Impact of the HER2 Expression on Survival and Fluorouracil-Based Adjuvant Chemotherapeutic Benefits in Stage II/III Gastric Cancer: A Multicenter Observational Study

Gao, Xintao; Zhao, Lulu; Zhang, Nannan; Han, Wei; Liu, Kun; Yan, Junya; Chen, Ling; Pan, Yan; Li, Renlong; Li, Wenjiao; Zhang, Haohao; Li, Hongwei; Wang, Shibo; Gao, Xiaoliang; Niu, Penghui; Wang, Wanqing; Ji, Gang; Zhao, Qingchuan; Lu, Yuanyuan; Li, Zengshan; Shang, Lei; Liang, Han; Wu, Kaichun; Deng, Jingyu; Chen, Yingtai; Nie, Yongzhan; Group, MAGIS Study

doi:10.2139/ssrn.4107700

Cited by 3 publications

(3 citation statements)

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“…Notably, Gao et al. involved 5622 consecutive stage II/III GC patients and observed that HER2 overexpression was independently associated with a lower 5‐year OS in stage II, but not in stage III GC 43 . These findings together revealed that the impacts of HER2 amplification and PD‐L1 expression on prognosis in patients with GC remains controversial and should be re‐considered under different circumstances (e.g., clinical, pathological stage, genomic, transcriptomic, and immune landscapes).…”

Section: Discussionmentioning

confidence: 99%

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Jing,

Luo,

et al. 2023

Cancer Medicine

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BackgroundAnti‐PD1/PD‐L1 antibody plus human epidermal growth factor receptor 2 (HER2) antibody and chemotherapy have become the new first‐line therapy for HER2 overexpression‐positive advanced gastric cancers (GC), suggesting that HER2 and PD‐L1 play a vital role in guiding systemic treatment for patients with GC. This study aimed to depict the genomic and immune landscapes of Chinese patients with GC and investigate their correlations with HER2 amplification and PD‐L1 expression.Patients and MethodsNext‐generation targeted sequencing and PD‐L1 immunohistochemistry were performed on tumor samples from 735 patients with pathologically diagnosed GC. The genomic and immune landscapes and their correlations with HER2 amplification and PD‐L1 expression were analyzed.ResultsThe most commonly mutated genes in Chinese GC were TP53 (64%), CDH1 (20%), ARID1A (18%), HMCN1 (15%), KMT2D (11%), and PIK3CA (11%). Seventy‐six (10%) patients were HER2 amplification, and 291 (40%) had positive PD‐L1 expression. Classifying the total population based on HER2 amplification and PD‐L1 expression level, 735 patients were divided into four subgroups: HER2+/PD‐L1+ (4.5%), HER2+/PD‐L1− (5.9%), HER2−/PD‐L1+ (35.1%), and HER2−/PD‐L1− (54.5%). The HER2+/PD‐L1− and HER2+/PD‐L1+ subgroups exhibited dramatically higher rate of TP53 mutations, CCNE1 and VEGF amplifications. The HER2+/PD‐L1− subgroup also had a markedly higher rate of MYC amplification and KRAS mutations. The HER2−/PD‐L1+ subgroup had significantly higher rate of PIK3CA mutations. HER2+/PD‐L1− subgroup had the highest TMB level and HER2−/PD‐L1+ subgroup had the highest proportion of patients with microsatellite instability‐high than other subgroups. Furthermore, we observed that different HER2 amplification levels had distinct impacts on the correlations between PD‐L1 expression and therapeutic genomic alterations, but no impact on the prognosis.ConclusionThe combination of HER2 amplification and PD‐L1 expression in Chinese patients with GC could stratify the total populations into several subgroups with distinctive genomic and immune landscapes, which should be considered when making personalized treatment decisions.

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Section: Discussionmentioning

confidence: 99%

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Jing,

Luo,

et al. 2023

Cancer Medicine

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“…The clinical information of the internal populations was drawn from the Xijing Hospital of Digestive Diseases Gastric Cancer Database (XJHDDGCD). 17,18 This database contains prospectively collected clinicopathologic data, biological specimens, and follow-up information on patients who were admitted to Xijing Hospital. Tissue samples from gastric cancer patients eligible for inclusion can be randomly selected for this study.…”

Section: Data Sourcesmentioning

confidence: 99%

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

Gao,

Han,

Chen

et al. 2023

Cancer Medicine

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BackgroundBetter predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil‐based adjuvant chemotherapy benefits.MethodsCDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193).ResultsIn the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2‐negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2‐negative and CDX2‐positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5‐year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery‐only, p < 0.001), whereas patients with CDX2 positive tumors did not (pinteraction = 0.004). Consistent results were obtained in the validation and ACRG cohorts.ConclusionsNegative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression.

