bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of anti-cancer immune response associated with immune-related adverse events in patients with kidney cancer.
Authors: Kato Taigo , Kiyotani Kazuma , Ishizuya Yu , Yamamoto Yoshiyuki , Hatano Koji , Kawashima Atsunari , Nonomura Norio 
Published: March 2023

711 Background: Some reports showed promising clinical efficacy among patients who discontinued immune checkpoint inhibitors (ICIs) due to immune-related adverse events (irAEs). In this study, we aimed to characterize T cell receptor (TCR) repertoire repertoire in peripheral blood mononuclear cells (PBMCs) before and after ICI treatment, and at the onset of irAE for understanding of irAE-provoked anti-cancer immune responses. Methods: We collected metastatic tumor tissues and peripheral blood samples from 54 patients with advanced kidney cancer before anti-programmed cell death protein 1 (PD-1) treatment and 1 month after treatment initiation. Furthermore, we applied a next-generation sequencing approach to characterize TCR repertoires using tumor tissues and PBMCs. Results: The number of irAEs was significantly higher in responder for nivolumab (p < 0.0001). We also confirmed that irAE present patients had better progression-free survival and overall survival when compared to irAE absent patients (p=0.0010 and p=0.011, respectively). TCR repertoire analysis revealed that diversity index for TCR alpha and beta in irAE present patients were significantly decreased at 1 month after nivolumab, indicating expansion of certain T cell clones even in PBMCs after nivolumab. We also examined morishita index to measure T cell similarity between pre- and post nivolumab samples. As a result, irAE present patients had significantly lower similarity than irAE absent patients, indicating a larger change in the T cell clones, and inducing newly expanded T cell clones in post-nivolumab PBMC samples. Importantly, irAE present patients had significantly higher numbers of peripheral T cell clones shared with metastatic tumor-infiltrating T cells than those in irAE absent patients at 1 month after nivolumab (as per the 100 most abundant T cell clonotypes in the peripheral blood; p=0.038). Conclusions: Our findings revealed that a certain number of irAE-provoked T cell clones can also circulate systemically and attack tumor cells in distant regions, leading to durable response in the patients with irAEs.
DNA alterations in papillary renal cancer.
Authors: Jackson-Spence Francesca , Ackerman Charlotte , Szabados Bernadett , Toms Charlotte , Jovaisaite Agne , Gunnell Rachel , Suárez Cristina , Larkin James , Patel Poulam , Valderrama Begoña Pérez , Rodriguez-Vida Alejo , Glen Hilary , Thistlethwaite Fiona C. , Ralph Christy , Srinivasan Gopalakrishnan , Mendez-Vidal Maria Jose , Markovets Aleksandra , Hartmaier Ryan James , Powles Thomas 
Published: March 2023

725 Background: The characterisation of DNA alternations in papillary renal cancer (PRC) is unclear. The CALYPSO trial (NCT02819596) prospectively evaluated combination therapy of savolitinib (MET inhibitor) and durvalumab (PD-L1 inhibitor) in PRC. The trial showed high response rates (RR) in the MET-driven population. Here we explore the relationship between MET, PD-L1 and TMB in these tumours and the relevance of other biomarkers including PIK3CA, PTEN and KRAS. Methods: FoundationOne analysis from 41 samples of PRC patients enrolled on the CALYPSO trial was performed. The relevance of co-positivity between MET/PD-L1 and MET/TMB as well as analysis of other DNA alterations such as PIK3CA, PTEN and KRAS was explored. Outcome parameters were correlated with RR, PFS and OS. Results: 41% of patients were MET-driven, 66% were PD-L1+ (vCPS≥1) and 3% were TMB >10mut/Mb. Further testing used TMB ≥ median (2.52mut/Mb) 32% of patients were both MET-driven and PD-L1+. 17% of patients were both MET-driven and TMB ≥ median. RR and survival outcomes for combinations are shown in the table. The overall RR in MET driven and non-MET-driven patients was 52.9% and 13%, respectively. The median PFS and OS in the MET-driven group was 12.0 months (95% CI: 2.9-19.4) and 27.4 months (95% CI: 9.3-not reached [NR]), respectively, compared to a median PFS and OS in the non-MET-driven group of 2.7 months (95% CI: 0.5-5.0) and 7.5 months (95% CI: 0.0-16.0), respectively. PIK3CA, PTEN and KRAS mutations occurred in 1, 4 and 2 patients, with RR of 0% (0/1), 25% (1/4) and 50% (1/2), in the PIK3CA, PTEN and KRAS groups, respectively. Conclusions: MET-driven papillary cancers have low mutational burden, but high PD-L1 expression. Small patient numbers limit definitive conclusions, but responses occur irrespective of the immune biomarkers investigated. Other DNA alterations are rare and did not appear to influence outcomes in this cohort. These data support the design of the SAMETA trial (NCT05043090), further investigating the savolitinib and durvalumab combination. [Table: see text]
ECOG score as a barrier for clinical trial eligibility in the patient population with genitourinary cancer: Is it time to adapt this criterion to real-world data?
Authors: Gortzak Uzan Limor , Lapidot Lena , Bader Tzvia , Gaziel Avital 
Published: March 2023

