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DISCOVER HOW

emerging biomarkers may play a crucial role in navigating the landscape of metastatic gastric cancer.

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Despite a landscape clouded in complexity,
established and emerging biomarkers are expanding
our view of patient populations, and biomarker
testing could provide a more comprehensive patient
profile and lead to more informed decisions.

 

Exploring biomarker advancements starts here.
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WELCOME TO

The Gastric Cancer Landscape

SELECT ONE OF THE BIOMARKERS BELOW TO FIND OUT MORE

This list of gastric cancer biomarkers is not exhaustive. Other biomarkers may exist that are not mentioned on this website.

CLDN18.2=Claudin 18.2; FGFR2b=fibroblast growth factor receptor 2b; HER2=human epidermal growth factor receptor 2; MSI=microsatellite instability; PD-L1=programmed death-ligand 1.

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AN UNMET NEED

Despite recent advances, there are still critical needs to address in metastatic gastric/gastro-oesophageal junction (mG/GEJ) cancers1

 

The 5-year survival rate of gastric cancer in the Nordic countries is
between 26-36%; the overall global rate is 20-30%.1,2
A large part of the patients are diagnosed at late stages with an overall
global 5-year survival rate of 5%-10% (stages IV and III, respectively).1,2

 


In 2020, 2414 new cases of gastric cancer were diagnosed in the Nordic countries, making it the 14th* most diagnosed cancer in the Nordic countries.3
* 15th in Sweden.


In 2020, over 1 million new cases of gastric cancer were diagnosed worldwide, making it the 5th most diagnosed cancer worldwide.3


In 2020, 1708 people died in the Nordic countries due to gastric cancer, making it the 9th most deadly cancer in Finland, the 11th in Denmark and the 13th in
Norway and Sweden.3


More than 768,000 people died worldwide from gastric cancer, making it the 4th most deadly cancer worldwide.4

 

As novel biomarkers emerge, they reveal more opportunities to advance care for mG/GEJ cancer

 

EMERGING BIOMARKERS

help identify previously undefined subsets of mG/GEJ cancer patients:

  • CLDN18.2 (Claudin18.2), is a splice variant of CLDN18, a component of tight junctions and has a critical role in cell-to-cell epithelial adhesion and regulating selective barrier properties5-8
  • FGFR2b (fibroblast growth factor receptor 2b) is a splice variant of FGFR2, a transmembrane tyrosine kinase receptor associated with the signalling pathway that intermediates diverse cellular behaviours and cellular processes, such as mitogenesis, differentiation, cell proliferation, angiogenesis and invasion9,10

ESTABLISHED BIOMARKERS

are used to inform clinical decisions:

  • HER2 (human epidermal growth factor receptor 2) is a tyrosine kinase receptor associated with activation of downstream signalling that leads to uncontrolled cell-cycle progression, cell division and proliferation, motility, invasion and adhesion11
  • MSI (microsatellite instability) is characterised as somatic alterations in microsatellite sequences that are associated with genomic instability9,12
  • PD-L1 (programmed death-ligand 1) can bind to the immune checkpoint receptor PD-1 (programmed death cell protein 1), which allows tumours to escape immune surveillance13

Emerging and established biomarkers can be detected by standard IHC staining methods.

 

EMERGING BIOMARKERS

CLDN18.2:
IHC14*

FGFR2b:
IHC, NGS15,16*†

ESTABLISHED BIOMARKERS

PD-L1:
IHC17,18*‡

HER2:
IHC, ISH, NGS17–19*§

MSI/MMR:
PCR, NGS/IHC17,18*

IHC=immunohistochemistry; ctDNA=circulating tumour DNA; ISH=in situ hybridisation; MMR=mismatch repair; NGS=next generation sequencing; PCR=polymerase chain reaction.
* Expression utilises IHC and PCR tests;17,18 amplification utilises ctDNA, ISH and NGS tests.16,17,19
† IHC detects FGFR2b overexpression; NGS detects FGFR2 gene amplification by ctDNA.15,16
‡ Varying diagnostic assays.20
§ Other ISH methods (FISH=fluorescent ISH; SISH=silver ISH; CISH=chromogenic ISH; DDISH=dual-colour dual-hapten ISH).19


