bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant dual checkpoint inhibition followed by immune-chemoradiation in patients with resectable gastric adenocarcinoma.
Authors: Pabon Cindy M. , Xiao Lianchun , Badgwell Brian D. , Mansfield Paul F. , Ikoma Naruhiko , Sewastjanow-Silva Matheus , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Coronel Emmanuel , Smith Grace L. , Holliday Emma , Tian Jessie , Das Prajnan , Minsky Bruce D. , Waters Rebecca E , Estrella Jeannelyn , Li Jenny Jing , Ajani Jaffer A. , Blum Murphy Mariela A. 
Published: June 2024

4067 Background: Localized gastric cancer is a potentially curable condition and long-term outcomes depend on YP staging. Currently, preferred adjunctive therapy depends on geographic location. Preliminary data from NCT01928394 have shown promising clinical activity of immunotherapy (IO) agents nivolumab (nivo) +/- ipilimumab (ipi) in the metastatic setting. We conducted a single-arm study using IO + chemotherapy followed by immune-chemoradiation prior to surgery, followed by adjuvant IO, in patients with localized gastric adenocarcinoma. Our primary objective was to determine safety and toxicity with this approach. Secondary objectives included efficacy by YP staging and R0 resection rate. Methods: Patients with localized gastric adenocarcinoma were enrolled into NCT03776487 (n=30). Participants received the following: (1) biweekly chemotherapy with 4 doses of 5-Fluorouracil (5-FU)/Oxaliplatin, (2) nivo 240mg q2weeks (x3) and ipi 1mg/kg q6weeks (x1), (3) immune-chemoradiation (biweekly nivo + 5FU Mon-Fri concurrently with a total of 45 Gy given in 25 fractions), and (4) surgical resection. Those with residual disease received adjuvant nivolumab monthly for 6 doses. Correlative studies are planned. To assess preliminary efficacy, the clinical and pathologic complete response rates (pCR) were estimated along with the corresponding exact 95% confidence interval. Adverse events and toxicities were summarized using descriptive statistics. Results: Median follow-up was 27.4 months at the time of data cutoff. Of 30 enrolled, 23 patients completed surgery and seven did not due to progression of disease(n=5) and worsening co-morbidities(n=2). The side effect profile was similar to prior IO studies, with no grade 5 events observed. Three patients (10%) experienced grade 4 events (acute kidney injury, myocarditis, and neutropenia). The most frequent grade 3 toxicity was nausea and vomiting (10%). From the 23 participants that underwent resection, 22 had pathologic data at the time of analysis, with 9 achieving ypT0ypN0 (40.9%, 95% CI: 20.7%, 63.7%). There was an 86% R0 resection rate. Conclusions: Our results are encouraging and support further development of this strategy for localized gastric adenocarcinomas. The regimen is safe and potentially generalizable. Clinical trial information: NCT03776487 .
Neoadjuvant immunotherapy (PD-1) combined with chemotherapy for locally advanced thoracic esophageal carcinoma (EC): A single-arm, open-label, phase II study.
Authors: Wang Qi , Deng Siyou , Shen Qian , Zhang Ni , Zhang Li 
Published: June 2024

4075 Background: This study aimed to evaluate the efficacy and safety of PD-1 combined with chemotherapy as neoadjuvant therapy in patients with locally advanced EC and sought to explore biomarkers related to treatment prognosis and efficacy prediction for screening patients who would benefit most from this therapy. Methods: In this phase 2 study, patients (pts) with histopathologically confirmed ESCC, diagnosed as clinical stage cT1-3N1-3M0 and ECOG PS 0-1 were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy with PD-1 blockade (Pembrolizumab/Tislelizumab on d1) plus nab-paclitaxel (260mg/m2 in total on d1 and d8) and cisplatin (60mg/m2 in total on d1-3) of each 21-day cycle, followed by esophagectomy. Biopsied pretreatment tumor tissues along with surgical tumor specimens were collected for RNA sequencing. The primary endpoint was complete pathologic response (pCR) rate. The secondary endpoints were overall response rate (ORR), event-free survival (EFS), overall survival (OS) and safety. Biomarkers associated with clinical prognosis were assessed as exploratory objectives. Results: From Jan 11, 2021 to, Apr 25 2022, 56 pts were enrolled and 42 pts received neoadjuvant therapy and operation. Among them, 66.7% (28/42) had clinical complete response, 50% (21/42) had partial response, and ORR was 78.6% (33/42). 