78 Background: ECOG score is a common eligibility criteria used in clinical trials (CT). Many CT recruit only patients in good physical condition (ie. minimal comorbidities and good performance status), which may misrepresent the real-world cancer population.This gap may result in safety and effectiveness data that may not be applicable to the real-world patient population. Furthermore, applying strict eligibility criteria augment a barrier for patient accrual to CT. In this study we analyzed the impact of ECOG performance status on Genitourinary (GU) oncology trials eligibility of patients who used the Trialjectory web-based platform. Methods: Trialjectory is an AI- based platform that matches cancer patients to CT based on a patient reported questionnaire that translates to an individual clinical profile. The profile includes disease status and stage, biomarkers, treatment history and comorbidities and demographics. Data from patients with prostate and urinary bladder cancer was analyzed. The number of matched trials per patient was determined based on the patient’s profile, location and travel preference. To assess the impact of ECOG score, we edited the data set to reflect a better performance status per patient. We used a paired samples Wilcoxon test to assess the association between decreasing the ECOG threshold and the number of matched CT. Results: Between May 2021 and August 2022 we analyzed 153 bladder cancer profiles with ECOG=2 and 71 with ECOG=3, and 90 and 27 prostate cancer profiles with ECOG=2 and ECOG=3, respectively. In a multiple regression analysis, high ECOG score was inversely and significantly associated with the number of matched trials per patient in prostate cancer (p=0.009), independent of cancer stage, patient ethnicity and gender; and in urinary bladder cancer (p=0.003), after adjustment for cancer stage, gender and ethnicity. Editing ECOG score from 2 to 1 resulted in a profound increase (233% for prostate cancer patients and 300% for urinary bladder cancer patients respectively) in the number of matched trials per patient, from a median of 3 trials to 7 and from 2 to 6 trials per patient respectively (V = 426, p-value <0.0001 and V = 14, p-value = 0.0002 respectively). Among Bladder Cancer patients, editing the ECOG score from 3 to 2 resulted in an increase of 200%, from a median 1 to 2 matched CT (V = 291, p-value = 0.0002). Conclusions: The results reflect a high magnitude reduction in eligibility for patients with higher ECOG scores. Excluding these patients may result in skewed reporting on effectiveness-toxicity of drugs that may not be applicable for the real-world patient population augmenting a significant barrier for CT accrual amongst the proactive population who seek it.
Prognostic role of geriatric assessment (GA) in patients with metastatic prostate cancer (MPCaP) attended in medical oncology.
Authors: Girones Regina , Arnal Maria , Forcano Silvia 
Published: March 2023

90 Background: The Geriatric Assessment (GA) represents the future of the geriatric oncology to reduce toxicities and treatment-related hospitalization in the elderly. It has demonstrated results in predicting chemotherapy feasibility and response to docetaxel in patients with metastatic castration-resistant prostate cancer (MCRPca) (Della pepa). GA has also been explored in patients suitable to oral treatment (ref). In order to understand the prognostic capabilities of GA, we developed this analysis. Methods: All patients with MPCa sent to evaluation for Medical Oncology from January 2020 to August 2022 were analysed. GA was applied to those with 70 years or more. A geriatrician and/or an oncologist performed the evaluation. Informed consent was signed for patients. Ethical committee approved the protocol. Results: 85 patients were sent to Medical Oncology, 40 young (40%), 51 elderly (50%). Median age for young patients was 62 (46-68) and 79 for elderly (70-91). A comparison between populations is shown. This was an observational prospective study involving 51 patients who were 70 years of age or older. We performed GA including five domains and divided our patients into “fit”, “lower frailty,” and “high frailty” using Rockwood frailty scale. The relation between GC group and overall survival was explored. After GA, 26 were fit (51%), 16 had lower frailty (30%) and 10 had high frailty (19%). We found a statistically significant relationship between GA group and overall survival. Fit patients had overall survival of 27,1 months (22,8-31,5) versus 15,1 months (9,7-19,4) for low frailty and 5,6 months (3,2-7,9) for high frailty (p;0,000). Conclusions: Although our analysis has a selection bias as we only explored elderly patients sent to Medical Oncology, we found that a GA may help clinicians to recognize frail patients, and hence to reduce toxicities and early treatment discontinuation. We demonstrate its capability to be incorporated into routine clinical practice. [Table: see text]
Urologic oncology and critical care: What are prognostic factors that correlate with 6-month mortality in patients (pts) with urological tumors referred to intensive care unit (ICU)?
Authors: Zanetta Giulia Kodja , Nassar Jr Antonio Paulo , Dettino Aldo A. 
Published: March 2023

