bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic alteration and ctDNA mutation profiling of esophageal cancer in Chinese patients.
Authors: Qingxin Zeng , Yang Yingnan , Zhou Gao , Jiang Haihua , Guo Jia , Zhao Shuhua 
Published: June 2023

e16046 Background: Esophageal cancer is the sixth most common cause of cancer-related mortality. There are two distinct histological types of esophageal cancer: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). In China, ESCC is the major subtype. Higher incidence of EAC is observed in western countries. Liquid biopsy detecting circulating tumor DNA is a non-invasive, real-time and highly sensitive approach that is able to identify and monitor the genetic mutations in tumor. Methods: In this study, we collected 490 Chinese esophageal cancer patients from 2018-2022 and characterized the mutational landscape of esophageal tumor tissue and circulating tumor DNA by whole exome sequencing or deep sequencing of targeted gene panel. The consistency of genetic alteration between tumor and ctDNA was also explored. Results: A total of 176 patients with plasma and 345 patients with cancer tissue were analyzed, among them, 31 patients had both ctDNA and tissue biopsy data. 277 genes with 1257 mutations were identified from plasma samples of 176 patients. The top frequently mutated genes were TP53 (89.1%), KMT2D (24.0%), SYNE1 (14.9%), NOTCH1 (14.3%), EP300 (13.7%), LRP1B (13.7%) and ZNF750 (10.3%). The mutation rates of these genes between ctDNA and tissue biopsy (N = 31 patients) were in concordance by Fisher's exact test (P > 0.05). Most frequent mutations were found in TP53 gene, which account for 89.1% of total plasma samples and 90.4% of tumor tissues. KMT2D gene mutations were detected in 24% of patients which encode histone methyltransferase that methylates the Lys-4 position of histone H3 and regulates transcriptional activation, indicating epigenetic regulation might be involved in the pathogenesis of esophageal cancer. Functional enrichment analysis was performed including Gene Ontology (GO) and KEGG analysis across all the three domains, Biological process, Molecular Function, and Cellular component. The KEGG terms with the highest enrichment score were PI3K−Akt signaling pathway, which is a key driver in carcinogenesis. In addition, we didn’t observe the mutually exclusive mutation or co-occurrence pattern of any gene pairs in our cohort. Conclusions: We demonstrated the utility of liquid biopsy to draw a ctDNA mutation profiling of esophageal cancer in Chinese patients. Genetic mutations identified from ctDNA showed consistency with mutations from tumor tissue.
Clinical analysis of immunotherapy rechallenge in advanced gastric cancer.
Authors: Zhang Xinxin , Hou Xinfang 
Published: June 2023

e16049 Background: To evaluate the efficacy and influencing factors of programmed cell death protein 1 (PD-1) monoclonal antibody rechallenge therapy in advanced gastric cancer (GC). Methods: The clinical data of patients with advanced GC who were treated with PD-1 monoclonal antibody rechallenge in the Department of Gastroenterology, Henan Cancer Hospital from January 2020 to December 2021 were retrospectively collected. Results: A total of 60 patients with PD-1 monoclonal antibody rechallenge therapy were collected; the median follow-up time was 12.2 months. The median progression-free survival (PFS2) of PD-1 monoclonal antibody rechallenge therapy was 2.9 months, and the objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.0%. The median PFS2 of the same PD-1 monoclonal antibody for the first and second versus different PD-1 monoclonal antibody rechallenge treatment was (3.5 months vs. 1.9 months, P=0.006). The median PFS2 of positive PD-L1 expression in rechallenge therapy was 3.4 months, ORR was 22.7%, and DCR was 63.6%; the median PFS2 was 4.5 months, ORR was 27.3%, and DCR was 54.5% in patients with median PFS1≥6 months. Multivariate analysis showed that peritoneal metastasis was independently associated with PD-1 monoclonal antibody rechallenge with median PFS2 ( P=0.034, HR=2.327, 95%CI 1.066-5.082). The incidence of adverse reactions in grade 1-2 and grade 3-4 of PD-1 monoclonal antibody rechallenge therapy was 83.3%, and 35.0%, respectively. and the safety was controllable. Conclusions: Rechallenge therapy with PD-1 monoclonal antibody is a feasible treatment in advanced GC, but the screening of suitable population for rechallenge therapy still needs prospective data analysis and verification.
The safety and efficacy of cadonilimab in combination with AK117 (anti-CD47 antibody) plus chemotherapy as first-line treatment for advanced gastric (G) or gastroesophageal junction (GEJ) cancer.
Authors: Xia Qing , Wu Tao , Wang Feng , Li Shengmian , Xia Yu , Li Baiyong , Wang Zhongmin Maxwell , Song Weifeng , Wang Liwei 
Published: June 2023

