Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma

Oki, Eiji; Okano, Shinji; Saeki, Hiroshi; Umemoto, Yuichiro; Teraishi, Koji; Nakaji, Yu; Ando, Koji; Zaitsu, Yoko; Yamashita, Nami; Shimada, Masahiko; Nakashima, Yasuhiro; Ohgaki, Kippei; Oda, Yoshinao; Maehara, Yoshihiko

doi:10.1159/000479231

Cited by 36 publications

(28 citation statements)

References 38 publications

(42 reference statements)

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“…Oki et al. found a positive relation between PD‐L1 and HER2 expression. On the contrary, the current study, as well as the work of Li et al.…”

Section: Discussionmentioning

confidence: 98%

“…However, reports focusing on the correlation between PD-L1 and HER2 had conflicting conclusions. Oki et al [34] found a positive relation between PD-L1 and HER2 expression. On the contrary, the current study, as well as the work of Li et al [27] indicated PD-L1 expression was significantly associated with lower HER2 expression.…”

Section: Pd-l1 Expression In Gastric Cancermentioning

confidence: 97%

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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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“…Oki et al. found a positive relation between PD‐L1 and HER2 expression. On the contrary, the current study, as well as the work of Li et al.…”

Section: Discussionmentioning

confidence: 98%

Section: Pd-l1 Expression In Gastric Cancermentioning

confidence: 97%

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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“…Nivolumab is recommended as a third-line or later-line therapy in gastric cancer patients who are likely to have received trastuzumab. Previous reports are suggestive of the impact of anti-HER2 therapy on the expression of PD-L1 [15][16][17][18] . It was thus hypothesized that HER2 expression and/ or prior use of trastuzumab might have had some influence on the efficacy of nivolumab in the ATT RAC TION-2 trial.…”

Section: Development Of New Active Agents For Her2+ G/gej Cancer Is Wmentioning

confidence: 99%

“…The relationship between HER2 and PD-L1 expression has been assessed in a few studies recently; however, there are conflicting conclusions regarding their correlation [15][16][17][18]. In a study evaluating the expression and impact of PD-L1/PD-1 in gastric cancer in Caucasian patients, almost 50% of PD-L1+ patients were HER2+ [15].…”

Section: Introductionmentioning

confidence: 99%

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

et al. 2019

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Background Data on immune checkpoint inhibitor efficacy in patients with human epidermal growth factor receptor 2-positive (HER2+) advanced gastric/gastroesophageal junction (G/GEJ) cancer are lacking. Because HER2 status was not captured in the ATT RAC TION-2 trial, we used patients with prior trastuzumab use (Tmab+) as surrogate for HER2 expression status to evaluate the efficacy and safety of nivolumab as third-or later-line therapy in these patients. Methods In ATT RAC TION-2, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial, patients were randomized (2:1) to receive nivolumab (3 mg/kg) or placebo every 2 weeks until disease progression or toxicity requiring study discontinuation. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed. Results Of 493 enrolled patients, 81 (nivolumab, n = 59; placebo, n = 22) were Tmab+ and 412 (nivolumab, n = 271; placebo, n = 141) were Tmab−. In both groups, patients receiving nivolumab showed a longer median OS vs placebo (Tmab+, 8.3 [95% confidence interval, 5.3-12.9] vs 3.1 [1.9-5.3] months, hazard ratio, 0.38 [0.22-0.66]; P = 0.0006; Tmab−, 4.8 [4.1-6.0] vs 4.2 [3.6-4.9] months, 0.71 [0.57-0.88]; P = 0.0022). PFS was longer in both groups receiving nivolumab vs placebo (Tmab+,.0] vs 1.5 [1.3-2.9] months, 0.49 [0.29-0.85]; P = 0.0111; Tmab−, 1.6 [1.5-2.4] vs 1.5 [1.5-1.5] months, 0.64 [0.51-0.80]; P = 0.0001). Conclusions Nivolumab was efficacious and safe as third-or later-line therapy regardless of prior trastuzumab use in patients with advanced G/GEJ cancer.

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“…Thus, PD-L1 protein expression is considered a potential biomarker of prognosis and therapeutic benefit. However, in GC patients, the prognostic significance of PD-L1 protein expression in tumor cells and immune cells is still controversial [6][7][8][11][12][13][14], as is that of PD-1 [8,15] and CD8 [12,14,16] protein levels, probably because of different antibody clones, cutoff values for positivity and technical methods [6]. On the other hand, although a few studies have evaluated the association between PD-L1 mRNA levels and prognosis in GC [17,18], data acquired by mRNA analysis are quite limited.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer

et al. 2020

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Introduction: Anti-programmed cell death 1 (PD-1) therapies have shown promising clinical activity against gastric cancer (GC). We evaluated the clinical significance of immune-related gene expression in GC tissues to better understand the tumor immune microenvironment. Methods: PD-1, PD-1 ligand 1 (PD-L1) and CD8 mRNA levels and clinicopathological factors, including survival, were examined by quantitative RT-PCR in 155 GC patients who underwent surgery. PD-1 and PD-L1 expression in tumor tissue from 24 GC patients was investigated by immunohistochemical analysis. Results: PD-1, PD-L1 and CD8 mRNA levels were significantly lower in tumor tissue than in normal tissue (p < 0.0001, p < 0.05, and p < 0.0001). GC patients with low PD-1, PD-L1 and CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, PD-L1 and CD8 mRNA levels, respectively (p < 0.001, p < 0.01 and p < 0.05). Low PD-1, PD-L1 and CD8 mRNA levels were more significantly associated with poor prognosis in undifferentiated-type GC pa-tients than in differentiated-type GC patients (PD-1: differentiated p = 0.0071 vs. undifferentiated p = 0.0024; PD-L1: p = 0.6527 vs. p < 0.0001; CD8: p = 0.4465 vs. p < 0.05). Multivariate analysis showed that lymph node metastasis, peritoneal dissemination, distant metastasis, low PD-1 mRNA levels and low CD8 mRNA levels were independent prognostic factors for worse OS (low PD-1 mRNA level: OR 2.16, 95% CI 1.10-4.58, p < 0.05; low CD8 mRNA level: OR 2.55, 95% CI 1.12-6.90, p < 0.05). PD-1 and PD-L1 mRNA levels in immune cells were significantly associated with PD-1 and PD-L1 protein levels (both p < 0.05), respectively. Conclusions: PD-1, PD-L1 and CD8 mRNA levels may reflect antitumor immunity in GC, and low PD-1 and CD8 mRNA levels are potential predictive biomarkers for poor prognosis in GC patients who underwent surgery.

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Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma

Cited by 36 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

Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer

Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer

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