91 Background: Defining which oncologic pts actually benefit from ICU admission can be a difficult task. There is a lack of data that consistently support indication and benefit with impact on patient survival when this care is offered. The present retrospective study sought to evaluate prognostic factors related to mortality in 6 months after hospital discharge of pts with urological tumors admitted to ICU at the A C Camargo Cancer Center. Methods: A retrospective cohort study of pts with urological cancers (bladder, prostate, kidney, testicular, and other) admitted to ICU in 2017-2018. We collected the following data to identify possible predictors of 6-month mortality: gender, age, Eastern Cooperative Oncology Group (ECOG) performance status, type of ICU admission (planned or unplanned), clinical stage at diagnosis (locoregional vs. metastatic). All these variables were included in a logistic regression model with mortality at 6 months as the dependent variable. Results: Assessing the medical record of 677 patients, the pts with ECOG grading >2 presented poorer results compared to the ones 0-2, with an Odds Ratio (OR) 5.10 [Confidence Interval 95% (CI) 2.46-11.69]. The urological tumor type did influence the 6-month mortality, with the best results for pts with testicular tumors: OR 0.27 (CI 0.05-0.99) and the worst ones to bladder tumors with an OR 2.35 (CI 1.44-3.87) when compared to prostate tumors. For metastatic diagnoses, as expected, the mortality results appeared to be worse than for pts with locoregional disease, with an OR 4.06 (CI 2.73-6.07). Finally, pts undergoing unplanned hospitalization at ICU, understanding clinical and surgical ones, presented poorer results compared to the elective ones, with an OR 3.22 (2.16-4.84). Conclusions: In this cohort of pts with urological cancers, 6-month mortality was 39%. Performance status, bladder cancer, metastatic disease and unplanned hospitalizations were all associated with increased mortality.
Clinical utility of IDC-P (intraductal carcinoma of the prostate) in the decision making of initial treatment for metastatic hormone-sensitive prostate cancer.
Authors: Naito Yushi , Kato Masashi , Yamamoto Akiyuki , Tsuzuki Toyonori 
Published: March 2023

93 Background: In recent years, the usefulness of using androgen receptor axis-targeted agents (ARAT) such as abiraterone, enzalutamide, and apalutamide for metastatic hormone-sensitive prostate cancer (mHSPC) in the up-front setting has been demonstrated. However, it is still unclear which patients could truly benefit from these treatments. On the other hand, intraductal carcinoma of prostate (IDC-P) is a known poor prognostic factor for prostate cancer patients. In the present study, we investigated the association between the presence of IDC-P and therapeutic response to mHSPC. Methods: This retrospective analysis included 318 patients with mHSPC from thirteen affiliated institutions between 2014 and 2021, and evaluated biopsy specimens for the presence of IDC-P. All patients were grouped by their first-line treatment, either ARAT (n=100, receiving a combination of androgen-deprivation therapy [ADT] and ARAT), or conventional therapy (n=218, receiving ADT with or without standard antiandrogen agents). We compared overall survival (OS) and second progression-free survival (PFS2) between the ARAT and conventional groups according to the presence of IDC-P to evaluate whether presence of IDC-P predicts response to each treatment. The PFS2 was defined as the period from diagnosis of mHSPC to disease progression on second-line therapy or death. Propensity score matching was used for one-to-one nearest neighbor matching in order to minimize the potential effects of selection bias and confounding factors. The clinicopathological variables of patients were well balanced after propensity score matching. Results: Most patients in the ARAT (79%) and conventional therapy (71%) groups were ICD-P positive. In the propensity score-matched cohort, OS and PFS2 of IDC-P positive cases were significantly prolonged in the ARAT group compared to the conventional group (OS: hazard ratio [HR], 0.36; p=0.047; PFS2: HR, 0.30; p<0.001). In contrast, IDC-P negative cases did not show a difference in OS and PFS2 between the ARAT and the conventional groups (OS: HR, 1.09; p=0.920; PFS2: HR, 0.40; p=0.264). Conclusions: The findings highlight a high prevalence of IDC-P among patients with mHSPC and suggest that IDC-P may be a reliable indicator to implement ARAT as first-line therapy.
TALAPRO-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) vs placebo plus ENZA in patients with DDR gene-mutated, metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Agarwal Neeraj , Saad Fred , Azad Arun , Mateo Joaquin , Matsubara Nobuaki , Shore Neal D. , Chakrabarti Jayeta , Chen Hsiang-Chun , Lanzalone Silvana , Niyazov Alexander , Fizazi Karim ,   for the TALAPRO-3 investigational group
Published: March 2023