e16050 Background: Despite the approval of anti-PD-1 antibodies plus chemotherapy as first-line (1L) therapy in advanced G/GEJ adenocarcinoma, benefit is very limited for patients (pts) with PD-L1 combined positive scores (CPS)< 5; novel therapeutic approaches are needed. Cadonilimab, a tetrameric bispecific antibody targeting PD-1 and CTLA-4, combined with chemotherapy showed promising activity in untreated pts with advanced G/GEJ adenocarcinoma were presented in ASCO GI 2022 (abstract#308). AK117 is a novel humanized IgG4 anti-CD47 antibody without hemagglutination effect. Blockade of CD47-SIRPα pathway by AK117 leads to a promising therapeutic strategy for cancer treatment with favorable safety features. Here we report the safety and efficacy of Cadonilimab in combination with AK117 and chemotherapy in the 1L treatment of advanced G/GEJ adenocarcinoma. Methods: This was an open-label, multi-center phase II study evaluating the safety and efficacy of Cadonilimab +AK117+ XELOX as 1L therapy in advanced HER2(-) G/GEJ adenocarcinoma. Cadonilimab (10 mg/kg, IV, D1, Q3W) plus AK117 (45mg/kg, IV, D1, QW or 45mg/kg, IV, D1, Q3W) and Oxaliplatin (130 mg/m2, IV, D1, Q3W) and Capecitabine (1000 mg/m2, po, bid, D1-14, Q3W) were administered until disease progression or unacceptable toxicity. The primary endpoints were safety (CTCAE ver. 5.0) and objective response rate (ORR) by RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate (DCR), time-to-response (TTR), progression-free survival (PFS) and overall survival (OS). Results: From Aug 4,2022 to Jan 13, 2023, 16 pts with advanced or metastatic G/GEJ adenocarcinoma were enrolled. Median age was 64 years (range 44-71), 75% male, 88% had ECOG 1, 100% with metastases (75% pts with≥2 metastatic organs), and 25% pts with signet ring cell carcinoma component. Median follow-up time was 2.6 months. The incidence of treatment-related adverse events (TRAEs) was 43.8% (7/16), ≥grade 3 TRAEs occurred in 25% (4/16) pts including 18.8% (3/16) G3 and 6.3% (1/16) G4, respectively. 6.3% (1/16) pts experienced TRAEs leading to discontinuation. The most common TRAEs (incidence≥10%) were anaemia, pyrexia and vomiting. Of 8 response-evaluable pts (had at least one post-baseline response evaluation) treated with Cadonilimab+AK117 (45mg/kg D1,QW)+XELOX, the ORR by investigator was 75% (6 PRs), tumor shrinkage exceeding 50% was observed in 5 pts (62.5%). The DCR was 100% (8/8), and the median DoR was not reached. The trial is ongoing, and additional data will be presented. Conclusions: The study of Cadonilimab combined with AK117 and chemotherapy demonstrated tolerable safety profile and encouraging anti-tumor activities in pts with unresectable locally advanced or metastatic HER2(-) G/GEJ cancer. Clinical trial information: NCT05235542 .
Effect of overexpression of ERK1/2 and MDR1 on chemoresistance in advanced gastric cancer patients.
Authors: Ghosh Sushmita , Pal Ranita , Mistry Tanuma , Sahoo Pranab Kumar , Mahata Sutapa , Sarkar Sinjini , Choudhury Trisha , Banerjee Raya , Chakrabarti Jayanta , Mukherjee Kalyan Kusum , Alam Neyaz , Mandal Syamsundar , Nasare Vilas 
Published: June 2023