42 pts underwent surgical resection, achieving a 100% (42/42) R0 resection rate and a pCR rate of 33.3% (14/42), tumor regression grade (TRG, Mandard system) 1, 2 and 3 were 14.3% (6/42), 14.3% (6/42) and 71.4% (30/42) respectively. With a median follow-up of 24.4 months (range 14.3-33.4), 12(28.6%) patients had disease recurrence. Within 24 months, 14.3% (2/14) pts who achieved pCR experienced recurrence. 2-year EFS rate was 54.8% (95%CI,43.4, 66.3% ), 2-year OS rate was 81.5% (95%CI,69.4, 90.2% ). Overall, grade ≥3 AEs included leukopenia (11.9% [5/42]), thrombocytopenia (4.8% [2/42]), and no deaths were due to TRAEs. With 34 patients of RNA sequenced, we divided the patients into two groups based on whether they had recurred within 24 months as favorable prognosis and poor prognosis respectively, to analyze gene expression in different treatment effect. The poor outcome patients had significant molecular differences were seen in PI3K−Akt pathway gene expression, markers of immune activation, and genes involved in ECM−receptor interaction and focal adhesion in baseline samples, and the pathway enriched by differential genes expression in samples after treatment validated this result. Conclusions: Combining PD-1 blockade with nab-paclitaxel and cisplatin is feasible and effective in patients with locally advanced resectable ESCC, and might be a promising approach for neoadjuvant treatment. Clinical trial information: NCT05028231 .
Comparing toripalimab combined with chemoradiotherapy versus chemoradiotherapy alone for locally advanced esophageal squamous cell carcinoma: A multicenter, open-label, randomized phase II clinical trial.
Authors: Xu Yujin , Cheng Qi , Wang Yu , Zhu Weiguo , Huang Jing , Du Dexi , Tian Zhifeng , Yang Haihua , Zhou Chao , Zhou Suna , Sun Xiaojiang , Wang Yuezhen , Wang Jin , Wang Zhun , Hu Xiao , Chen Ming 
Published: June 2024

4079 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype in Asia, representing approximately 90% of all esophageal cancer cases. Despite definitive chemoradiotherapy (CRT) being the standard treatment for unresectable locally advanced ESCC, the prognosis remains poor. The introduction of PD-1 inhibitors has shown significant improvement in survival outcomes for advanced ESCC. This study aims to evaluate the efficacy and safety of combining induction and consolidation toripalimab (a PD-1 inhibitor) with CRT in patients with locally advanced ESCC (Clinical trial information: NCT04084158). Methods: Patients aged 18-75 years with unresectable, locally advanced ESCC and an ECOG performance status of 0-1 were eligible. Participants were randomly assigned (1:1) to either two cycles of toripalimab (3mg/kg q2ws) followed by concurrent CRT with 50.4Gy+weekly paclitaxel and carboplatin (TC), TC consolidation, and toripalimab (study arm), or standard CRT alone (control arm). The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and objective response rate (ORR). Results: Between September 2019 and July 2020, 46 ESCC patients (40 males) were screened for eligibility across four participating centers in China. Forty-four patients were eligible for survival analysis, all with histopathologically confirmed ESCC. Median ages were 64 years (range 49-75) in the study arm and 61 years (range 47-74) in the control arm, with similar clinical AJCC stages. As of the February 1, 2024 cutoff, the median follow-up was 50.6 months. Median PFS was 10.0 months in the study arm and 17.8 months in the control arm (HR: 1.567, 95% CI: 0.755-3.251, p=0.228). Median OS was 23.7 months and 25.9 months, respectively (HR: 1.140, 95% CI: 0.536-2.427, p=0.733). ORR rates were 64% and 86% (p=0.164), respectively. The incidence of grade 3 or worse treatment-related adverse events was similar between groups, with the most common adverse event being lymphopenia. Conclusions: Our findings indicate no significant benefit in adding induction and consolidation immunotherapy to CRT for treating locally advanced ESCC. However, the combination of radiotherapy and immunotherapy warrants further exploration. Ongoing analyses of biomarker correlates of response and survival will provide additional insights. Clinical trial information: NCT04084158 .