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“…Currently, surgery is the prime treatment for early-to mid-stage GC. For locally advanced or distant metastatic GC, surgery is combined with chemotherapy, radiotherapy, immunotherapy, and molecular targeted therapy [4][5][6] . Despite the rapid and potent effects of chemotherapy and targeted drugs, patients with GC frequently develop drug resistance over time.…”

Section: Introductionmentioning

confidence: 99%

UBR1 is a prognostic biomarker and therapeutic target associated with immune cell infiltration in gastric cancer

Wang¹,

Han²,

Wu³

et al. 2023

Preprint

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Background Ubiquitination is a targeted protein modification process mediated by intracellular molecules. UBR1 encodes a protein that binds to unstable N-terminal residues of substrate proteins and contributes to the formation of substrate-linked polyubiquitin chains. However, the cellular pathways and the function of UBR1 in tumors have received inadequate attention. Therefore, the aim of this study is to examine the potential of UBR1 as a prognostic biomarker and immunotherapy target for stomach adenocarcinoma (STAD) as well as its biological function and molecular mechanism in relation to the disease. Methods Differential expression and pan-cancer GSEA analyses were performed using TCGA, GEO and GTEx datasets. Immunohistochemical differences between cancer and paraneoplastic tissues were analyzed using the HPA database to identify pathways enriched by UBR1 in AGS cells. Besides, with the help of Kaplan-Meier curves, univariate and multivariate Cox regression, and receiver operating characteristic (ROC) curve studies, the prognostic and diagnostic roles of UBR1 can be identified and determined. The correlation between UBR1 expression and clinical parameters was predicted by using the TCGA and GEO databases. The UBR1 mutation data were retrieved from the cBioPortal database. The biological mechanisms of UBR1 were investigated using GO and KEGG enrichment analyses. TIMER and EPIC computational methods were utilized to establish the connection between UBR1 and immune infiltration. Protein expression was determined using immunohistochemistry (IHC) and Western blot analysis (WB). In regard to mRNA expression, Quantitative Real-time PCR (qRT-PCR), it was analyzed by taking advantage of Quantitative Real-time PCR (qRT-PCR). Quantitative Immunoprecipitation (IP) assays were used to detect protein-protein interactions. Cell proliferation was evaluated using CCK8 and colony formation assays. Cell invasion was determined using wound healing assays and Transwell. Apoptosis was analyzed using flow cytometry. Result UBR1 was upregulated in 28 cancer types,including STAD, and its overexpression was validated in gastric cancer cell lines and tissues. UBR1 expression was associated with advanced pathological characteristics. High UBR1 expression was linked to poor prognostic outcomes, including progression-free interval (PFI), overall survival (OS), disease-specific survival (DSS), surgery, chemotherapy, and HER2 expression. UBR1 expression was significantly correlated with clinical parameters, such as age, gender, TMN stage, pathological stage, tumor resection, and anti-reflux therapy. Amplifications and deletions were the frequent genetic alterations associated with UBR1. According to the KEGG and GSEA, UBR1 was significantly associated with several cancer pathways, oxidative phosphorylation, and the TNF-NFκB pathway. UBR1 exhibited a significant correlation with immunotherapy and immune cell infiltration, and a direct interaction with CD274. Also, the proliferation and invasion of STAD cells were inhibited due to the UBR1 knockdown, but apoptosis was promoted in a contrary way. Conclusion The results of this investigation show that UBR1 is overexpressed in STAD, promoting its progression, and positively correlates with immune cell infiltration and immunotherapeutic responses. Therefore, UBR1 could be a promising biomarker in the prognosis and immunotherapy field of STAD.

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Impact of the HER2 Expression on Survival and Fluorouracil-Based Adjuvant Chemotherapeutic Benefits in Stage II/III Gastric Cancer: A Multicenter Observational Study

Cited by 3 publications

References 32 publications

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

UBR1 is a prognostic biomarker and therapeutic target associated with immune cell infiltration in gastric cancer

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