e16051 Background: Gastric cancer (GC) is late diagnosed disease with a poor prognosis. The emergence of multidrug resistance (MDR) increases the disease burden, and treatment failure in the patients. Several molecular and circulating biomarkers have been identified and evaluated for the clinical relevance in the management of gastric cancer. The aim of this study is to decipher the involvement of ERK1/2 and MDR1 in relation to MDR phenotype and major clinicopathological characteristics in gastric cancer patients. This will help to select effective drug combinations to improve the treatment success rate. Methods: This study recruited 64 individuals with newly diagnosed gastric cancer between 2019 and 2022. Patients were recommended for surgery or neoadjuvant chemotherapy (NACT). NACT group treated with docetaxel (60 mg/m2), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), and 5-fluorouracil (2,600 mg/m2 as a 24 hr infusion), all given on day 1 and administered every 2 weeks before surgery. Based on CECT report, patients were categorized as responders (CRs), partial responders (PRs), and non-responders (NRs). Tissue and blood samples were analyzed for ERK1/2 and MDR1expression using IHC, immuno-blotting and qRT-PCR analyses. Rhodamine123 (Rh123) accumulation assay and flowcytometry was performed to measure the degree of resistance among patients. Descriptive statistics, and Pearson’s Chi-square test was carried out to evaluate the expression distribution of ERK1/2 and MDR1. Results: Out of 64 patients, between the ages of 41-60 (53.08±10.51), 54.5% have ≥5 cm tumor size in the antrum site (56.1%) and diagnosed with stage III (56.1%). Majority of observations were intestinal type (60.6%) with lymphovascular invasion (71.2%). Among all 29.4%, 20.6% and 50.0% were CRs, PRs, & NRs respectively and 36.5% patients underwent NACT. The IHC scoring analysis revealed 25 (37.9%) & 18 (28.6%) individuals for ERK1/2 and 18 (27.3%) and 26 (39.4%) individuals for MDR1 had moderate to strong expressions respectively. Simultaneously, the expressions were highly significant with tumor site (antrum), tumor size (≥5 cm), wall thickening (radiological finding), signet ring cell carcinoma, grade 3, stage III (T3N2), NRs, lymphovascular, peritoneal and serosal invasions (p=0.000). ERK1/2 was more prevalent in diffuse type patients (p=0.000). Also, protein and mRNA level for both genes were more pronounced in NACT group (p<0.005). Flowcytometry showed FLOT receivers had lower Rh123 accumulation, indicating MDR1overexpression (11.5± 8.9) compared to baseline (49.5 ±38.3). The Pearson χ2 test revealed positive correlation between ERK1/2 and MDR1 (p=0.000). Conclusions: ERK1/2 and MDR1 found to over-express in stage III, predicts the degree of resistance and MDR phenotype in the GC patients.
The mutational landscape of circulating cell free DNA in patients with gastric cancer.
Authors: Qian Yan , Cai Shirong , Zhu Dandan , Zhou Junfeng , Guo Jia , Zhao Shuhua , Chen Shifu , Sheng Shihou 
Published: June 2023

e16055 Background: Gastric cancer (GC) is a malignant tumor with a high lethality rate, with the highest incidence occurring in China. Gastric cancer is phenotypically heterogeneous, therefore the identification of genomic alteration is crucial for guiding clinical treatment. In this study, we aimed to use liquid biopsies to detect somatic mutations of GC patients and describe the mutational landscape of circulating tumor DNA. Methods: The blood samples of 157 Chinese patients with gastric malignancies were collected between 2018 to 2022. Somatic alterations were detected by either whole exome sequencing or high-depth targeted gene panel sequencing of ctDNA, using white blood cells as germline DNA control. Results: In our cohort, 1002 alterations of 323 genes were detected from plasma samples. We used MutSigCV tool to define the significantly mutated genes (SMG) and identified 16 SMG. Overall, the five most common mutated genes were TP53 (52.6%), LRP1B (15.4%), ARID1A(14.7%), SYNE1(12.2%), CDH1(10.9%). Recurrent mutations were identified in TP53 genes including c.524G > A, c.713G > T, which lead to loss of function of P53 protein according to evidence of clinical actionability from OncoKB (http://oncokb.org/). Genetic amplification of ERBB2 was detected in 8 patients (5.1%). 6 out of 95 samples were microsatellite instability (MSI), 3 were MSI-H and 3 were MSI-L.The median blood tumor mutation burden (bTMB) of all samples was 1.97 (range 0–143.51) mutations/Mb, 2 patients (1.27%) to high bTMB (≥ 20 mutations/Mb), 37 patients (23.57%) to intermediate bTMB (5-19 mutations/Mb), 118 patients (75.16%) to low bTMB ( < 5 mutations/Mb). The Co-occurrence and mutual exclusivity of gastric cancer variations was investigated. Mutually exclusive mutation patterns were observed in TP53-KRAS (p < 0.05), TP53-ARID1A (p < 0.05), TP53-CDH1 (p < 0.05) gene pairs. In addition, Gene Ontology (GO) and KEGG analysis were performed to analyze enrichment of somatic mutated genes and understand their biological function. The altered signaling pathway included PI3K−Akt signaling, MAPK signaling, Ras signaling, Rap1 signaling etc. 61 genes with somatic mutations were enriched to PI3K–Akt signaling pathway. Conclusions: In this study, we characterized the somatic mutational landscape of gastric cancer in 157 Chinese patients utilizing ctDNA which might guide clinical treatment.
Identification of FEN1 as a prognostic marker and novel therapeutic target in gastric cancer harboring TP53 mutations.
Authors: Deng Ting 
Published: June 2023

