυπο έργο και στην προσαρμογή του (adaptation) σε κόμικς, εξετάζοντας, παράλληλα, την αισθητική αξία του έργου, η οποία προκύπτει από τη μεταγραφή και τη συμβολή του στην προώθηση της λογοτεχνίας.