New therapeutic options opened by the molecular classification of gastric cancer

Abstract

Gastric cancer (GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC.

Keywords: Gastric cancer; Molecular classification; Immunotherapy; Targeted therapy; Clinical trials

Core tip: A new molecular classification of gastric cancer (GC) became available after publication of three landmark studies: The Cancer Genome Atlas, “Singapore-Duke” study, and Asian Cancer Research Group, allowing patient selection for specific targeted therapy. The Epstein-Barr virus positive, microsatellite stable TP53-active or microsatellite-unstable tumors subtypes presents tumour infiltrating patterns with overexpression of PD-1, PD-L1, PDL-2. Preliminary data show high response rate to immunotherapy and open new avenues to gene therapy. Currently effective therapies for diffuse GC are lacking. Mutations in e-cadherin and Ras homolog family member A genes, or Claudin-18-ARHGAP6/26 fusions may be exploited as therapeutic targets. The only targeted therapies approved so far for chromosomal instability and microsatellite stable TP53-inactive subtypes of GC are trastuzumab and ramucirumab (HER2 and VEGFR2 inhibitors).