e16057 Background: As a common tumor suppressor gene, TP53 gene mutation leads to persistent activation of multiple downstream effectors that drive the cancer phenotype. Approximately 50% of gastric cancer (GC) patients harbor TP53 mutations, which confer stronger tumor biology and shorter overall survival (OS). Given that TP53-mutated proteins have proven difficult to target directly, identifying genes that function closely with TP53 and targeting these genes appears to be a promising therapeutic strategy for TP53-mutated GC patients. Methods: TP53 functionally sensitive genes were identified by evaluating the correlation between gene-dependent scores from CRISPR knockout screens and TP53 mRNA expression in TP53 mutant GC cell lines in the Cancer Cell Line Encyclopedia (CCLE) database. If the correlation coefficient is ≥0.6, the gene was considered as TP53 functional sensitive gene. Then TP53 functionally sensitive genes associated with prognosis were screened out in The Cancer Genome Atlas (TCGA). PockDrug-Server was used to predict drug susceptibility of candidate genes. Results: The results showed that in 9 GC cell lines with TP53 mutations and 14 with TP53 wild-type, 4 genes (KLF5, FEN1, CCNA2, CCNB1) were identified as TP53 functional sensitive genes. Among the 4 genes, only FEN1 expression was significantly correlated with OS (HR=1.85, 95CI 1.06−3.26, P=0.029). Multivariate Cox regression analysis showed that high FEN1 expression was an independent predictor of prognosis in TP53-mutated GC. Pocket druggability prediction analysis presented that FEN1 had 8 drug-able pockets, four of which all have a druggability score of 0.8 or higher, including one pocket with a score of 1. Conclusions: These findings suggested that FEN1 was promising prognostic marker and therapeutic target in TP53-mutated GC.
A risk-scoring prognostic model of gastric cancer based on angiogenesis.
Authors: Wu Chen , Li Shuai , Hou Xinfang , Luo Su-xia 
Published: June 2023

e16058 Background: Gastric cancer (GC) is a worldwide malignancy that represents a serious threat to human health. However, there is a lack of research on prognostic signatures of angiogenesis and prognosis, immune cell infiltration, and individualized treatment guidance in GC. Methods: Based on NCBI and MsigDB, Angiogenesis-related genes (ARGs) were obtained, and GO and KEGG enrichment analysis were performed. The risk scoring model was constructed by screening ARGs prognosis-related genes through a single-factor COX regression model, combined with Lasso regression to remove redundant factors. The prognostic value was assessed by combining TCGA and GEO databases. Immune infiltration difference analysis was performed. Furthermore, the variability of mutations was analyzed, and CNV differential display was performed. The predictive efficacy for immunotherapy was assessed by analogy to the melanoma immunotherapy suppression data from the GEO. The predictive efficacy of the TIDE assessment risk score for immunotherapy was additionally assessed. Finally, independent prognostic factors of risk scores were analyzed and a nomogram was construction. Results: We finally obtained 575 ARGs, and GO annotation showed that they were associated with angiogenesis, cell migration movement and ligand receptor activity. KEGG showed that it was related to Ras, MAPK and PI3K pathways. A risk score model containing 9 genes was constructed. It was found that the evaluation had a good prognostic value. Analysis of immunoinfiltration differences showed that there were differences. In addition, there was some variability in mutations between the high-risk and low-risk subgroups. It was found to have a better predictive effect of immunotherapy. TIDE assessment risk score was also a good predictor of immunotherapy efficacy. Finally, a nomogram was constructed based on clinical characteristics and risk scores. Conclusions: In this study, a prognostic risk score model for gastric cancer was established, and it was found to have a good predictive effect on immunotherapy effect.
Intratumoral heterogeneity as a predictive biomarker in immunotherapy for advanced esophageal cancer.
Authors: Chen Jingde , Hai Yanan , Bao Wenfang , Chen Chen 
Published: June 2023

