Clinicopathological and prognostic features of Epstein‐Barr virus infection, microsatellite instability, and PD‐L1 expression in gastric cancer

Pereira, Marina Alessandra; Ramos, Marcus Fernando Kodama Pertille; Faraj, Sheila F.; Dias, André Roncon; Yagi, Osmar Kenji; Zilberstein, Bruno; Cecconello, Ivan; Alves, Venâncio Avancini Ferreira; Mello, Evandro Sobroza de; Ribeiro, Ulysses

doi:10.1002/jso.25022

Cited by 65 publications

(59 citation statements)

References 38 publications

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“…In our study, the positive expression of PD‐L1 was observed in 37.3% cases. PD‐L1 was detected in 15% to 75% of GC patients according to previous literatures . We suppose varied antibodies, different tissue handling methods, and evaluating systems used to define PD‐L1 positivity may all lead to such a wide range of distinct expression rates.…”

Section: Discussionmentioning

confidence: 92%

Programmed death‐ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2‐negative status

Wang

Zhang

et al. 2018

Cancer Medicine

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Gastric cancer (GC) is one of the most common malignancies. Immunotherapy is a promising targeted treatment. The immune regulatory programmed death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) axis has been used as a checkpoint target for immunotherapy. Currently, considerable discrepancies exist concerning the expression status of PD‐L1 and its prognostic value in GC. We aimed to evaluate the expression rates of PD‐L1 in GC, and further assess its relationship with mismatch repair (MMR), and human epidermal growth factor receptor 2 (HER2) status. We retrospectively collected 550 consecutive cases of GC in Fudan University Shanghai Cancer Center from 2010 to 2012. PD‐L1, MMR protein, and HER2 status were detected by immunohistochemistry (IHC). Fluorescence in situ hybridization was further used in HER2 IHC 2+ cases. Cases with at least 1% membranous and/or cytoplasmic PD‐L1 staining in either tumor cells (TCs) or tumor‐infiltrating immune cells (TIICs) were considered as PD‐L1 positive. The correlation between clinicopathological parameters, HER2, MMR, and PD‐L1 expression status was determined using chi‐squared tests. About 37.3% cases (205/550) showed PD‐L1 expression in TCs and/or TIICs. 17.3% cases (95/550) showed PD‐L1 expression in TCs, 34.5% (190/550) cases showed PD‐L1 expression in TIICs. There were 45 deficient MMR (dMMR) cases (8.2%), which showed higher rates of PD‐L1 expression compared with MMR‐proficient carcinomas (60.0% vs. 35.2%, P = 0.001). HER2 was positive in 66 (12.0%) cases. The expression of PD‐L1 occurred more frequently in HER2‐negative group than HER2‐positive cohorts (39.0% vs. 24.2%, P = 0.020). The survival analysis revealed that PD‐L1 was not associated with prognosis. This study evaluated the association between the PD‐L1 expression and a specific subgroup (dMMR and HER2‐negative) in a large Asian cohort of GC. GC patients with dMMR and HER2‐negative status exhibited higher PD‐L1 expression rates. Our finding indicated that MMR and HER‐2 status might be potential biomarkers for anti‐PD‐L1 therapy.

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Section: Discussionmentioning

confidence: 92%

Programmed death‐ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2‐negative status

Wang

Zhang

et al. 2018

Cancer Medicine

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“…In an international pooled analysis, TNM stage was inversely associated with tumor EBV positivity . In the previous studies related with EBVaGC, TNM stage used was AJCC 6th in which Stage IV was defined as T4 or N3 or M1 and there was no information of metastasis status . In the TCGA data, EBVaGC accounted for 15% (3/20) metastatic GC patients among the 295 sequencing patients, which is higher than in Stage I to III patients .…”

Section: Discussionmentioning

confidence: 92%

“…12 In the previous studies related with EBVaGC, TNM stage used was AJCC 6th in which Stage IV was defined as T4 or N3 or M1 and there was no information of metastasis status. [29][30][31][32][33] In the TCGA data, EBVaGC accounted for 15% (3/20) metastatic GC patients among the 295 sequencing patients, which is higher than in Stage I to III patients. 3 However, the number of metastatic GC patients was only 20.…”

Section: Discussionmentioning

confidence: 99%

Prospective observation: Clinical utility of plasma Epstein–Barr virus DNA load in EBV‐associated gastric carcinoma patients

Qiu

et al. 2019

Intl Journal of Cancer

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Epstein–Barr virus (EBV)‐associated gastric carcinomas (EBVaGCs) may account for 8–9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV‐DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat‐sen University Cancer Center for EBER examination. We detected EBV‐DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV‐DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV‐negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3‐year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV‐DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV‐DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV‐DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.

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Section: Discussionmentioning

confidence: 99%

“…In MAGIC and CLASSIC trials MSI GC had a better prognosis irrespective of treatment received, and it is postulated that the production of new immunogenic epitopes due to the defective repair system activates peritumoral lymphocyte infiltration and systemic T cell activation, which could be downregulated by cytotoxic chemotherapy. 10,11,13 Despite the lack of benefit of POP/AD treatment for MSI and EBV tumors, another finding deserves be discussed. Patients with an aberrant p53 expression in gastric tumor cells had a pronounced benefit of POP/AD therapy in DFS (P = .001) and OS (P < .001).…”

Section: Treatment Features and Survival Outcomesmentioning

confidence: 99%

Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype?

Ramos

Pereira

Amorim

et al. 2019

Journal of Surgical Oncology

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Background Gastric cancer (GC) has been defined in distinct molecular subtypes with different therapeutic implications. However, its clinical significance and prognosis regarding standard chemotherapy (CMT) remains unclear. This study aimed to analyze the impact of perioperative or adjuvant treatment among subtypes of GC. Methods We retrospectively evaluated all stage II/III patients with GC who underwent a curative gastrectomy. Based on immunohistochemistry and in situ hybridization techniques, GC was classified into five subtypes: Epstein‐Barr virus (EBV) positive, microsatellite instability (MSI), e‐cadherin aberrant, p53‐aberrant, and p53‐normal. Results Among the 178 CG included, 111 patients received CMT and 67 were treated with surgery alone. Survival analysis showed that p53‐aberrant GC treated with CMT had better disease‐free survival (DFS) compared with surgery alone (P = .001).There was no significant difference in DFS between patients who received CMT and those with surgery alone for EBV, MSI, E‐cadherin, and p53‐normal GC. An improvement in overall survival was observed only for E‐cadherin (P = .001) and p53‐aberrant (P < .001) patients who received CMT. Conclusions CMT showed different impact on the survival of CG according to the molecular subtype. No survival benefit was observed for EBV and MSI groups who received CMT. GC with p53‐aberrant had a significant benefit in survival with standard therapy.

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Clinicopathological and prognostic features of Epstein‐Barr virus infection, microsatellite instability, and PD‐L1 expression in gastric cancer

Abstract: EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.

Cited by 65 publications

References 38 publications

Programmed death‐ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2‐negative status

Programmed death‐ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2‐negative status

Prospective observation: Clinical utility of plasma Epstein–Barr virus DNA load in EBV‐associated gastric carcinoma patients

Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype?

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