Emerging biomarkers are highly prevalent among mG/GEJ biomarkers.21,22
 

Biomarker prevalence estimates from select studies are reported below. Prevalence data can vary amongst studies due to tumour heterogeneity, differences in patient population, clinical trial methodology, and diagnostic assays used.11,21,22,24

EMERGING BIOMARKERS GLOBAL PREVALENCE RATES

CLDN18.2
(high expression) *†

33–36%14,21

FGFR2b
(positive)

30%22

* 2+/3+ staining by IHC in ≥70% of tumour cells. Includes locally advanced unresectable or mG/GEJ adenocarcinoma.14,21
† High expression: 2+/3+ IHC staining in ≥75% of tumour cells.21

ESTABLISHED BIOMARKERS GLOBAL PREVALENCE RATES

PD-L123,24
(Variable due to multiple factors)††

CPS ≥1: 67-73%23,24
CPS ≥5: 29-31%23,24
CPS ≥10: 16-18%23,24

HER211
(Positive)

22%11

MSI25
(MSI-high)

4–6%25,26

CPS=combined positive score.

**PD-L1 prevalence at various CPS thresholds is still being explored. Data are from a randomised controlled trial and a real-world, retrospective medical records study.23,24

 

Timeline of targetable biomarker discoveries26–33

In 2021, American Society of Clinical Oncology (ASCO) recognised molecular profiling in gastrointestinal cancer as ‘Advance of the Year’.36

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CLDN18.2
Claudin18.2

CLDN18.2 gastric cancer biomarker

CLDN18.2

CLDN18.2 is an emerging biomarker that may help you learn more about your patients with mG/GEJ cancer 8, 37

Claudins are a family of transmembrane proteins:5,34

Claudins are a major component of epithelial and endothelial tight junctions, which are involved in controlling the flow of molecules between cells.5-7

Claudins are present throughout the body, but two specific splicing isoforms of CLDN18 are localised to certain tissue types:5,34

  • CLDN18.2 is the dominant isoform in normal, healthy gastric epithelial cells5,34
  • CLDN18.1 is the dominant isoform in normal, healthy lung tissue5,34

Preclinical studies have shown that CLDN18.2 may become more exposed and accessible to antibodies as gastric tumours develop.5,38,39

CONFINED IN HEALTHY TISSUE

 

CLDN18.2 in healthy gastric epithelial cells.
CLDN18.2 in healthy gastric epithelial cells.

 

In gastric epithelial cells, CLDN18.2 is typically buried in the tight junction supramolecular complex.5,7,39

It functions to regulate selective barrier properties and contributes to cell-to-cell
epithelial adhesion.5–8

EXPOSED IN TUMOURIGENESIS

 

CLDN18.2 exposure during tumorigenesis.
CLDN18.2 exposure during tumorigenesis.

 


Malignant transformation leads to polarity disruptions and structure loss.38,39  As a result, CLDN18.2 may be more exposed and accessible to antibodies.5,38,39

RETAINED DURING TRANSFORMATION

 

CLDN18.2 presence throughout malignant transformation.
CLDN18.2 presence throughout malignant transformation.

 

The presence of CLDN18.2 is retained throughout malignant transformation, both in the primary tumour site and metastatic disease.5,38

Although not present in healthy tissues beyond gastric epithelial cells, CLDN18.2 may become activated in oesophageal, pancreatic, lung, and ovarian tumours as well.5

Detecting the presence of CLDN18.2 identifies a previously undefined patient population



While approximately 70% of locally advanced and mG/GEJ cancers express CLDN18.2 (at any level), recent studies have shown approximately 33% of mG/GEJ patients are CLDN18.2 positive (high expression).21

  • High expression: 2+/3+ IHC staining in ≥75% of tumour cells21
  • CLDN18.2 is a highly selective biomarker for G/GEJ adenocarcinoma5
  • Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers14

Few patients with locally advanced or mG/GEJ cancer who are CLDN18.2+ (high expression*) also test positive for other biomarkers.21

When evaluating the relationship between CLDN18.2 and other biomarkers, current data suggest there is limited overlap.21

  • In a real-world, mono-institutional study,†CLDN18.2+ samples were also positive for the following biomarkers:21


* High expression levels of  CLDN18.2: 2+ and 3+ intensity in ≥75% tumour cells.

