bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of hypoxic status on survival and therapeutic responses in gastric cancer.
Authors: Dai Chan , Duan Xiaohong , Yang Chunyan , Zhou Qiming , Pei Zhihua , Wang Dongliang , Fang Yueyu
Published: June 2023

e16003

Background: As a significant factor of tumor microenvironment (TME), hypoxia is closely related to cancer metastasis, immune escape and drug resistance. The potential prognosis of hypoxia, as well as its influence on the TME, and therapeutic response have not yet been comprehensively studied in gastric cancer (GC). Here, we developed a prognosis risk assessment model (hypoxia_pred model) based on genes related to hypoxia, and further explored the exact role an impact of hypoxia in GC. Methods: Clinical information and gene expression profile were obtained from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). 375 patients from TCGA-STAD cohort were used as training set. A 21-hypoxic genes expression dataset from TCGA-STAD was performed an unsupervised clustering analysis for different molecular subtypes of GC. Genes associated prognosis were screened by univariate Cox analysis with a cutoff of pvalue＜0.05. The prognostic risk model based on 9-genes transcriptome data of both hypoxia and prognosis related genes was constructed by Least Absolute Shrinkage and Selection Operator regression analysis. Another two gene expression datasets including 409 patients from GEO (GSE62254 and GSE26901) were employed for verifying the forecast performance of this model. In addition, we used ESTATE and single sample Gene Set Enrichment Analysis (ssGSEA) to explore tumor immune infiltration and potential molecular mechanism of hypoxia in GC. We also evaluated the influence of hypoxia on the prognosis, targeted therapy and immunotherapy of GC patients by survival analysis, targeted drug sensitivity analysis and the assessments of the Cancer Immunome Atlas database. Results: We found hypoxia_pred model is a valuable predictor for the survival of GC in validation cohort (AUC > 0.7). AUC for 1- and 3-year overall survival of GC patients in the TCGA cohort were 0.71 and 0.73. In GC, it was supposed that the aggravation of hypoxia was accompanied by the increase of immune rejection phenotype and the infiltration of immunosuppressive cells. In the validation set, patients predicted high risk by the model have worse immunotherapeutic response and prognosis, and may profit from drugs that inhibit cell cycle signaling pathways. In addition, the outcomes by hypoxia_pred for changes in TME, efficacy of immunotherapy and drug sensitivity were quite hypoxia_pred. targeted drug sensitivity, immune microenvironment, biological function, immunotherapeutic response, and immune cell infiltration were found to be significantly different in those molecular subtypes and risk groups. Conclusions: The model based on hypoxic environment provides theoretical foundation for predicting tumor prognosis and clinical treatment, and may improve the prognosis of GC patients by recommending personalized immunotherapy.
Efficacy and safety of second-line treatment for advanced gastric cancer: A network meta-analysis of randomized controlled trials.
Authors: Ma Xiaoting , Yang Lin
Published: June 2023

e16018

Background: To evaluate the difference of curative effect between different treatment regimens in patients with advanced gastric cancer (AGC) who have previously received fluorouracil based first-line chemotherapy. Methods: We searched PubMed, PMC and EMBASE databases for published randomized controlled trials (RCTs). The number of people who reached the objective response rate (ORR) and the hazard ratio (HR) and its 95% confidence interval (CI) of progression-free survival (PFS) and overall survival (OS) were extracted. R (version 4.0.5) and R Studio were used to conduct meta-analysis of relevant data based on the Bayesian framework. Gemtc software package facilitates statistical analysis. To provide a ranking for each treatment regimen, surface under the cumulative ranking curve (SUCRA) was calculated. Survival analysis was conducted based on WinBUGS 14. STATA17.0 was used to draw the network diagram and funnel plot. Results: A total of 17 RCTs were included in this meta-analysis, and a total of 15 treatment regimens were used in the second-line treatment of AGC. There was no publication bias or other bias in the studies. Ramucirumab combined with paclitaxel and nab-paclitaxel weekly regimens have obvious advantages in efficacy and safety. Among them, ramucirumab combined with paclitaxel (83.6%) has great advantages in ORR, while the probability of anemia (36.6%) and anorexia (22.7%) is low, and the probability of leucopenia (66.6%) is high. However, the ORR of nab-paclitaxel weekly regimen (71.4%) is only second to that of ramucirumab combined with paclitaxel, and the probability of anemia (46.3%) and anorexia (44%) is also low, and the probability of leucopenia (53.8%) is high. In terms of OS and PFS, ramucirumab combined with paclitaxel has the best effect according to the probabilistic settlement table. Pembrolizumab and 5-Fu have poor therapeutic effects in terms of PFS. Conclusions: Ramucirumab combined with paclitaxel and nab-paclitaxel can significantly improve the survival outcome of patients with AGC. The effect of ramucirumab combined with paclitaxel is significantly better than that of paclitaxel, and the effect of nab-paclitaxel is only second to that of ramucirumab combined with paclitaxel. The safety of multi-drug combination should also be carefully considered. These findings may help clinicians better choose the second-line treatment strategy for patients with AGC.
Predictors of resistance to trastuzumab deruxtecan (T-DXd) in esophagogastric adenocarcinoma (EGC).
Authors: Tsai Charlton , Chou Joanne F. , Biachi de Castria Tiago , Tang Laura H. , Ilson David H. , Ku Geoffrey Yuyat , Schultz Nikolaus , Capanu Marinela , Janjigian Yelena Y. , Maron Steven Brad
Published: June 2023

