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alone, the oncolytic virus therapy talimogene laherparepvec “T-VEC”, or other immunotherapies,
targeting therapies, or chemotherapies. Investigation into whether or not these drugs with or without some
combinations improve GC prognosis is the next possible step.

Although molecular targeted therapy and immunotherapy have been already accepted based on phase III
trials, many clinical trials have resulted in negative results. Some possible specific problems in GC exist.
First, GCs have heterogeneous characteristics with diverse histological types and genotypes . A previous
[49]
study revealed associations between histological subtypes and germline mutations. Furthermore, infection
with Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV) has been shown to promote carcinogenesis
in GC. The frequencies and association with H. pylori, EBV and GC or cancer control including prevention
of these infections differed in each country and the conditions of these infections might affect the results of
clinical trials. Based on this knowledge, development of a global consensus for gastritis with these infections
has begun . In recent years, The Cancer Genome Atlas (TCGA) analyzed many DNA alternations of GC
[50]
and proposed four GC subtypes: EBV-infected tumors, microsatellite instability (MSI) tumors, genomically
stable tumors, and chromosomally unstable tumors, at the molecular levels . In addition, EBV-infected
[51]
tumors are associated with high PD-L1 expression, and high MSI tumors are associated with high response
rates to immunotherapies in other types of solid tumors [51,52] . Especially, MSI tumors have been reported to
be possibly associated with sensitivity toward immune checkpoint blockade, regardless of the cancer tissue’s
origin . Therefore, GC subtypes or tumor mutation must also be evaluated as a predictor of response to
[53]
targeted therapy and immunotherapies.

Second, no established biomarkers exist to select optimum patient groups in GC treatment. Accordingly,
discovery of useful biomarkers in GC treatment in previous clinical trials has not been reached. As
aforementioned, in CRC, significant clinical benefits have been gained from selecting treatment methods
based on genetic mutation as a predictive biomarker of response to targeted therapy, such as KRAS
mutation. Therefore, identifying reliable biomarkers to accurately select patients would lead to selection of
best treatment for each personalized tumor, implementating personalized medicine.

To overcome such problems, new technology such as miRNA, lncRNA which considered potential biomarker
or to regulate GC progression at the transcript or transcript level has also been developed . Although these
[54]
researches are still in the preclinical stage, they have been expected as a solution for the recent problems.

In future, development of multidisciplinary treatment, including targeted therapy and immunotherapy, is
expected to contribute to performing individualized therapy depending on the characteristics of the GC.
Revealing each patient’s genomic, biological, and immunological condition will contribute to selecting the
most curate treatment. However, these approaches are unable to overcome our big health problem, GC.

DECLARATIONS
Authors’ contributions
The conception and design of the study: Kiyozumi Y, Iwatsuki M, Baba H
Literature search: Kiyozumi Y
Data acquisition: Kiyozumi Y, Yamashita K, Koga Y
Manuscript preparation: Kiyozumi Y, Iwatsuki M
Manuscript editing: Iwatsuki M, Yoshida N
Manuscript review: Baba H

Availability of data and materials
Not applicable.