PD-L1 is an independent prognostic predictor in gastric cancer of Western patients

Böger, Christine; Behrens, Hans‐Michael; Mathiak, Micaela; Krüger, Sandra; Kalthoff, Holger; Röcken, Christoph

doi:10.18632/oncotarget.8169

Cited by 259 publications

(319 citation statements)

References 30 publications

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“…Several studies have demonstrated that PD-L1 immunoexpression is heterogeneous in GC, as in other tumour models. PD-L1 overexpression is associated with high densities of CD3+ and CD8+ tumour-infiltrating lymphocytes [67][68][69], GC with lymphoid stroma morphology [70], and both an EBV+ and MSI-high molecular status [69,[71][72][73][74]. However, the correlation with PD-L1 amplification, prognosis, and response to targeted immunotherapies is still debated and deserves further study.…”

Section: Moving Towards Molecular Subtyping and Precision Medicinementioning

confidence: 99%

Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

Gullo

Carneiro²,

Oliveira³

et al. 2017

Pathobiology

108

103

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Gastric cancer (GC) represents a global health concern. Despite advances in prevention, diagnosis, and therapy, GC is still the third leading cause of cancer mortality worldwide, with more than 720,000 estimated deaths in 2012. Overall survival for advanced disease is about 1 year, a dismal prognosis that is partly due to the high levels of biological heterogeneity found in GC. Indeed, GC is a highly heterogeneous disease from morphological and molecular standpoints. The numerous histological and molecular classifications currently available reflect such heterogeneity. Although recent high-throughput studies cluster the molecular data obtained into subgroups with clinical relevance, we still need a practical, prognostic, and predictive classification system, integrating morphological and molecular features, towards the identification of novel therapeutic targets. It is noteworthy that GC heterogeneity encompasses not only interpatient variability (intertumour heterogeneity), but also variations within the same tumour (intratumour heterogeneity). The latter encompasses spatial heterogeneity (in different tumour areas) and temporal heterogeneity (along progression from primary to recurrent and/or metastatic disease). In this review, we analyse the morphological, immunophenotypic, and molecular heterogeneity in GC as the basis for a better understanding of the disease, and discuss the practical implications for diagnostic pathology, prognostic evaluation, and precision therapy.

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Section: Moving Towards Molecular Subtyping and Precision Medicinementioning

confidence: 99%

Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

Gullo

Carneiro²,

Oliveira³

et al. 2017

Pathobiology

108

103

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“…PD-L1 has been detected in the tumor microenvironment of GCs including tumor cells, stromal and immune cells. The largest gastro-esophageal cancer cohort reported, to date, examined PD-L1 expression in 465 German gastric/gastro-esophageal junction (GEJ) cancer cases by immunohistochemistry (IHC) (antibody E1L3N clone, Cell Signaling) (27). The following expression patterns were found:…”

Section: Pd-1/pd-l1 Pathwaymentioning

confidence: 99%

“…In both studies, PD-L1 tumor-cell positivity had an association with favorable overall survival that was either statistically significantly (27) or trended toward significance (28). However, other investigations in gastro-esophageal cancer have reported an adverse association between PD-L1 expression and survival (30)(31)(32)(33)35,36).…”

Section: Pd-l1 Expression In Gastro-esophageal Tumorsmentioning

confidence: 99%

The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

Jin

Yoon

2016

J. Gastrointest. Oncol.

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Preliminary clinical studies of anti-programmed cell death-1 (anti-PD-1) therapy in gastroesophageal cancers have suggested promising single-agent activity. In patients who received prior treatment for advanced disease, pembrolizumab has been associated with a response rate of 20% in programmed cell death-1 ligand 1 (PD-L1)-positive tumors, and nivolumab with a response rate of 12% in unselected tumors.Both agents yielded a median duration of response lasting ~6-7 months. PD-L1 expression and microsatellite instability (MSI) have emerged as potential predictive markers for PD-1/PD-L1 blockade. PD-L1 expression in tumor cells and in immune cells within the tumor microenvironment has been detected in 14-24% and ~35% of patients with gastro-esophageal cancer, respectively. PD-L1 tumor cell expression appears to be more common in Epstein-Barr virus (EBV)-positive gastric cancers (GCs) and has been associated with an increased density of tumor-infiltrating lymphocytes (TIL). To date, data are too sparse to determine whether PD-L1 expression predicts efficacy of anti-PD-1 therapy in gastro-esophageal cancer, but data from other tumor types have not been consistent regarding its predictive value. MSI occurs in 10-20% of gastro-esophageal cancers and arises from deficient mismatch repair (MMR). MSI is highly correlated with non-synonymous mutation burden, as well as a dense accumulation of TILs. MSI has been associated with improved response to anti-PD-1 therapy in gastrointestinal cancers. Multiple studies are ongoing which examine therapeutic blockade of the PD-1/PD-L1 axis in unselected patients with gastro-esophageal cancer, as well as patients whose tumors express PD-L1 or exhibit MSI. These studies will clarify their activity in this disease and potentially can determine whether identify a strong predictive biomarker can be identified.Checkpoint inhibition is also being studied in combination with curative-intent chemo (radio) therapy and surgery.Keywords: Programmed cell death-1 (PD-1); programmed cell death-1 ligand 1 (PD-L1); gastro-esophageal cancer; microsatellite instability (MSI)

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“…A molecular classification was proposed, which categorizes four subtypes, i.e., Epstein–Barr-virus-associated (EBVa), microsatellite instable (MSI), chromosomal instable (CIN) and genomically stable (GS) GCs 2 , 3 . Two of the four molecular subtypes, EBVa and MSI GC, are significantly associated with an increased PD-L1 expression and are thereby suggested to be particular suitable for an immune checkpoint therapy 4 . Moreover, MSI GCs are characterized by a high-mutational load, which is associated with a better response to anti-PD-1/PD-L1 immune checkpoint therapies in several tumor entities 5 .…”

Section: Introductionmentioning

confidence: 99%

The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: A future perspective for a combined gastric cancer therapy?

et al. 2017

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A combined blockade of V-domain Ig suppressor of T-cell activation (VISTA) and PD-1 is a promising new cancer treatment option, which was efficient in murine tumor models and is currently tested in first phase I studies. Here, we analyzed the VISTA expression in a large and well-characterized gastric cancer (GC) cohort on 464 therapy-naive GC samples and 14 corresponding liver metastases using immunohistochemistry. Staining results were correlated with clinico-pathological characteristics, genetic alterations and survival. VISTA expression in tumor cells was detected in 41 GCs (8.8%) and 2 corresponding liver metastases (14.3%). Moreover, VISTA expression in immune cells was observed in 388 GCs (83.6%) and 6 liver metastases (42.9%). VISTA expression was associated with the Laurén phenotype, tumor localization, Epstein–Barr virus infection, KRAS- and PIK3CA-mutational status and PD-L1 expression. There was no significant correlation with patient outcome. Moreover, a change of VISTA expression in immune cells during tumor progression was observed. The co-incidence of VISTA and PD-L1 expression indicates a dual immune evasion mechanism of GC tumor cells and makes GC an interesting target for novel combined immune checkpoint inhibitor treatments.

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PD-L1 is an independent prognostic predictor in gastric cancer of Western patients

Cited by 259 publications

References 30 publications

Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1

The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: A future perspective for a combined gastric cancer therapy?

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