bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of potential biomarkers with alternative splicing landscape of HIPEC-treated ovarian cancer: An RNAseq sub-analysis of a HIPEC clinical trial.
Authors: Dellinger Thanh Hue , Hansen Nathaniel P. , Ruel Nora H. , Frankel Paul Henry , Yost Susan Elaine , Invernizzi Marta , Eng Melissa , Han Ernest Soyoung , Raoof Mustafa , Wu Xiwei , Cho Hyejin , Lee Stephen , Kebria Mehdi , Hakim Amy , Wang Edward Wenge , Paz Isaac Benjamin , Rodriguez-Rodriguez Lorna , Pirrotte Patrick 
Published: June 2024

e17577 Background: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy improves survival in ovarian cancer patients. Currently, no biomarkers exist to select for patients who best benefit from HIPEC. We compared the slicing landscape of ovarian cancer tumors of good and poor HIPEC responders in a Phase I clinical trial, to identify potential predictive biomarkers. Methods: A total of 35 ovarian cancer patients enrolled in a Phase I HIPEC trial (NCT01970722), in which nine patients had paired pre-and post treatment tissue samples collected. Pre-HIPEC tumor samples had RNA isolated, and whole-transcriptome library construction performed. FASTQ files from tumor samples were aligned to GRCH38 and ran through SplAdder (PMID:26873928) to identify alternative splicing events. Outlier splice events were ranked by mean log-likelihood score and converted to amino acid sequences using Bisbee (PMID:34031440). The top 15 outlier events were run through NetMHCpan (PMID:32406916) and DeepHLApan (PMID:31736974) to predict putative neoantigens. Results: Among nine HIPEC-treated ovarian cancer patients with available RNAseq data, five were considered good responders (≥12months PFS), and four as poor responders (<12 months PFS). Alternative splicing analysis identified 519splice events as outliers between good and poor responders, with 250reported to be novel. Of the 250 novel splicing events, we identified a novel protein coding 3’ end splice event in CPNE1 which was alternatively spliced in at a Percent-Spliced-In (PSI) of 99% in three out four poor responders. The same splice event was alternatively spliced at a PSI of 30.3% in four out of five good responders. CPNE1 plays a role in calcium mediated intracellular processes, and is involved in the TNF-alpha receptor signaling pathway, thus playing an important role in cell proliferation, differentiation, apoptosis, and modulation of immune responses and induction of inflammation. The encoded novel peptide from the CPNE1 splice event produced six predicted strong binding sites based on a binding score>0.80 and an immunogenic score>0.80. Conclusions: CPNE1 was identified as a differentially spliced event in poor HIPEC responders with ovarian cancer. Poor HIPEC responders had higher immunogenic score. Alternative splicing analysis may be a promising method to determine potential biomarkers for HIPEC treatment in ovarian cancer patients. Clinical trial information: NCT01970722 .
Early detection, clinicopathological subtyping and prognosis prediction for patients with endometrial cancer using fragmentoimcs-based liquid-biopsy assay.
