Abstract
Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called “precision medicine” even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions.
Highlights
During the last years, “precision medicine” has deeply changed the therapeutic landscape of several malignancies
While CDH1 and RHOA mutations are highly prevalent in the The Cancer Genome Atlas (TCGA) Genomically Stable (GS) subtype, in Asian Cancer Research Group (ACRG) MSS/EMT, these mutations are extremely rare, making these two subtypes absolutely not equivalent or synonyms. Possible reasons for this partial overlap between these classifications include differences related to the patient population (Korea in ACRG versus USA and Western Europe in TCGA), tumor sampling, and technological platforms (six different molecular platform in TCGA, versus only mRNA expression and targeted gene sequencing in ACRG)
The PI3K/AKT/mTOR pathway is a fundamental promoter of cell growth, metabolism, survival, and cell migration: it is mainly activated by cell surface tyrosine kinase receptors, but in human cancer, many component of this pathway could be affected by activating mutation (PIK3CA) or inactivating genetic events (PTEN), like gene deletion
Summary
“precision medicine” has deeply changed the therapeutic landscape of several malignancies. Trastuzumab (anti-HER2 monoclonal antibody) and ramucirumab (anti-VEGFR monoclonal antibody) have proven to be successful weapons among all of the several molecular drivers identified, but currently still lacking of any clinical utility; for these reasons, the standard systemic chemotherapy still represents a “forced” mainstay of the treatment of advanced disease. All of these efforts led to a fundamental acquisition: gastric cancer should be considered to be a collection of different molecular entities, rather than a single homogeneous disease. This review aims to critically overview the available molecular classifications and the latest findings for GC and to outline the possible future scenarios and implications of these acquisitions
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