The clinical utility of plasma cell-free DNA (cfDNA) in NET-02: Randomised, phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line (2L) therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: McNamara Mairead Geraldine , Pearce Simon , Swain Jayne , Halford Mollie Anne , Sharma Rohini , Faluyi Olusola Olusesan , Wadsley Jonathan , Morgan Carys , Wall Lucy R. , Chau Ian , Reed Nick , Sarker Debashis , Margetts Jane , Anthoney Alan , Oughton Jamie B. , Lamarca Angela , Hubner Richard , Rothwell Dominic G. , Valle Juan W. , Clipson Alexandra 
Published: June 2024

4130 Background: In NET-02, nal-IRI/5-FU, but not docetaxel, met the primary endpoint of 6-month (mo) progression-free survival (PFS) rate in pts with progressive PD-EP-NEC (1). The prognostic potential of cfDNA in progressive PD-EP-NEC has not been explored in a prospective randomised trial. Methods: NET-02 was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI/5-FU/folinic acid, Q14 days (ARM A), or IV docetaxel, Q21 days (ARM B), as 2L therapy in pts with progressive PD-EP-NEC. Plasma samples were taken at baseline (T0), following 6 weeks of treatment (T1) and at progression (T2). Samples were analysed using a multi-omic next-generation sequencing (NGS) approach (T7-MBD-seq) (measures genome-wide methylation and low pass whole genome copy number alterations (CNA)). The tumour fraction (TF) of cfDNA was determined using ichorCNA and correlated with clinical outcomes using Cox proportional hazards model and Logistic regression. Results: Of 56 pts evaluable for efficacy, there were 54 (96%) T0 samples (48 passed quality control), 31 (55%) at T1 and 20 (36%) at T2. At T0, 36/48 (75%) samples had detectable TF by copy number (using 3% TF cut-off). For the entire cohort, T0 TF was negatively prognostic for overall survival (OS) (Hazard Ratio (HR) 1.17, 95% Confidence interval (CI) 1.00-1.37, P=.044), but not for 6 mo PFS rate (Odds ratio (OR) 1.25, 95% CI 0.91-1.73, P=.17), response rate (RR) (OR 1.11, 95% CI 0.67-1.76, P=.65) or PFS (HR 1.04, 95%CI 0.91-1.20, P=.53). In the entire cohort, median OS split by TF (N=16 each) was 10.2 mo (95% CI 4.1-not available (NA)) for low (TF≤8.6%), 6.9 mo (95% CI 3.4-14.8) for medium (8.6<TF≤24.3%) and 3.7 mo (95% CI 2.8-NA) for high (TF>24.3%). T0 TF was also negatively prognostic for 6 mo PFS rate and OS in ARM A (P=.02, P=.03), but not ARM B (P=.61, P=.48), but was not prognostic for RR or PFS (Table). TF correlated with the presence of liver metastases (Wilcoxon Rank Sum P=.009), but not with ECOG PS (P=.14), sex (P=.10), Ki-67 (P=.39) or age (Spearman rank correlation P=.45). Longitudinal copy number and methylation cfDNA analysis is on-going. Conclusions: These results suggest that it may be possible to stratify prognosis based on amount of baseline TF in patients with progressive PD-EP-NEC, and may also identify patients who would benefit most from the nal-IRI combination. 1. McNamara 2023, EClin Med. Clinical trial information: 03837977. [Table: see text]
Prognostic value of circulating tumor DNA testing in surgically resected pancreatic cancer.
Authors: Miceli Madeline Rose , Littman Dalia , Masri Lena , Becker Daniel Jacob , Oberstein Paul Eliezer 
Published: June 2024

4134 Background: The majority of patients with pancreatic cancer who undergo curative intent resection have recurrence, but optimal surveillance is unknown. Circulating tumor DNA (ctDNA) tests, custom-designed multiplex-PCR tumor assays unique to each patient’s tumor, may assist in monitoring for recurrence. Methods: We performed a single center retrospective review of patients with surgically resected pancreatic cancer who had at least 1 ctDNA test performed post-operatively between 8/1/21 and 11/13/23 with Natera Inc.’s Signatera assay. Primary outcomes were documented radiographic progression and death. Results: 74 patients were identified, of whom 36 were positive for ctDNA at any point during the study (median follow up from surgery 19.1 months) while 38 remained negative for ctDNA (15.3 months). There was no difference in age (≥ or < 70), sex, or race. Positive ctDNA at any time point was associated with advanced stage disease (p=0.013), positive resection margins (p=0.008), and having received neoadjuvant therapy (p=0.005). Those with any positive ctDNA were more likely to have radiographic progression (p<0.0001) or death (p=0.0005) by the end of the study. These differences remained when the population was examined in subgroups of first post-operative ctDNA positive, first ctDNA negative but at least one subsequent ctDNA positive, and all ctDNA negative. In Cox proportional hazard models, both any positive ctDNA test and positive first ctDNA test (first ctDNA limited to ≤120 days post-op) were associated with higher risk of radiographic progression and/or death compared to never testing positive for ctDNA and negative first ctDNA test, respectively (HR 12.6 (3.0-51.9), p=0.0005; HR 5.6 (1.4-22.8), p=0.02). Conclusions: Positive ctDNA tests, both in the immediate post-operative and subsequent settings, are associated with higher risk of radiographic progression or death in patients with resected pancreatic cancer. These data suggest that ctDNA testing provides independent, meaningful prognostic information superior to traditional pathologic risk factors and CA19-9 testing alone. These findings have implications for future clinical study design and decisions about surveillance and treatment. [Table: see text]
Effect of ctDNA whole-exome sequencing in pancreatic adenocarcinoma on prognostic value, actionable alterations, and organ tropisms in metastatic disease.
