Microsatellite Instability, Epstein–Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer

Yu, Hung-Yuan; Li, Chung–Pin; Huang, Yi Hsiang; Hsu, Shih-Kuang; Wang, Yen‐Po; Hsieh, Yu Chi; Fang, Wen-Liang; Huang, Kuo Chin; Li, Anna Fen–Yau; Lee, Rheun‐Chuan; Lee, Kang-Lung; Wu, Yuan‐Hung; Lai, I-Rue; Yang, Wen‐Hsien; Hung, Yi‐Ping; Wang, Yuchao; Chen, Shuhui; Chen, Ming-Huang; Chao, Yee

doi:10.3390/cancers14010218

Cited by 17 publications

(11 citation statements)

References 33 publications

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“…CheckMate-649 enrolled 1581 GC patients, and first-line nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0.71, P < 0.0001) and PFS (HR 0.68, P < 0.0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more; moreover, additional results showed that the OS and PFS benefits were retained in patients with CPS ≥1% (HR = 0.77, P < 0.0001; HR = 0.74, retrospectively) [ 57 ]. Yu et al also found that MSI-H, EBER, and CPS are meaningful biomarkers for predicting the efficacy of immunotherapy, and combined biomarkers could differentiate better PFS ( P = 0.01) in patients with GC [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Prevalence of Epstein–Barr Virus Infection and Mismatch Repair Protein Deficiency and the Correlation of Immune Markers in Tibetan Patients with Gastric Cancer

Shi

Yang

Wang

et al. 2022

BioMed Research International

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Background. Gastric cancer (GC) is a major cause of cancer-related death in China. Immunotherapies based on PD-1/PD-L1 inhibitors have improved the survival of some patients with GC. Epstein–Barr virus (EBV) infection, mismatch repair (MMR) deficiency, and tumor immune microenvironment (TIME) markers (such as CD3, CD8, and PD-L1) may help to identify specific patients who will respond to PD-1/PD-L1 inhibitors. Considering racial heterogeneity, the pattern of TIME markers in Tibetan patients with GC is still unclear. We aimed to identify the prevalence of EBV infection and the MMR status and their association with immune markers in Tibetan GC to aid in patient selection for immunotherapy. Materials and Methods. From 2001 to 2015, we retrospectively collected 120 tissue samples from consecutive Tibetan GC patients and constructed tissue microarrays. EBV infection was assessed by Epstein–Barr-encoded RNA (EBER) in situ hybridization, and MMR protein levels were measured. Immune markers (including CD3 and CD8) in intraepithelial, stromal, and total areas were detected by immunohistochemistry (IHC). PD-L1 expression was assessed by the combined positive score (CPS). We also analyzed the relationships of EBV infection and MMR status with immune markers. Results. Of the 120 samples, 11 (9.17%) were EBV positive (+), and 6 (5%) were MMR deficient (dMMR). PD-L1 CPS ≥1% was found in 32.5% (39/120) of Tibetan GC patients. EBV infection was associated with higher numbers of CD3+ T cells ( P < 0.05 ) and CD8+ T cells ( P < 0.05 ) and higher PD-L1 expression ( P < 0.05 ). For the limited number of dMMR patients, no significant relationship was observed between dMMR and TIME markers ( P > 0.05 ). Conclusions. In Tibetan GC patients, the rates of EBV infection, dMMR, and positive PD-L1 expression were 9.17%, 5%, and 32.5%, respectively. EBV infection was associated with the numbers of CD3+ T cells and CD8+ T cells and PD-L1 expression within the tumor. These markers may guide the selection of Tibetan GC patients for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Prevalence of Epstein–Barr Virus Infection and Mismatch Repair Protein Deficiency and the Correlation of Immune Markers in Tibetan Patients with Gastric Cancer

Shi

Yang

Wang

et al. 2022

BioMed Research International

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“…22,23 Immunotherapy produced a durable response in selective gastric cancer cases. 24 Thus, immunotherapy may be a treatment of choice for patients with GASC, particularly for those with a high positivity rate of prediction markers in the tumor.…”

