Comprehensive Analysis of Clinicopathological and Molecular Features to Predict Anti-PD-1-Based Therapy Efficacy in Patients with Advanced Gastric Signet Ring Cell Carcinoma

Abstract

Background: Signet ring cell carcinoma (SRCC) is a specific type of gastric cancer. The clinicopathological and molecular characteristics that can be used to predict the response to anti-PD-1 therapy for these patients are still not clear. Methods: Patients with advanced SRCC who received first-line anti-PD-1-based treatment were enrolled in this study. The clinicopathological characteristics of these patients were obtained from their medical records. The molecular features of these patients were analyzed by means of a next-generation-sequencing-based panel. The predictive significance of clinicopathological and molecular features for efficacy was analyzed. Results: A total of 71 patients with measurable lesions were included in this study, among which 46 patients had enough tissues for next-generation sequencing. The overall objective response rate (ORR) was 46.4%. ORR was significantly higher in mismatch repair (MMR)-deficient (dMMR) patients than in MMR-proficient (pMMR) patients, in patients with lymph node metastasis only than those with other metastasis sites, and in patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 than with a PS of 1 or 2. The progression-free survival was significantly longer in patients with dMMR, lymph node metastasis only, PD-L1 combined positive score (CPS) ≥ 5, and CDH1 wild type. Conclusions: Several clinicopathological and molecular features are associated with anti-PD-1 treatment efficacy in SRCC, which might be used to identify patients who can benefit most from these therapies.

PD-L1 has a heterogeneous and dynamic expression in gastric cancer with implications for immunoPET

“…The low sub-nanomolar K d value associated with avelumab suggests that [ 89 Zr]Zr-DFO-avelumab can detect lower concentrations of PD-L1 compared to [ 89 Zr]Zr-DFO-atezolizumab. This difference in K d values aligns with previous research findings, which reported a 5-fold increase in the K d value for radiolabeled atezolizumab when compared to avelumab ( 7 , 28 , 34 ). The superior binding affinity of avelumab may explain its enhanced uptake in our preclinical models of gastric cancer.…”

“…Several biomarkers, ranging from tumor mutation burden and PD-L1 expression to microsatellite instability and Epstein–Barr virus infection status, have been proposed as potential indicators for identifying susceptibility to PD-1/PD-L1 inhibitors in gastric cancer ( 7 , 8 ). However, the outcomes of several clinical trials utilizing these biomarkers at an individual level exhibit inconsistency and, in some instances, even contradiction ( 9 – 11 ).…”

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“…The low sub-nanomolar K d value associated with avelumab suggests that [ 89 Zr]Zr-DFO-avelumab can detect lower concentrations of PD-L1 compared to [ 89 Zr]Zr-DFO-atezolizumab. This difference in K d values aligns with previous research findings, which reported a 5fold increase in the K d value for radiolabeled atezolizumab when compared to avelumab (7,28,34). The superior binding affinity of avelumab may explain its enhanced uptake in our preclinical models of gastric cancer.…”

“…Several biomarkers, ranging from tumor mutation burden and PD-L1 expression to microsatellite instability and Epstein-Barr virus infection status, have been proposed as potential indicators for identifying susceptibility to PD-1/PD-L1 inhibitors in gastric cancer (7,8). However, the outcomes of several clinical trials utilizing these biomarkers at an individual level exhibit inconsistency and, in some instances, even contradiction (9)(10)(11).…”