† Study population was limited to 350 Caucasian patients with mG/GEJ cancer, of which 117 patients had high expression of CLDN18.2. FGFR2b was not evaluated in this study.22

CLDN18.2 is expressed in both diffuse-type tumours and intestinal-type tumours.7

  • Tumours with diffuse histology, more often seen in the UK, US and other Western countries, are associated with poorer prognosis than those with intestinal histology40,41

FGFR2b
fibroblast growth factor receptor 2b

FGFR2b gastric cancer biomarker

FGFR2b

FGFR2b is an emerging biomarker that allows identification of another distinct subset of patients with mG/GEJ cancer10

 

FGFR2b is a receptor tyrosine kinase that has a role in normal cell development42

  • FGFR2b is a member of the FGFR family and is a splice isoform of FGFR2 expressed in various types of epithelial cells where tumours may begin to grow35,43
  • FGFR signalling plays a key role in many biological processes, but it also offers important information about how cancer may develop42,44
  • FGFR2 may be associated with higher T stage (size of the tumour and any spread into nearby tissue) and higher N stage (extent of nodal metastasis)10
  • FGFR2 amplification is significantly associated with FGFR2 receptor overexpression in gastric cancer45
  • Detection of specific FGFR2 isoforms (e.g., FGFR2b) or FGF ligand overexpression may represent novel and enriching predictive biomarkers for gastric cancer46

    NORMAL CELL

In normal cells, FGFR signalling is an essential component for cell development. Deregulated FGFR2 pathway, through mutations or translocations, plays a critical role in several tumour types.46

  GASTRIC CANCER CELL





FGFR2 overexpression and up-regulated signalling may be key events in a subtype of gastric cancer. Detection of FGFR2 amplification has been the mainstay for pre-screening patients for FGFR2 receptor overexpression.46


FGFR2b is an emerging biomarker that introduces another way to identify patients with mG/GEJ cancer10

 

FGFR2b positivity can be observed in 30% of mG/GEJ cancers.22


FGFR2b positivity: overexpression (IHC) and/or gene amplification by ctDNA (NGS).

 

Detecting FGFR2b can be done with the following tests:15,16

  • FGFR2b overexpression using IHC
  • FGFR2 gene amplification by ctDNA using NGS
  • FGFR2b is a relatively new biomarker in gastric cancer and, therefore, sparse data are available regarding its overlap in expression with other biomarkers
Biomarker Biomarker Prevalence overlap Reference
FGFR2bCLDN18.2Unknown*Presently unavailable*
FGFR2bPD-L1+ Unknown†Presently unavailable†
FGFR2HER2 (3+)0.3%Su 201447
FGFR2bMSI/MMRUnknown‡Presently unavailable‡


* A PubMed search using the search terms (gastric cancer) AND (FGFR2) AND (CLDN182) produced no articles.
† A PubMed search using the search terms (gastric cancer) AND (FGFR2) AND (PD-L1) produced five articles, none of which included information pertaining to the prevalence overlap of these two biomarkers.
‡ A PubMed search using the search terms (gastric cancer) AND (FGFR2) AND (MSI) produced seven articles, none of which included information pertaining to the prevalence overlap of these two biomarkers. A search using the search terms (gastric cancer) AND (FGFR2) AND (MMR) produced two articles, neither of which included information pertaining to the prevalence overlap of these two biomarkers.



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HER2
human epidermal growth factor receptor 2

HER2 gastric cancer biomarker

HER2

HER2 was the first biomarker used to guide clinical decisions in mG/GEJ cancer9



HER2 (human epidermal growth factor receptor 2) is a receptor-tyrosine kinase that is overexpressed and/or amplified in mG/GEJ cancer.9 HER2 expression is considered a prognostic factor in gastric cancer.48

HER2 is a proto-oncogene that is involved in signalling pathways, which leads to cell growth and differentiation.19

  • Since its discovery in breast cancer, studies have shown HER2 is present in several cancers, including colorectal, ovarian, prostate, lung, gastric and gastro-oesophageal tumours19,31
  • When HER2 is overexpressed and/or amplified, it can lead to uncontrolled cell growth and tumourigenesis11