e16059 Background: Previous studies have shown that the acquired resistance to anti-cancer therapy is largely due to intratumoral heterogeneity (ITH), thus leading to unfavourable prognosis. As known, there is no comprehensive research using ITH as a biomarker to predict the efficacy of immunotherapy in advanced esophageal cancer (ESCA) patients. Methods: Bioconductor R package Maftools was used to analyze somatic variants of advanced ESCA from MSK-IMPACT-1611 study cohort (PMID: 30643254) with data from 39 patients. We then used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH score and analyzed the difference in the genetic profile between the ITH score high (ITH-H) and ITH score low (ITH-L) groups, the association with tumor mutational burden (TMB), and the effect of ITH on the prognosis of immunotherapy. Results: There were significant differences in gene mutation spectrum between ITH-H and ITH-L groups. The genes with the highest mutation frequency in ITH-H group were TP53 (93.75%), CDKN2A (37.5%), PREX2 (31.25%), PTPRD (25%), ALK (18.75%), ERBB4 (18.75%), and KMT2D (18.75%), while the genes with the highest mutation frequency in ITH-L group were TP53 (69.57%), CDKN2A (21.74%), PIK3CA (21.74%), APC (17.39%), ARID1A (17.39%), LATS1 (17.39%), and RNF43 (17.39%).There was significant difference in median overall survival (mOS) between ITH-L and ITH-H groups (not reach versus 5 months, hazard ratio (HR) = 3.96, 95%CI 1.02−15.39, P = 0.034). There was no significant difference in median TMB levels between ITH-L and ITH-H groups (7 Muts/Mb versus 8 Muts/Mb, P = 0.09). The TMB high (TMB-H) patients had no significantly better mOS than the TMB low (TMB-L) group (HR = 0.27, 95%CI 0.06−1.26, P = 0.072). A pooled analysis of ITH and TMB show that mOS in the ITH-L+ TMB-H group was significantly better than that in the ITH-L+TMB-L, ITH-H+TMB-H, and ITH-H+TMB-L group (HR = 2.03, 95%CI 0.06−7.69, P = 0.002). Conclusions: The results suggest ITH is a predictor of ESCA immunotherapy efficacy independent of TMB.
Personalized circulating tumor DNA (ctDNA) analysis in predicting residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma (ESCC).
Authors: Liu Zhichao , Yang Yang , Liu Jun , Zhang Hong , Yu Hong , Han Yuchen , Fu Xiao-Long , Zhang Hao , Xiang Jianxing , Chen Songan , Li Xi , Zhu Mingjun , Li Zhigang 
Published: June 2023

e16062 Background: For ESCC patients who receive nCRT, high pathological complete response (pCR) rates could be achieved. A “Watch and Wait” strategy has been proposed for patients with clinical complete response (cCR) after nCRT. However, clinical assessments would inevitably misclassify non-pCR as cCR. We previously showed that ctDNA analysis with tumor-naïve fixed panel could improve the prediction of cCR. This study further investigates the value of personalized ctDNA analysis in predicting tumor response and residual disease after nCRT in ESCC. Methods: This is a side study of the prospective, diagnostic preSINO trial (NCT03937362). After completion of nCRT, patients underwent one or two clinical response evaluations (CREs) before planned surgery. CRE‐1 was 4–6 weeks after nCRT. CRE‐2 was 10–12 weeks after nCRT for patients without histological evidence of residual tumor at CRE-1. Individual tumors and matched white blood cells at baseline (B0) were whole-exome sequenced and somatic mutations were identified. Serial plasma samples were analyzed by brPROPHET tracking up to 50 somatic mutations at three timepoints: B0, CRE-1, CRE-2. This assay was developed to detect residual disease with a limit of detection of 0.004% and sample-level specificity of greater than 99% in the analytical validation. Residual disease was also detected and quantified through TNFP in the same samples for a head-to-head comparison. We correlated post-nCRT ctDNA status with pCR and major locoregional residual disease (MLRD) (>10% residual cancer or any residual nodal disease). Results: At this interim analysis, 55 ESCC patients (stage III, 87%) who received per-protocol treatments had sufficient sample to test ctDNA. The pCR rate was 27 % (15/55). 98% (2918/2966) of variants selected for patient-specific panel design were private to a specific patient, only 3% (92/2966) of variants were included in the fixed panel. After nCRT, ctDNA was detected by brPROPHET prior to nCRT in 100% of samples (n=55), significantly higher than that by TNFP assay (73%, 40/55). ctDNA was detected in 55% (30/55) of patients at CRE-1, 43% (10/23) at CRE-2. Importantly, the brPROPHET achieved higher sensitivity than TNFP in predicting non-pCR and MLRD owing to its ability to detect extremely low ctDNA fractions (to 1.14 x 10-5). Moreover, combining brPROPHET with CREs could further improve the sensitivity. Conclusions: Personalized ctDNA analysis can supplement the clinical assessment to decrease the false negative rate in identifying patients with residual disease after nCRT, and might become useful in the “Watch and Wait” strategy for the management of ESCC. Clinical trial information: NCT03937362 . [Table: see text]