Authors: Rao Qunxian , Zhou Hui , Weng Wanying , He Yiru , Tang Wanxiangfu , Chen Xiaoxi , Wu Xuxiaochen , Bao Hua , Lin Zhongqiu , Zhang Bingzhong 
Published: June 2024

e17584 Background: Endometrial cancer (EC) is among the most common types of gynecologic malignancies worldwide. Currently, it is estimated that there are approximately 66,200 incidences and 13,030 cancer-related mortalities each year in the USA. If detected early, the five-year survival rate for localized endometrial cancer patients is at an optimistic 95%. However, the survival rates plunge dramatically to only 17.8% for patients with distant malignancies. Thus, timely diagnosis for endometrial cancer patients at an early stage can significantly enhance the chances of successful treatment, which is essential for reducing EC-related deaths. Methods: A cohort enrolled 120 patients with endometrial cancer and 120 female healthy volunteers from December 2018 to October 2019, was used to develop a predictive model for early detection of endometrial cancer. Five different fragmentomic features were profiled from low-pass WGS data and were used by four different algorithms for constructing base models before assembling to a final predictive model. An independent perspective test cohort, consisting of 62 endometrial cancer patients and 62 healthy controls enrolled from February to December 2020, was used for performance assessment of the final early detection model. Additional models were also developed for predicting clinicopathological features such as stage, grade, histological subtype, MSI and recurrence-free survival. Results: Our early detection model showed an excellent AUC of 0.96 in the independent test cohort, reaching a sensitivity of 75.8% at 96.8% specificity. Our model maintained its predictive power across different stages, yielding sensitivities of 74.4%, 85.7%, 75% and 75% for stage I to IV, respectively. Additionally, our models showed moderate predicting power for various clinicopathological features including stage (AUC: 0.72), histological subtypes (AUC: 0.73), grade (AUC: 0.59) and MSI (AUC: 0.77), respectively. Furthermore, a LASSO Cox regression model was capable of predicting patients’ recurrence-free survival. The model predicted risk score could identify high-risk patients who were 8.6 times more likely to develop recurrence, independent from other clinical factors (Hazard Ratio = 8.6, p < 0.001). Finally, an unsupervised similarity network fusion divided the endometrial cancer patients into a high-risk cluster and a low-risk cluster, while patients in the high-risk cluster had a 6.2 times higher risk for recurrence (HR = 6.2, p = 0.049). Notably, high-risk patients predicted by both methods had an even higher risk (HR = 10.1, p < 0.0001). Conclusions: By utilizing a fragmentomic-based liquid biopsy assay and machine learning algorithms, our model showed great clinical potential for the early detection, clinicopathological subtyping and prognosis prediction in patients with endometrial cancer.
Enfortumab vedotin plus pembrolizumab in the treatment of locally advanced or metastatic bladder cancer of variant histology: A phase II study.
Authors: Nazha Bassel , Brown Jacqueline T , Liu Yuan , Kissick Haydn , Carthon Bradley Curtis , Kucuk Omer , Harik Lara R , Narayan Vikram M , Joshi Shreyas S , Bilen Mehmet Asim 
Published: June 2024

TPS4615 Background: Bladder cancers of variant histology (BCVH) account for up to 25% of bladder cancer incidence and affected patients (pts) usually have poor outcomes. The treatment options are limited due to the underrepresentation or exclusion of BCVH pts from trials for locally advanced or metastatic urothelial cancer (mUC). Enfortumab vedotin (EV) is an antibody-drug conjugate specific for Nectin-4. In the EV 302 Phase III trial, EV+pembrolizumab (pembro) significantly prolonged overall survival (OS) compared to platinum-based chemotherapy in mUC (HR 0.47, 95% CI 0.38-0.58) and was recently FDA-approved as standard of care in 1L mUC. Translational studies from our center show Nectin-4 expression in many BCVH pts and data support immune-checkpoint inhibitor (ICI) activity in subsets of these pts. We hypothesize the presence of clinical activity of this combination in BCVH. Therefore, we designed this trial to assess the efficacy and safety of EV+pembro in locally advanced or metastatic BCVH (mBCVH). Methods: This is a Phase II, open-label, single-center trial at the Winship Cancer Institute of Emory University (NCT05756569) for pts with mBCVH. Pts will receive pembro 200mg IV on Day 1 and EV 1.25mg/Kg IV on Days 1 and 8 of a 21-day cycle for up to two years. The eligibility criteria include histologically confirmed variant histology or non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (according to the WHO 2016 Classification), ECOG 0-1, and any line of therapy. Pts with neuroendocrine bladder cancer, non-epithelial cancers (e.g. sarcoma, lymphoma), prior ICI and/or EV treatment are excluded. Overall response rate (ORR) per RECIST 1.1 is the primary outcome and will be tested using Simon's two-stage design (n=25). The first interim analysis is planned after 15 patients. The desirable target is ORR≥30% relative to a null hypothesis of ORR ≤10%. This statistical design yields a type I error rate of 0.05 and a power of 80% for a true ORR≥30%. Key secondary outcomes include OS, progression-free survival, duration of response, and incidence of adverse events per CTCAE v5.0. Correlative biomarker analyses using blood- and tissue-based assays will be conducted during screening and at disease progression. The trial is currently open for enrollment. Clinical trial information: NCT05756569 .
