Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches

Abstract

Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.

Tumor immune response and immunotherapy in gastric cancer

“…MSI-H GC was proposed as a distinct subgroup of GCs by two large scale molecular studies, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group classification [65,68,69]. The incidence of MSI-H GCs varies between countries and ethnicity, ranging from 5.6 to 22.7% [65,68,[70][71][72][73].…”

Dissection of gastric cancer heterogeneity for precision oncology

“…Although significant advancement has been made in distinguishing various molecular subtypes of GC, effective translation of these GC classifiers into clinical practice continues to depend upon two major factors: (i) their execution in the diagnostic laboratory; and (ii) the therapeutic implications of the classifiers. With respect to execution, clinically used genetic or histochemical techniques already exist for the identification of EBV, MSI and ERBB2 ‐positivity, whereas stratification of other more complex and heterogeneous subtypes is more technically challenging. For example, follow‐up work of the ACRG study developed a mesenchymal subtype 71‐gene signature using the NanoString platform, which showed high concordance with the Affymetrix microarray method in identifying patients of the MSS/EMT subtype .…”

Cost-Effectiveness Analysis of Biomarker-Guided Treatment for Metastatic Gastric Cancer in the Second-Line Setting

“…MSI-H GC patients show significantly higher PD-L1 expression, compared to MSS GC patients (25.9% versus 8.4%, p � 0.003) [18,19] and accumulating data suggest improved survival and durable response to immunotherapy among patients with MSI-H status. e KEYNOTE-059 and KEYNOTE-061 trials report overall response rates (ORR) of 57.1% and 46.7%, respectively, although the numbers of MSI-H patients were small (n � 7 and n � 15, respectively) [6,10].…”