Authors: Huerta Marisol , Martín-Arana Jorge , Gimeno-Valiente Francisco , Carbonell-Asins Juan Antonio , García-Micó Blanca , Martínez-Castedo Belén , Camblor Daniel G. , Fleitas Tania , García Bartolomé Miguel , Alfaro-Cervello Clara , Garcés-Albir Marina , Dorcaratto Dimitri , Muñoz-Forner Elena , Mora-Oliver Isabel , Gambardella Valentina , Roselló-Keränen Susana , Sabater Luis , Roda Desamparados , Cervantes Andres , Tarazona Noelia 
Published: June 2024

4149 Background: The dismal prognosis associated with pancreatic ductal adenocarcinoma (PDAC) needs a deeper understanding of progression mechanisms and personalized treatment. While the prognostic value of ctDNA has already been established, this study purposes to apply plasma whole-exome sequencing (WES) to identify molecular alterations beyond KRAS. This approach aims to predict survival, uncover progression mechanisms, and identify therapeutic targets. Methods: Eighty metastatic PDAC patients were prospectively recruited and divided into two consecutive cohorts: discovery (n=37) and validation (n=43). Tumor and plasma obtained at diagnosis were analyzed using WES. The variant allele frequency (VAF) of KRASmutations was quantified by ddPCR in plasma at baseline and at response from all patients (n=80). Results: Plasma WES identified at least one pathogenic variant across all individuals, which can be categorized into four pathways: oncogenic mechanisms, DNA repair, microsatellite instability and TGFb pathway alterations. 7 unique druggable mutations were detected in tissue and 11 in plasma. Other targetable mutations ( CDK12, NF1, BRCA2, and TSC2), were prevalent in plasma but absent in tissue. Patients with survival less than 11 months showed enrichment in cellular organization pathways and exclusive targetable CDK12 mutations. Longer survival cases exhibited exclusive mutations in DNA regulation and repair genes. Patients with liver metastasis displayed unique mutations not just in KRAS but also in the adaptive immune response pathway genes. Baseline plasma KRAS mutations detected by ddPCR was associated with worse progression-free survival. (HR=2.315, CI 95%= 1.027-5.217, p = 0.038; and HR= 3.022, CI 95% = 1.299 - 7.030, p= 0.007 in the discovery and validation cohort, respectively). A significant risk of progression (p = 0.006) was observed if KRAS VAF at response assessment did not decrease, at least, 84.75% in both cohorts. Conclusions: ctDNA WES unveils molecular signatures of rapid progression, potential actionable alterations, and liver metastasis-specific mutations in the adaptive immune response pathway. KRAS detection at baseline and its evolution during treatment emerge as prognostic biomarkers. [Table: see text]
Fragmentomics of cell-free DNA as a sensitive biomarker for early detection of pancreatic cancer.