A phase III randomized trial of eribulin (E) with gemcitabine (G) vs standard of care (SOC) for patients (pts) with metastatic urothelial carcinoma (mUC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937 updated design.
Authors: Sadeghi Sarmad , Plets Melissa , Lara Primo N , Tangen Catherine , Berg Stephanie A. , Brown Jason R , Bangs Rick , Nakagawa Darrell , Daneshmand Siamak , Ian M. Jr.  , Flaig Thomas W. , Petrylak Daniel P. , Lerner Seth P. 
Published: June 2024

TPS4617 Background: UC is 2nd most common genitourinary cancer. Enfortumab vedotin (EV) + pembrolizumab became a SOC in 2023 in frontline mUC setting. In previously treated mUC setting, erdafitinib is approved for pts with FGFR alterations, while all pts have the option of sacituzumab govitecan (SG) with objective response rate (ORR) of 27% (N=113). A phase I/II CTEP study of eribulin (E) for mUC established the activity of E with ORR of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 71% ORR (n=7) for GE vs 24% for E (n=49). This trial has now been amended to account for first-line treatment changes and to include SG as a control arm option. Methods: This is an updated phase III, randomized trial comparing GE vs. SOC (SG, docetaxel, paclitaxel, or G monotherapy). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle and G is given at 1000 mg/m2 on D1 and D8. SOC follows approved dosing. There is no limit to the number/sequence of prior regimens. In brief, all pts must have: received systemic therapy with EV; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab. The study seeks to find at least a 50% increase in the primary endpoint of OS (Hazard Ratio (HR) = 0.667). The secondary endpoints include ORR, and progression free survival (PFS). One-sided 0.05 type I error to account and 80% power to detect a 50% improvement in OS. We require 92 eligible pts in each arm for a total of 184. The amended and restructured study was approved in January of 2024. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Eribulin is provided by Eisai. Clinical trial information: NCT04579224 .
A phase II trial of enfortumab vedotin for locally advanced and metastatic squamous cell carcinoma of the penis.
Authors: Pagliaro Lance C. , Moore Cassandra N. , Tan Winston , Bobek Olivia , Hillman David W. , Gupta Sounak , Tekin Burak , Herrera Hernandez Loren 
Published: June 2024

TPS5108 Background: Penile cancer is a devastating malignancy that affects just over 2000 patients per year in the United States and approximately 40,000 worldwide. Metastatic or unresectable penile cancer is rapidly fatal in most cases and there are few effective systemic therapy options.1 There is an urgent need for alternatives to chemotherapy such as immunotherapy or targeted therapy. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 protein on the tumor cell surface and having efficacy in treatment of metastatic urothelial carcinoma.2 Recent studies have demonstrated frequent and strong expression of nectin-4 in penile squamous cell carcinoma (PSCC).3,4 In this setting, Mayo Clinic is leading a phase II trial of EV for advanced PSCC, currently in progress. Methods: This single arm, open-label, two-stage, phase II trial evaluates best overall response rate (BRR) to EV in patients with PSCC regional lymph node involvement or distant metastatic (M1) disease. Participants may have had any prior systemic therapy or be treatment naïve. Previously untreated patients must be ineligible for or have refused surgery or radiotherapy, have N2-N3 disease and are ineligible for or have refused neoadjuvant chemotherapy, or have clinical evidence of M1 disease. Participants will receive treatment with EV until disease progression, withdrawal, death, or limiting toxicity. Participants will receive EV 1.25 mg/kg intravenous on days 1, 8, and 15 of a 28-day cycle, with tumor assessment performed at 8-week intervals. The primary endpoint is the combined BRR of partial and complete responses (whether confirmed or unconfirmed) according to RECIST 1.1. Secondary endpoints are confirmed response rate, duration of response, progression-free survival, overall survival, adverse events, and BRR in HPV related and unrelated subgroups. Stage 1 will consist of 15 participants, and if there are 2 or more responses will proceed to Stage 2 with an additional 10 participants. The trial opened to enrollment in December 2023, and is active at Mayo Clinic sites in Minnesota, Arizona, and Florida. Clinical trial information: Funding and drug supplied by Astellas Pharma Global Development, Inc./Seagen Inc. NCT06104618. 1. Chahoud J, et al., Curr Opin Urol. 2022 Jan 1;32(1):8-16. 2. Powles T, et al. N Engl J Med. 2021 Mar 25;384(12):1125-1135. 3. Tekin B, et al. Hum Pathol. 2023 Dec;142:42-50. 4. Grass GD, et al. Eur Urol Open Sci. 2023 Jan 10;49:1-5. Clinical trial information: NCT06104618 .