TPS279 Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) that has shown efficacy in metastatic castration-resistant prostate cancers with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR). ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition may increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “ BRCAness” phenotype. These studies suggest that TALA in combination with ENZA may significantly improve clinical outcomes for men with mCSPC and DDR-HRR alterations. The phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA vs placebo plus ENZA in this setting. Methods: Approximately 550 patients with mCSPC harboring DDR-HRR alterations will be randomized to TALA (0.5 mg once daily [QD]) plus ENZA (160 mg QD) or placebo (once daily) plus ENZA (160 mg QD). Patients will be stratified according to de novo mCSPC vs relapsed mCSPC, high-volume disease vs low-volume disease, where high-volume disease is defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis, and BRCA vs non-BRCA mutational status. Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in at least one of 12 DDR/HRR genes known to sensitize patients to PARPi ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is radiographic progression-free survival (defined as time to radiographic progression in soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 or in bone per Prostate Cancer Working Group 3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned/ongoing at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. As of 30 September 2022, a total of 319 patients have been randomized in the study. This study was approved by an Institutional Review Board. Clinical trial information: NCT04821622 .
A real-world registry of patients with metastatic castration-resistant prostate cancer (mCRPC): REMPRO study.
Authors: Gonzalez Francisco , Kodagali Rohit , Tung Teresa , Masoud Mohamed , Rajadhyaksha Viraj 
Published: March 2023

TPS286 Background: Rapidly expanding treatment armamentarium for mCRPC calls for an appropriate patient and treatment selection, and sequencing with existing agents. Data describing mCRPC management are fragmented across Africa, Asia Pacific, Latin America, and the Middle East with marked cross-country differences in treatment practices and patient outcomes. To address these gaps, we have established an mCRPC registry (REMPRO) that aims to describe the real-life treatment patterns and their associated survival outcomes in patients with mCRPC in non-US and non-European region. The results of this study may serve as baseline data for the policy makers in devising access programs for novel therapies in this region. Methods: REMPRO is an ongoing multinational, multicenter, retrospective, non-interventional real-world cohort study in adults diagnosed with histologically or radiologically confirmed mCRPC between 01 January 2016 and 31 December 2018 who have progressed on androgen deprivation therapy alone and received at least one line of treatment in routine clinical care, with at least 12 months of available records. After obtaining informed consent, clinical information from medical records (from index date [mCRPC diagnosis] to end of follow-up [until death, last record entry or date of data extraction]) is captured into electronic system. Data collection includes demographics, clinico-pathological characteristics, disease status, treatments received, outcomes, laboratory results, comorbidities, and healthcare resource utilization. Primary outcome analysis will describe real-world treatment patterns (monotherapy or as combinations) for overall cohort, each country, and in pre-defined subgroups like castration sensitivity, ECOG performance, AJCC staging, Gleason grade and/or score, site of metastases, and genetic alterations ( BRCA1/BRCA2 and/or HRRm). Secondary outcome analysis will include overall and real-world progression-free survival associated with different treatment regimens using Kaplan–Meier method. Of the planned sample size of 991 patients, a total of 760 patients with mCRPC have been enrolled until 26 August 2022 from 34 oncology centers across 8 countries (Colombia: 51, Egypt: 83, India: 200, Peru: 32, Saudi Arabia: 16, South Korea: 300, Turkey: 53, UAE: 25). Analysis of the dataset for primary and secondary endpoints have not been performed. Clinical trial information: NCT04801186 .
A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA.
Authors: Nauseef Jones T. , Sun Michael Philip , Thomas Charlene , Bissassar Mahelia , Patel Amie , Tan Angela , Fernandez Escarleth , Davidson Zachary , Chamberlain Tessa , Earle Kara , Wunder Rebecca , Huicochea Castellanos Sandra , Gregos Peter , Osborne Joseph , Ballman Karla V. , Molina Ana M. , Sternberg Cora N. , Nanus David M. , Bander Neil Harrison , Tagawa Scott T. 
Published: March 2023

TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr > 3 heme toxicity or Gr > 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .