Optimized PD-L1 scoring of gastric cancer

Abstract

Background PD-1/PD-L1-Immunotherapy has been approved for gastric carcinoma. PD-L1 assessment by immunohistochemistry is the principle biomarker. Are biopsies able to map the actual PD-L1 status of the entire tumor? Methods Whole tumor slides of 56 gastric carcinoma were analyzed to determine the distribution of PD-L1 positive cells in the entire tumor areas. Tissue micro arrays with four cores of the tumor surface, which represents the endoscopically accessible biopsy zone, were built from the same tumors. The PD-L1 CPS value was determined separately for each core. Preoperative diagnostic biopsies were available for 22 of the tumors. PD-L1 prevalence, sensitivity and specificity were analyzed using the whole tumor slides as reference scores. Molecular subtyping was performed and related to the PD-L1 status. Results 27.3% of cases were PD-L1 negative (CPS < 1), 43.6% showed low PD-L1 expression (CPS ≥ 1 to < 5), 12.7% moderate (CPS ≥ 5 to < 10) and 16.4% strong expression (CPS ≥ 10). The biopsies showed best test characteristics if four surface biopsies were analyzed combined, i.e., the CPS was calculated across all four biopsies. The prevalence showed a distribution similar to the resection specimens, sensitivity was 0.73 and specificity 1.0. Using fewer surface biopsies decreased sensitivity and specificity and caused false-negative classifications. Compared to the TMAs, the preoperative biopsies showed reduced sensitivity (0.412). Conclusions This is the first comprehensive study to optimize PD-L1 assessment in gastric cancer using endoscopically available tissue. The obtained PD-L1 prevalence is consistent with data of current clinical studies. Calculation of the test characteristics shows that surface biopsies can be indicative of the true PD-L1 status based on the resection specimen. However, an adequate number of biopsies is required. In this study, n = 4 biopsies yielded best results.

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“…Although the consensus on PD-L1 positivity is lacking in NEN, CPS 1 is considered a cutoff value for ICI treatment in gastric cancers, cervical cancers, and head and neck squamous cell carcinomas [ 42 , 43 , 44 ]. As we classified, regarding the cases based on the PD-L1 CPS 1, the PD-L1 CPS ≥ 1 subgroup showed significantly higher intra-tumoral, stromal, and combined TIL densities, compared to the PD-L1 CPS < 1 subgroup (intra-tumoral TIL: 7.13/mm 2 (2.89–17.18) vs 2.95/mm 2 (1.62–6.44), p < 0.001; stromal TIL: 200.9/mm 2 (97.12–432.24) vs 120.5/mm 2 (69.14–257.16), p < 0.001; combined TIL: 86.7/mm 2 (47.06–201.31) vs 56.1/mm 2 (33.81–110.12), p = 0.004) ( Figure 3 ).…”

Combined Positive Score for Programmed Death Ligand-1 Expression and Inflammatory Microenvironment in Gastrointestinal Stromal Tumors

“…This method was developed after studies had shown that TPS alone is not a useful predictive biomarker for treatment response and MIDS is not easily reproducible, although it is useful. These two methods combined proved to be a robust and reproducible modality for scoring PD-L1 in tumors [ 16 , 25 ].…”

Inhibition of MACC1-Induced Metastasis in Esophageal and Gastric Adenocarcinomas

“…The approval of trastuzumab for Her2Neu-expressing tumors and nivolumab as a checkpoint inhibitor for PD-L1-expressing tumors were big advantages in the treatment of AGE/S in recent years [ 30 , 31 ]. Unfortunately, only a few patients are eligible for these new therapy options: the predictive biomarker Her2Neu is expressed in approximately 18% of AGE/S tumors [ 32 ], and about 28% of gastric cancer are eligible for checkpoint inhibition by having a sufficient PD-L1 expression with a combined positive score >5 [ 33 ]. In all published patient cohorts, about 60% of the population were MACC1-positive, and in our study, 79% were positive.…”