ProstACT GLOBAL: A phase 3 study of best standard of care with and without 177Lu-DOTA-rosopatamab (TLX591) for patients with PSMA expressing metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug.
Authors: Sartor Oliver , Tagawa Scott T. , Lenzo Nat , Cade David , Agarwal Neeraj 
Published: June 2024

TPS5115 Background: The treatment of advanced prostate cancer (PC) is challenging, with no curative therapy to date and undesirable side effects that may impact patient quality of life. Monoclonal antibodies enable high specificity with low rates of off-target organ exposure, prolonged retention in PSMA+ tumors, and a predictable safety profile. There is a strong rationale for further investigation of the 177Lu-labeled, chelator-conjugated antibody, 177Lu-DOTA-rosopatamab (hereafter, TLX591), with prior studies demonstrating a favorable safety profile and efficacy, particularly with a fractionated (dose-dense) regimen Phase 1 ProstACT SELECT preliminary results demonstrate consistent uptake between TLX591 and 68Ga-PSMA-11 imaging and reinforces advantages of this first-in-class radio-antibody drug conjugate investigational therapy. Methods: In this multinational, multicenter, prospective, randomized, open label phase 3 study, patients (N=400) with PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior treatment with an androgen-receptor pathway inhibitor (ARPI) will be enrolled in a 2:1 ratio to receive best protocol-defined standard of care (SoC) with or without 2 intravenous injections of 2.8 GBq of TLX591, given 14 days apart. SoC may be alternative ARPI or docetaxel. Eligible patients must have received 1 prior ARPI in the mCSPC, nmCRPC, or 1L mCRPC setting. Patients must have 150x109 /L platelets, and have PSMA-positive disease on 68Ga-PSMA-11 PET/CT imaging. The primary endpoint is radiographic progression-free survival. Secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, health-related quality of life, and treatment-related adverse events count. An alpha control and 95% confidence intervals will be used; patients will be substratified between TLX591 + 2nd ARPI or TLX591 + docetaxel. This study is currently enrolling. This study is funded by Telix Pharmaceuticals. Clinical trial information: NCT04876651 .
Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with new hormonal agents in patients with metastatic castration-sensitive prostate cancer with and without homologous recombination repair mutation (EvoPAR-Prostate01).
