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Microsatellite instability and Epstein-Barr gastric cancer subtypes do largely benefit from anti-PD-1 inhibition
Several trials with the check-point inhibitors pembrolizumab or nivolumab demonstrated some antitumour efficacy in chemorefractory advanced gastric cancer with a response rate ranging from 10% to 26%. However, no clear predictive biomarkers were found to facilitate a proper selection of patients. A series of 61 patients with advanced gastric cancer received second-line or third-line treatment with pembrolizumab in a prospective phase 2 trial.1 In a cooperative effort carried out by Korean and American investigators, a molecular characterisation of all tumours was performed including whole-exome sequencing and RNA sequencing of tissue biopsies, as well as circulating tumour DNA (ctDNA) from plasma. Six out of seven (85%) patients with microsatellite instability (MSI) showed very good responses (three complete and three partial responses). Moreover, all six cases with Epstein-Barr positive (EBV+) tumours showed partial responses. The only MSI case in which pembrolizumab failed was presenting heterogeneous areas with or without MLH1 immunohistochemical staining. These areas did show specific features of MSI when MLH1 positive and, in those in which MLH was lost, the biological features indicated microsatellite stability. When the rest of the six responding MSI patients were explored for this heterogeneity phenomenon, the pattern was very homogeneous in all of them and no heterogeneity at all was observed among them.
Mutational burden and PD-L1 positivity have been associated with responses to anti-PD1 antibodies in many tumour types. In gastric cancer, mutational burden is particularly high in MSI subtypes, and PD-L1 is generally overexpressed. However, the mutational burden was low in five of the six responding patients who were EBV+, indicating that EBV+ gastric tumours respond to anti-PD1 antibodies, regardless of the low mutational …
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