Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer

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Abstract

Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.

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Microsatellite instability detection by next generation sequencing.

Stephen Salipante, H Hampel, Claire E. Turner … (2014)

Microsatellite instability (MSI) is a useful phenotype in cancer diagnosis and prognosis. Nevertheless, methods to detect MSI status from next generation DNA sequencing (NGS) data are underdeveloped. We developed an approach to detect the MSI phenotype using NGS (mSINGS). The method was used to evaluate mononucleotide microsatellite loci that were incidentally sequenced after targeted gene enrichment and could be applied to gene or exome capture panels designed for other purposes. For each microsatellite locus, the number of differently sized repeats in experimental samples were quantified and compared to a population of normal controls. Loci were considered unstable if the experimental number of repeats was statistically greater than in the control population. MSI status was determined by the fraction of unstable microsatellite loci. We examined data from 324 samples generated using targeted gene capture assays of 3 different sizes, ranging from a 0.85-Mb to a 44-Mb exome design and incorporating from 15 to 2957 microsatellite markers. When we compared mSING results to MSI-PCR as a gold standard for 108 cases, we found the approach to be both diagnostically sensitive (range of 96.4% to 100% across 3 panels) and specific (range of 97.2% to 100%) for determining MSI status. The fraction of unstable microsatellite markers calculated from sequencing data correlated with the number of unstable loci detected by conventional MSI-PCR testing. NGS data can enable highly accurate detection of MSI, even from limited capture designs. This novel approach offers several advantages over existing PCR-based methods. © 2014 American Association for Clinical Chemistry.

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Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers

Sarah Derks, Xiaoyun Liao, Anna M. Chiaravalli … (2016)

Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV)+ GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-γ driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors.

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Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma.

Hye-Jong Song, Amitabh Srivastava, Jeeyun Lee … (2010)

Lymphoepithelioma-like carcinoma (LELC) is a rare subtype of gastric carcinoma (GC) with a better survival rate than other GCs; most cases of LELC are associated with Epstein-Barr virus (EBV) infection. We investigated whether the survival advantage of LELC is related to the EBV infection itself or to associated inflammatory immune responses. From 1994 to 2008, 123 EBV-associated GCs were identified and compared with 405 EBV-negative GCs. EBV-associated GCs were subclassified, based on the pattern of host inflammatory immune responses, into 3 histologic subtypes: typical LELC (n = 53, 43.1%), Crohn's disease-like lymphocytic reaction (CLR) (n = 52, 42.3%), and conventional adenocarcinoma (n = 18, 14.6%). Patients with curatively resected EBV-negative GC were controls. Univariate and multivariate analyses were used, with Bonferroni correction. Patients with EBV-associated GC had tumors of proximal location, lower N stage (P < .0001), and lower T stage (P = .02) and were older than controls (P = .0003). Upon univariate analysis, patients with EBV-associated GC had longer survival times than controls (P < .004); this difference was not significant in a multivariate analysis with Cox proportional hazards. Stratification of EBV-associated GCs by host cellular immune responses showed that patients with LELC and LELC+CLR have significantly longer overall survival time (hazard ratio, 0.09 and 0.42, respectively) and disease-free survival (hazard ratio, 0.05 and 0.46, respectively; P < .02). Prognosis of EBV-associated GCs depends on the patient's inflammatory response. The definition of LELC should be expanded to include EBV-associated GCs with CLR because these have a prognosis similar to LELC. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.