Authors: Chi Kim N. , Agarwal Neeraj , Armstrong Andrew J. , Hellmis Eva , Schlürmann Friederike , Sugimoto Mikio , Ürün Yüksel , Xing Nianzeng , Aregay Mehreteab , Lima Julianne , Meulendijks Didier , Azad Arun 
Published: June 2024

TPS5123 Background: PARP inhibitors (PARPi) in combination with new hormonal agents (NHAs) are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). PARPi utilization in earlier lines of treatment may result in greater magnitude of benefit. Saruparib is a potential best-in-class PARPi, which selectively inhibits and traps PARP1, has minimal effect on PARP2, and hence may offer an improved therapeutic window compared with currently approved nonselective PARPi. The efficacy and safety of saruparib plus NHAs for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) and mCRPC are being assessed in the phase I/IIa PETRANHA study (NCT05367440). The phase III EvoPAR-Prostate01 study (NCT06120491) is evaluating the efficacy and safety of saruparib plus physician’s choice of NHA (abiraterone, darolutamide, or enzalutamide) compared with placebo plus physician’s choice of NHA in participants with mCSPC. Methods: This is a 2-cohort, 2-arm, randomized, double-blind, placebo-controlled, multicenter global study. Key eligibility criteria include age ≥18 years, histologically confirmed mCSPC ( de novo or recurrent low- or high-volume disease), ECOG PS 0-1, and confirmed, prospectively defined homologous recombination repair gene mutation (HRRm) status (defined by the presence/absence of pathogenic/likely pathogenic mutations in ≥1 of the genes BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D,and BARD1). Participants must be receiving androgen deprivation therapy throughout the study or have undergone bilateral orchiectomy, and must be suitable for treatment with NHAs. Key exclusion criteria include prior therapy with PARPi, prior chemotherapy or NHAs in the mCSPC setting (prior NHAs for localized disease permitted), and history of, or suspected, myelodysplastic syndrome/acute myeloid leukemia. Participants are allocated to either the HRRm or non-HRRm cohort based on prospective testing of both tumor tissue and circulating tumor DNA. Participants are randomized 1:1 to receive saruparib plus physician’s choice of NHA or placebo plus physician’s choice of NHA. Treatment continues until disease progression, unacceptable toxicity, or participant-initiated withdrawal. The primary endpoint is radiographic progression-free survival (rPFS), with overall survival (OS) a key secondary endpoint. Planned statistical analyses of rPFS and OS will be conducted within each cohort using a stratified log-rank test. Approximately 1,800 participants (550 HRRm; 1,250 non-HRRm) will be randomized. Enrollment began in November 2023 and is ongoing. Clinical trial information: NCT06120491 .
Randomized PROSTATE-IQ trial to reduce ADT treatment burden for patients with biochemical recurrence after prostatectomy.
Authors: Hoffman Karen E. , Kollmeier Marisa , Nguyen Paul L. 
Published: June 2024

TPS5130 Background: Men with PSA recurrence of prostate cancer after prostatectomy often receive Androgen Deprviation Therapy (ADT) with salvage radiation therapy to the prostate resection bed. Traditional ADT improves cancer control; however, it also causes fatigue, sexual dysfunction, hot flashes, cognitive changes, metabolic dysregulation, body composition changes, and negatively impacts men’s quality of life. Methods: The PROSTATE-IQ trial is a randomized multi-center clinical trial that is investigating ways to reduce the adverse effects of ADT treatment. First, the trial uses intrinsic cancer properties assessed by ArteraAI and clinical-pathologic variables to personalize the intensity of Androgen Axis Therapy (AAT). Those with low ArteraAI score are assigned to the Artera Low Cohort and those with either high ArteraAI score, PSA >0.5 ng/ml or nodal involvement are assigned to the Higher-risk Cohort. Second, the trial randomizes men between traditional ADT and apalutamide-based therapy. We hypothesize that the apalutamide-based therapy will reduce the adverse effects of treatment and thereby improve quality of life. 220 men in the Artera Low Cohort are being randomized between 6 months of ADT vs. 6 months of apalutamide monotherapy. 220 men in the Higher-risk Cohort are being randomized between 24 months of ADT (winning arm of RADICALS-HD trial) vs. 6 months of apalutamide and ADT (winning arm of FORMULA 509 trial). We hypothesize that the apalutamide-based treatments will reduce fatigue and boost activity, sleep, and cognitive function. Patients wear an activity and sleep tracker, undergo cognitive assessments, and complete validated fatigue, leisure activity, and mental health questionnaires. We will compare fatigue, activity, sleep, mental health, body composition, metabolic dysregulation, quality of life, and cancer control between treatment arms. This trial will be impactful because it is the first to use the validated ArteraAI test to personalize intensity of androgen axis therapy and because it will reduce the adverse effects of treatment and improve quality of life for prostate cancer survivors treated with salvage radiation and androgen axis therapy.