Section: Discussionmentioning

confidence: 99%

Immunoprofile of adenosquamous carcinoma in gastric cancer

Lai

Teng

et al. 2023

Journal of the Chinese Medical Association

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Background: Gastric adenosquamous carcinoma (GASC) is a rare subtype of gastric cancer. Research on GASC treatment is limited, and its outcome is usually poor. We investigated the clinical features, immunoprofile of GASC, and determined the optimal treatment modality for these patients. Methods: Patients with GASC from Taipei Veterans General Hospital were retrospectively reviewed. Clinical features and treatment outcomes were evaluated. Adequate samples were examined for surrogate biomarkers for immunotherapy by IHC staining. Results: Total 14 (0.35%) GASC patients were found among 4034 gastric cancer patients. The median tumor size was 6.8 cm in 10 patients with stage III GASC, and all these patients underwent radical gastrectomy followed by adjuvant therapy. The median progression-free survival (PFS) and overall survival (OS) were 6.0 and 11.5 months, respectively. Two patients with stage IV GASC received frontline immunotherapy. Their median PFS and OS were 9.0 and 12.5 months. In immunoprofiling, 25.0% (n = 3), 75.0% (n = 9), and 33.3% (n = 4) of the samples had deficient mismatch repair (dMMR) protein, combined positive score (CPS) of ≥1, and CPS of ≥10, respectively. The univariate analysis revealed that programmed death-ligand 1 ≥5% (HR: 0.12; 95% CI: 0.01-0.97; p = 0.047) was significant associated with superior OS. One stage IV patient with CPS ≥10 and dMMR proteins received nivolumab monotherapy as frontline treatment that resulted 14-month PFS. Conclusion: Patients with GASC are more likely to yield positive results for CPS and dMMR. Biomarkers should be examined, and immunotherapy can be considered as frontline systemic treatment.

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“…Immunotherapy is approved in selected cases of gastric cancer, but the correlation between biomarkers and prognosis is still unclear ( 29 ). Several potential predictive biomarkers have been identified in some exceptional responders with gastric cancer, such as PD-L1, HER2, MMR, and EBER ( 1 , 30 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic characteristics and clinical response to immunotherapy targeting programmed cell death 1 for patients with advanced gastric cancer with liver metastases

Liang

Huang

et al. 2022

Front. Immunol.

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BackgroundThe specific efficacy of immunotherapy for patients with liver metastases of gastric cancer is unclear. This study set out to explore the treatment response and related prognostic factors for patients with liver metastases of gastric cancer treated with immunotherapy.Patients and methodsThis retrospective cohort study included 135 patients with unresectable advanced gastric cancer. According to the presence of liver metastases and/or first-line treatment with immunotherapy, patients were divided into the following three groups: I-LM(-) group(patients without liver metastases treated with immunotherapy, n=66), I-LM(+) group(patients with liver metastases treated with immunotherapy, n=36), C-LM(+) group(patients with liver metastases treated with chemotherapy and/or target therapy, n=33). Cox regression analyses were used to identify factors associated with survival in all patients and the three groups, respectively.ResultsFor the patients with liver metastases treated with immunotherapy, multivariate analysis showed that only the presence of peritoneal metastases was significantly associated with shorter PFS [hazard ratios (HR), 3.23; 95% CI, 1.12-9.32; P=0.030] and the patients with peritoneal metastases had shorter median PFS than patients without peritoneal metastases(3.1 vs 18.4 months; P=0.004), while the objective response rate was 100% in patients with HER2-positive (2 complete radiographic responses and 2 partial responses; 3 of 4 patients were still ongoing benefits [median follow-up time, 15.3 months ; interquartile range(IQR), 6.3-17.9 months]).ConclusionsThe findings suggest that patients with various types of gastric cancer liver metastases respond differently to immune checkpoint inhibitors, HER2-positive patients may derive clinical benefits from immune checkpoint inhibitors, while the presence of peritoneal metastases is associated with resistance.

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Microsatellite Instability, Epstein–Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer

Cited by 17 publications

References 33 publications

Prevalence of Epstein–Barr Virus Infection and Mismatch Repair Protein Deficiency and the Correlation of Immune Markers in Tibetan Patients with Gastric Cancer

Prevalence of Epstein–Barr Virus Infection and Mismatch Repair Protein Deficiency and the Correlation of Immune Markers in Tibetan Patients with Gastric Cancer

Immunoprofile of adenosquamous carcinoma in gastric cancer

Prognostic characteristics and clinical response to immunotherapy targeting programmed cell death 1 for patients with advanced gastric cancer with liver metastases

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