Heterogeneity of predictive biomarkers in gastric cancer with peritoneal dissemination

Background. Gastric cancer (GC) is the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Peritoneal dissemination has been described in 10-20% of all patients, and despite diagnostic and therapeutic advances it is still associated with a poor prognosis, with a median survival time of 4 months. Aim of the study. Temporal and spatial molecular heterogeneity is a well-established mechanism of resistance to targeted and immune therapy in GC, and while systemic treatments primarily address the metastatic disease, biomarker status is currently evaluated in the primary tumor. The aim of this study is to assess the differences in predictive biomarkers expression between primary GCs and paired peritoneal metastases. Materials and methods. A total of 82 cases of primary GCs and paired peritoneal metastases were analyzed by immunohistochemistry for HER2, PD-L1, Claudin18.2 (CLDN18.2), DNA mismatch repair complex (MMR) proteins, p53 and E-cadherin, and in situ hybridization for EBER. Samples with HER2 score 2+ were tested by fluorescent in situ hybridization for HER2 gene status. Results. The primary GCs of our cohort were more frequently poorly cohesive (49.4%) or mixed-type (35.4%); they showed low rates of HER2 overexpression (5.1%), MMR deficiency (3.8%), and EBER positivity (1.3%). CLDN18.2 was positive in 30.4% of cases, and PD-L1 was CPS≥1 in 78.5%. The highest discordance rate between primary GCs and paired metastases was observed for PD-L1 CPS<1/1≤CPS<10/CPS≥10 (32.4%) and CLDN18.2 (13.5%). A relatively low discordance was reported for HER2 (2.7%), E-cadherin (5.4%), and p53 (1.4%). When scoring HER2 as 0/low/high, the discordance rate increased (27.0%). All cases were concordant for MMR and EBER status. Overall, up to 20/74 patients (27.0%) were found to be eligible for further treatment following biomarker evaluation in the metastasis. Conclusions. Our data suggests that GCs with peritoneal metastases have specific morphologic features and might present clinically-relevant spatial molecular heterogeneity in the setting of peritoneal dissemination. With the introduction of novel biomarkers (i.e., HER2-low and CLDN18.2) in clinical practice, the need to address heterogeneity between primary tumors and metastases is becoming more pressing. Multisite sampling, liquid biopsy and cell blocks prepared from malignant effusions should be explored to more accurately identify patients eligible for targeted therapy, and to overcome spatial heterogeneity fueling resistance to treatments.