e16024

Background: In DESTINY-Gastric01/02, T-DXd improved objective response rates (ORR) and overall survival (OS) relative to chemotherapy in patients (pts) with trastuzumab-refractory HER2+ EGC. We sought to identify clinicopathologic features that predict response and resistance to T-DXd, in a cohort from Memorial Sloan Kettering Cancer Center (MSKCC). Methods: Demographics of pts with HER2+ (HER2 IHC 3+ or IHC 2+/FISH+) advanced EGC at MSKCC treated with T-DXd in 2nd line or later (2L+) from 2017 to 2022 were reviewed via the medical record. Progression-free survival (PFS) and OS were calculated from T-DXd initiation to event or last follow up. Univariate (UV) and multivariable (MV) analyses of PFS were performed using Cox proportional hazards models. Categorical comparisons used the χ2 or Fisher’s exact test when subgroup n < 5. Results: 57 pts received 2L+ T-DXd (25 2L, 18 3L, 14 4L+). Median age at treatment was 64.5 years and most pts were male (74%) and white (82%) with primary tumors in the esophagus/GE junction (72%) and HER2 IHC 3+ expression (82%). With median follow up of 12 months (mos), ORR was 49% with median PFS (mPFS) of 5.4 mos (95% CI 3.2 – 6.8) and median OS (mOS) of 13 mos (95% CI 8.5 – 19). Pts with HER2 IHC 2+ EGC had lower ORR (30% vs 53%, p = 0.3) and inferior PFS compared to IHC 3+ in UV analysis (HR 2.58, 95% CI 1.08 – 6.13 mos, p = 0.03). Pts with HER2 retesting (n = 22) within 1 mo prior to T-DXd had higher ORR (64% vs 40%, p = 0.08); HER2 IHC in 4 of these pts decreased from 3+ to 2+. Despite irinotecan (irino) ORR of 38% prior to T-DXd in 8 pts, only 1 (12%) had OR to T-DXd. Furthermore, only one of the 12 pts (8%) who received irino following T-DXd had OR to irino, despite T-DXd ORR of 42% among these pts. Irino-treated pts also had worse PFS on T-DXd (vs no prior irino, HR 4.91, 95% CI 2.09 – 11.5 mos, p < 0.001). Prior checkpoint inhibition was not associated with PFS on T-DXd. In MV analysis, prior irino therapy remained significantly associated with progression/death (HR 4.12, 95% CI 1.63 – 10.4 mos, p = 0.003), and not HER2 IHC 2+ (vs 3+) nor 3L+ treatment (vs 2L). Additional correlations with genomic alterations will be presented. Conclusions: Consistent with DESTINY-Gastric trials, approximately half of pts with EGC at MSKCC had OR to T-DXd with mOS > 1 year. However, our real-world findings suggesting lower ORR in patients with sequential T-DXd and irinotecan-containing therapy and those without pre-T-DXd HER2 IHC confirmation merit further validation in future studies.
Efficacy and safety of camrelizumab combined with apatinib in the treatment of advanced gastric cancer: Preliminary results from a multicenter, prospective study.
Authors: He Yifu , Hu Bing , Liu Ke , Cheng Xiaofei , Cheng Huaidong , Chen Mo , Hu Changlu , Li Chenghui , Mei Xinkuan , Liu Jianfeng , Liu Hu , Wang Gang , Li Hongxia , Zhang Dingqing , Luo Huiqin
Published: June 2023