Authors: Yin Lingdi , Cao Cheng , Lin Jianzhen , Zhang Kai , Peng Yunpeng , Xu Cheng , Yang Ruowei , Zhu Dongqin , Wang Fufeng , Chang Shuang , Bao Hua , Guo Feng , Tu Min , Chen Jianmin , Wei Jishu , Wu Junli , Gao Wentao , Miao Yi , Lu Zipeng , Jiang Kuirong 
Published: June 2024

4173 Background: Pancreatic ductal adenocarcinoma (PDAC) is one for the most lethal types of cancer. Nearly 80% of the PDAC patients are diagnosed at advanced unresectable stages. Therefore, an accurate early diagnosis assay is urgently needed for reducing PDAC related mortalities. In this study, we aim to utilize cfDNA fragmentomics and machine learning techniques for sensitively detecting PDAC patients. Methods: Total647 cases were prospectively enrolled in this study. Plasma samples were collected from each participant for shallow WGS (~5X). After quality control process, 166 PDAC patients and 167 healthy controls were enrolled as a training cohort. Additional 112 PDAC patients and 111 healthy controls were included as an independent validation cohort. Additional 67 cases with pancreatic benign cystic tumors were also enrolled for model validation including IPMN (Intraductal papillary mucinous neoplasms), MCN (Mucinous cystic neoplasms) and SCN (Serous cystic neoplasms). Four fragmentomics profiles, including copy number variation, fragment size, mutation signatures, and FRAGmentomics-based Methylation Analysis (FRAGMA) were utilized by a machine learning algorithm for developing a predictive model. Results: The predictive model showed an exceptional performance to distinguish PDAC patients from healthy controls, yielding Area Under the Curve (AUC) of 0.993 in the training cohort (5-fold cross validation) and 0.990 in the validation cohort. In the training cohort, our model was capable of detecting PDAC patients at sensitivity of 95.8% and specificity of 95.2% while using 0.49 as cutoff. The validation cohort achieved 99.1% sensitivity at 91.0% specificity while applying the same cutoff. Conclusions: Our model was able to accurately detect PDAC at early stages, by incorporating fragmentomics features through machine learning. It can potentially be used for PDAC early screening, and therefore reducing PDAC related mortalities.
Durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced (LA) and borderline resectable (BR) pancreatic cancer (PDAC): Long-term outcomes and correlative insights.
Authors: Keane Fergus , Tuli Richard , O'Connor Catherine A , Schwartz Carly , Park Wungki , Varghese Anna M. , Perry Maria , Singhal Anupriya , Vardhana Santosha , Hendifar Andrew Eugene , Tarcan Zeynep , Basturk Olca , McDermott Raymond S. , Reyngold Marsha , Crane Christopher H. , O'Reilly Eileen M. , Schoenfeld Joshua David 
Published: June 2024

4174 Background: Immune checkpoint blockade (ICB) has limited activity in genomically unselected patients (pts) with PDAC. While anti-tumor activity with combination SABR/ICB has been shown, biomarkers of response are poorly defined. We conducted a phase 1/2 study of PD-L1 inhibitor Durvalumab (D) and SABR after induction chemotherapy in LA and BR PDAC (NCT03245541). We report long-term outcomes and correlative biospecimen analyses. Methods: A multi-institutional, single arm phase 1/2 trial was conducted at Cedars-Sinai and Memorial Sloan Kettering. Initial clinical data reported by Tuli et al, ASCO 2023. Pre-treatment tissue assessed for p40 and GATA3 to determine classical vs basal subtype by immunohistochemistry. Tissue interrogated by immunofluorescence for PD-L1 expression and infiltration of immune cell subsets. Multiparametric immunophenotyping of peripheral blood mononuclear cells (PBMCs) by flow cytometry conducted on baseline and on treatment samples. Wilcoxon rank sum test used to determine difference in biomarkers from each timepoint; p-value <0.05 significant. Results: N= 36 enrolled from 08/2017-05/2022; N=31(86%) LA, N=5 (14%) BR. N= 9 (25%) underwent resection; all R0. At median follow up 36.5 months, 6- and 12-month PFS 69%, 36%. Median PFS 8.7m (95% CI 6.1-14), median OS 16m (95% CI 13-26). N=2 (6%) alive without disease progression. Correlative analyses summarized (table). Key findings; Classical/basal subtyping feasible on N=9 (8 classical, 1 basal). Median PD-L1 score not associated with survival. Peri-tumoral, but not intratumoral CD8+ cells associated with PFS >6 months. Flow cytometry feasible for 70 samples from N=35. Frequency of pre-treatment non-naïve CD4+ FoxP3+ Treg associated with PFS >12. CD103+ CD8+ T Cells significantly expanded on treatment only in patients with PFS>12m (p=0.038) and were significantly enriched relative to PFS<12m on treatment. Conclusions: A proportion of pts with LA PDAC achieve durable control with D and SABR after induction chemotherapy. Baseline peri-tumoral CD8+ cells and peripheral CD103+ CD8 T cells and CD4+ Treg in PBMCs at baseline and on treatment may predict for benefit. Further analyses ongoing and validation in larger cohorts is warranted. Clinical trial information: NCT03245541 . [Table: see text]