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

Abstract

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.

Molecular Classification of Gastric Cancer among Alaska Native People

“…In our study, PD-L1 expression in immune and tumor cells was observed in 17% of AN gastric cancer patients. A PD-L1 combined positive score greater than 1 was significantly correlated with MMR deficient patients, similar to previous studies in breast [65], colorectal [66], gastric [67], and esophageal cancers [68,69]. Moreover, in gastric cancer, it has been well-known that PD-L1+ tumors frequently have PIK3CA mutations, which are also strongly associated with MSI-high and EBV+ tumors [13,59,70,71], as we observed in our cohort.…”

Neutrophil-to-lymphocyte ratio as a predictive or prognostic factor for gastric cancer treated with nivolumab: a multicenter retrospective study

“…In many studies regarding ICIs, biomarkers have been investigated. The expression of PD-L1 or PD-L2 [ 15 ], mutation burden [ 16 ], dMMR [ 17 ] are said to be associated with the efficacy of ICIs. Furthermore, the expressions of PD-L1 and PD-L2 are associated with the response to ICIs [ 15 ].…”

“…The expression of PD-L1 or PD-L2 [ 15 ], mutation burden [ 16 ], dMMR [ 17 ] are said to be associated with the efficacy of ICIs. Furthermore, the expressions of PD-L1 and PD-L2 are associated with the response to ICIs [ 15 ]. In patients with lung cancer, pembrolizumab was more effective for higher expression of PD-L1 [ 18 ].…”

“…In patients with lung cancer, pembrolizumab was more effective for higher expression of PD-L1 [ 18 ]. However, in patients with gastric cancer, the rate of positivity for PD-L1 (>1%) was only 17.3% [ 15 ]. When somatic mutation burdens of melanoma and non-small cell lung cancer were high [ 19 ], then the efficacy of ICIs was very high [ 16 ].…”

Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis

“…Also, PD-L1 expression is associated with clinical response in patients with non-squamous non-small cell lung cancer [22]. PD-L1 positivity is observed in up to 65% of GC specimens [20], and even though it is widely associated with negative features, such as tumour size, lymph node metastasis and depth of invasion, there is no consensus on the role of PD-L1 expression as a prognostic biomarker in GC [23]. While the KEYNOTE-061 trial confirmed a better outcome with pembrolizumab in patients with PD-L1-positive tumours [13] data from the JAVELIN Gastric 300 and ATTRACTION-2 trials did not support the concept of PD-L1 positivity as a predictive response marker to ICIs [14,15].…”