e16035

Background: There is an urgent need to find new therapeutic drugs/regimens for advanced gastric cancer. Camrelizumab combined with apatinib and chemotherapy has shown a high objective response rate and survival benefit in the first- and second-line treatment of advanced gastric cancer. Therefore, we conducted a prospective, observational study to analyze the efficacy and safety of camrelizumab combined with apatinib and chemotherapy in the first- and second-line treatment of advanced gastric cancer. Methods: This was a multicenter, observational study enrolling patients aged ≥ 18 years with an ECOG PS of 0-2 and pathologically or histologically confirmed advanced gastric cancer. Results: By January 9, 2023, 207 patients with advanced gastric cancer from 32 centers were enrolled. Most patients were male (138 [66.7%]), stage IV (151 [72.9%]), and ECOG PS of 1 (145 [70.0%]) with a median age of 66 years. The degree of differentiation was mainly moderate and low (155 [74.9%]). 109 patients (52.7%) had a surgical history of the primary lesion, 123 (59.4%) had previously received chemotherapy, and 115 (55.6%) had received COVID-19 vaccine. The first-line treatment included camrelizumab plus chemotherapy for 4-6 cycles followed by apatinib in 68 patients (32.9%), and camrelizumab plus chemotherapy and apatinib in 51 (24.6%). Second-line treatment included camrelizumab plus apatinib for 35 patients (16.9%), chemotherapy and apatinib for 44 (21.3%), and other treatments for 9 (4.3%). Clinical efficacy was evaluated in 52 patients. There were 20 patients with partial response, 26 with stable disease, and 6 with progressive disease. The overall objective response rate (ORR) was 38.46% and disease control rate (DCR) was 88.46%. The ORR and DCR in the first-line setting were 50.00% and 100.00%, and ORR and DCR in the second-line setting were 16.67% and 66.67%. Furthermore, the ORR was 40.63% and the DCR was 90.63% in patients vaccinated against COVID-19 compared to 40.00% and 85% in unvaccinated patients. The median PFS and OS have not been reached. The incidence of adverse events (AEs) was 80.4% and the incidence of grade≥3 AEs was 3.5%. The most common AEs were reactive cutaneous capillary endothelial proliferation (71.3%), nausea (51.0%), leukocyte reduction (38.46%), and hypertension (13.3%). Conclusions: In this real-world study of gastric cancer, the first-line treatment showed good efficacy, suggesting early administration with combination treatment may bring more benefits to the patients. Additionally, COVID-19 vaccination did not affect the efficacy of combination treatment. Further validation of these preliminary results is warranted. Clinical trial information: ChiCTR2200059650 .
Effect of MDSC-targeted TFF2-MSA with PD-1 blockade therapy in advanced gastric cancer models.
Authors: Qian Jin , Ryeom Sandra , Daugherty Bruce L , Lederman Seth M. , Wang Timothy C.
Published: June 2023

e16037

Background: Recent studies revealed chemotherapy increases anti-PD1 response of gastric cancer (GC) by reducing myeloid-derived suppressor cells (MDSCs). However, a more specific MDSC-targeted treatment is needed to further improve anti-PD1 efficacy in advanced GC. Trefoil factor family 2 (TFF2), a partial agonist of CXCR4 and a secreted anti-inflammatory peptide, can suppress MDSC expansion. Here, we developed a novel MDSC-targeted peptide TFF2-MSA and investigated whether it can synergize with anti-PD1 in syngeneic GC mouse models. Methods: Murine serum albumin (MSA) was fused to murine TFF2 to generate TFF2-MSA peptide with an extended serum half-life. ACKP (Atp4b-Cre; Cdh1-/-; LSL-KrasG12D; Trp53-/-) GC cells developed from a highly malignant diffuse GC mouse model were grafted subcutaneously into HDC-GFP transgenic mice in which the immunosuppressive histidine decarboxylase (HDC)-expressing myeloid cells were traced with GFP. These recipient mice then received either TFF2-MSA or anti-PD-1 antibody or both when tumors reached 150 mm3. At the endpoint, flow cytometry analysis was performed to examine immune profiles. In parallel, a group of the s.c. tumor bearing mice were followed up for survival differences in response to the treatments. In the orthotopic model, ACKP-luc cells were implanted to stomach submucosa, and recipient mice received the same treatments started after 1 week. In the metastasis model, subcutaneous flank tumors were resected in ACKP-grafted mice once tumors reached 500 mm3 to permit spontaneous lung metastasis, and mice then received the same treatments. Results: While either TFF2-MSA or PD-1 antibody showed little benefit as a single agent (TGI 15% and 25% respectively, p>0.05), their combination dramatically suppressed ACKP s.c. tumor growth (TGI 78%, p<0.0001) and markedly prolonged median survival (64 days vs. 32.5 days in control) in a synergistic manner. The combination therapy efficiently reduced tumor HDC-GFP+ MDSCs by 67%, and profoundly increased tumor-infiltrating cytotoxic CD8+ T cells by 18 fold. The myeloid/lymphoid progenitor and output ratio in the bone marrow were decreased by the combination, to a similar level of tumor-free mice. While standard chemotherapy (5-fluorouracil and oxaliplatin) showed no efficacy, adding chemotherapy to the combination further improved treatment efficacy (TGI 91%) and extended median survival to 73 days. In addition, in the orthotopic model, the TFF2-MSA/PD-1 antibody combination eradicated GC in 80% mice without recurrence compared to 0% with either monotherapy. Finally, the combination of TFF2-MSA/PD-1 antibody significantly reduced 80% lung metastasis (vs. control, p<0.0001), compared to minimal inhibition with either monotherapy (p>0.05). Conclusions: Targeting MDSCs using TFF2-MSA synergizes with PD-1 blockade therapy in advanced and metastatic syngeneic mouse models of gastric cancer.
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]
Short-term locally advanced gastric cancer management: A cost-effectiveness analysis.
Authors: Prasath Vishnu , Quinn Patrick L. , Arjani Simran , Li Sharon , Oliver Joseph B. , Mahmoud Omar Mee , Jaloudi Mohammed , Hajifathalian Kaveh , Chokshi Ravi
Published: June 2023

e16065

Background: Across the nation, patients with locally advanced gastric cancer (LAGC) are managed with modalities including upfront surgery (US), neoadjuvant chemoradiation therapy (NCRT), and perioperative chemotherapy (PCT). Treatment modalities themselves are associated with adverse effects which can lead to difficulty with treatment adherence in the short-term. As preoperative therapies have demonstrated survival benefits over US, long-term outcomes are expected to vary, but it is not known if differences in adherence impacts short-term treatment outcomes. We sought to perform a decision analysis comparing costs and quality-of-life associated with short-term outcomes in the treatment of patients with LAGC to identify the most cost-effective option. Methods: We designed a decision tree model to investigate the survival and costs associated with the three utilized management modalities for T2 or higher gastric cancer in the United States: US, PCT, and NCRT. The tree described costs and treatment strategies over a six-month time horizon to incorporate the complete treatment regimen and various treatment failure points encountered during therapy. Costs were derived from 2022 Medicare reimbursement rates using the third-party payer perspective for physicians and hospitals. Effectiveness was represented using quality-adjusted life months (QALMs). One QALM equates to one month of perfect health, while zero QALMs is equivalent to death. One-way, two-way, and probabilistic sensitivity analyses were utilized to test the robustness of our findings. Results: PCT was the most cost-effective treatment modality for LAGC over US and NCRT with a cost of $40,792.16 with 4.14 QALMs. US had a cost of $55,575.57 with 4.20 QALMs. NCRT was dominated by the other options with a cost of $56,510.64 with 3.70 QALMs. Across 100,000 Monte-Carlo simulations, 55.2% of trials favored PCT and the remainder favored US (44.8%). NCRT was not favored in the probabilistic sensitivity analysis. Finally, one-way and two-way sensitivity analyses did not identify any situations where alternative treatment modalities were preferred over PCT. Conclusions: In our simulated patients with diagnosed gastric cancer, the most cost-effective treatment strategy was PCT. This further confirms the preference of this modality over others in LAGC. While US demonstrated improved QALMs over PCT, the associated cost was too great to justify the benefits. [Table: see text]
Comparison of multi-omics biomarkers via liquid biopsy in early detection of gastric cancer.
Authors: Wang Xuefei , Tang Zhaoqing , Wang Yanan , Yang Jinyu , Shi Zhongyi , Liu Dan , Zhou Qiaoxia , Xu Yu , Qiu Fujun , Gu Yuan , Min Lingqiang , Ding Chen , Zhou Peng , Sun Yihong
Published: June 2023

e16066

Background: Effective and convenient early detection methods are still lack for gastric cancer. Liquid biopsy, by detecting cell-free DNA (cfDNA) methylation, circulating tumor DNA (ctDNA) mutation, and serum protein markers etc., may provide a non-invasive method to early detect cancer. However, head-to-head comparison of these biomarkers have not been studied. Here, we report the results of the Assessment of Early-Detection Based on Liquid Biopsy in Gastric Cancer (ASCEND-GASTRIC, NCT05224596), a case-control study to early detect gastric cancer via cfDNA methylation, ctDNA mutation, and pre-specified serum protein markers. Methods: Blood samples from gastric cancer patients were prospectively collected from the Department of General Surgery of Zhongshan Hospital, Fudan University. Blood samples from age-matched healthy controls were also prospectively collected. Blood samples were subjected to a methylation panel of ~490,000 CpG sites sequenced by the ELSA-seq, a mutation panel of ultra-deep sequenced 168 genes, and tumor protein assays. All blood samples (cancer, n=134; healthy control, n=330) were randomly assigned into the training and the test sets. Results: In the training set, cfDNA methylation and ctDNA mutation efficiently discerned cancer patients from healthy controls, while the commonly used protein markers of gastric cancer were not significantly higher in the cancer patients than in the healthy controls. In the test set, cfDNA methylation achieved 65.6% sensitivity (95% confidence interval [CI], 52.5%‒77.1%) at 96.8% specificity (95% CI, 89.9%‒100%), while ctDNA mutation exhibited lower sensitivity of 16.5% (95% CI, 9.1%‒26.5%) at 95.9% specificity (95% CI, 86.0%–99.5%). On top of the methylation-based model, the mutation-based model slightly increased sensitivity (70.7%; 95% CI, 57.3%‒81.9%) at the cost of reduced specificity (91.8%; 95% CI, 80.4%‒97.7%). Conclusions: In this study, cfDNA methylation exhibited better effectiveness than ctDNA mutation and serum protein markers in the early detection of gastric cancer. Based on cfDNA methylation, ctDNA mutation might not further provide value for the detection of gastric cancer. Our study highlights the potential clinical utility of the methylation-based early detection model for gastric cancer. A further expanded validation study is ongoing. Clinical trial information: NCT05224596 . [Table: see text]
A phase 2 study of modified chemotherapy plus pembrolizumab as perioperative therapy for stage II/IIIA esophageal squamous cell carcinoma.
Authors: Yang Bo , Xiong Qi , Song Qi , Hou Xiaobin , Wang Zhanbo
Published: June 2023

e16081

Background: Immunotherapy plus chemotherapy has shown benefits for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal dose, administration interval, and sequence between chemotherapy and immune checkpoint inhibitor are still elusive. In this study, we prospectively analyzed the efficacy and safety of modified chemotherapy followed by anti-programmed cell death protein 1 as perioperative therapy for stage II/IIIA ESCC. Methods: Patients with stage II/IIIA esophageal squamous cell carcinoma were eligible for this study. The patients were treated with 2 cycles of attenuated nab-paclitaxel and cisplatin (180-220mg/m2 for nab-paclitaxel, 60 mg/m2 for cisplatin) on day one and pembrolizumab (200 mg for patients weighted ≥60kg or 100 mg for patients weighted <60kg) delayed on day five every 3 weeks. Subsequently, the patients received surgery four to six weeks after the second cycle treatment followed by 2 more cycles of treatments. The primary endpoints were major pathological response rate (MPR), and the second endpoints were pathological complete response rate (pCR), DFS, safety, R0 resection rate, and OS. The last follow-up time was January 31st, 2023. Results: A total of 23 patients were enrolled in our study and received whole 4 cycles of perioperative treatment. Of the whole patients, the mean age was 57.5. The median follow-up time was 19.2 months (range: 4.1-30.1). All patients underwent surgery and received R0 resection after 2 cycles of neoadjuvant attenuated chemotherapy plus delayed pembrolizumab. Down-stage was achieved in 9 of 21 (42.8%) patients with confirmed stage pre- and post- surgery. The MPR rate was 43.5%, and pCR rate was 26.1%. Up to the last follow-up, 1 patient reported death due to brain metastases, and 4 patients experienced disease progression. The median DFS and OS were not reached. The rates of one-year DFS and OS were 88.2% (15/17) and 94.4% (17/18) respectively. 21 patients (95.5%) reported treatment-related adverse events (TRAEs), most of which were grade 1-2. Two patients reported grade 3 leukopenia, and 1 patient reported grade 4 elevated transaminases and discontinued immunotherapy after surgery. The most common TRAEs were nausea (59.1%), rash (36.4%), asthenia or fatigue (31.8%), and leukopenia (27.3%). Conclusions: Our study suggested that modified nab-paclitaxel and cisplatin followed by delayed pembrolizumab as perioperative treatment was effective and well tolerated for locally advanced ESCC. Clinical trial information: ChiCTR2000034925 . [Table: see text]