    • However, the mechanisms that lead to gene amplification remain largely unknown49
  • In normal cells, few HER2 receptors exist at the cell surface (see figure below) so few heterodimers are formed, and growth signals are relatively weak and controllable50

When HER2 is overexpressed, multiple HER2 protein receptors are formed and cell signalling is stronger, which results in enhanced responsiveness to growth factors and malignant growth.50

    NORMAL CELL

Normal cell with low HER2 protein receptor expression and few HER2 receptor heterodimers at the cell surface.50

      HER2+ CANCER CELL

 



HER2 is overexpressed and/or amplified, multiple HER2 receptor heterodimers are formed at the cell surface and cell signalling gets enhanced.50


HER2 positivity has been reported in 22% of advanced G/GEJ cancers.11


HER2 positivity: overexpression (IHC3+) and/or gene amplification (FISH-positive).


Detection of HER2 may be done with IHC, ISH methods and NGS, and is generally more associated with intestinal type tumours.11,17,19*

  • Guidelines recommend starting with IHC and following with ISH methods when expression is 2+ (equivocal)17

    • ISH methods include FISH, SISH, CISH and DDISH17,19
  • Positive (3+) or negative (0 or 1+) IHC results do not require further testing via ISH17
  • There is limited overlap between HER2 and other gastric cancer biomarkers with three studies reporting minimal overlap between HER2 and CLDN18.2
Biomarker Biomarker Prevalence overlap Reference
HER2CLDN18.212-15%Pellino 2021,21 Pellino 2019,51 Baek 201952
HER2PD-L1+7.4%Angell 201853
HER2MSI11.1%Angell 201853
HER2FGFR20.3%Su 201447

* IHC/ISH should be considered first, followed by additional NGS testing as appropriate.17

MSI
microsatellite instability

MSI gastric cancer biomarker

MSI

MSI/MMR is an established biomarker that can be found in a broad range of solid tumour types, including mG/GEJ cancer12



MSI expression is associated with genomic instability and increased susceptibility to tumour development.9

Microsatellites are repeated sequences of nucleotides in DNA.12

  • Microsatellite instability (MSI) is caused when the DNA mismatch repair (MMR) system does not function appropriately12

    • This loss prevents normal repair and correction of DNA, allowing mismatches to occur12
    • The MMR proteins are the most frequently mutated genes in cancer12
    • Tumours with ≥30% expression of unstable microsatellites are referred to as MSI-high (MSI-H)9
  • MSI is most commonly found in colorectal cancers, but it has also been detected in many other types of cancers, including gastric cancer and endometrial cancer12
  • High level MSI GCs exhibit distinct aggressive biologic behaviours and a gastric mucin phenotype54
  • The main mechanisms by which failure occurs in the MSI/MMR system are via genetic and epigenetic changes in h-MLH1 and h-MSH2, and less frequently in h-MSH6 and h-PMS255
  • Because somatic mutations in MSI GCs are common, it is difficult to pinpoint the target genes in which mutations lead to MSI gastric carcinogenesis, however, MSI tumours are more prone to exhibit mutations in the oncogenes EGFR, KRAS, PIK3CA and MLK3 55

 

    MICROSATELLITE STABLE TUMOUR

      TUMOUR WITH HIGH MSI/MMRd

 

tumour-with-high-msimmrd.png

MMRd=MMR deficiency

In genomically stable tumours, with a functional MMR system, DNA replication errors occur rarely. Conversely, in the presence of high MSI/MMRd, DNA replication errors go undetected and unrepaired, leading to a tumour with a high mutational burden. Such hyper-mutated cancer cells excessively produce mutation-associated neoantigens, which are presented by MHC molecules on the cell surface to stimulate T-cell activation and tumour infiltration by immune cells. To counteract this vigorous immune response, tumour cells expose checkpoint molecules, e.g., PD-L1, to inhibit anti-tumour activity.56,57


MSI-H/MMRd expression has been reported in 4% of mG/GEJ cancers.26


MSI-H=MSI-high.

Detection of MSI/MMR is typically assessed with various methods.4

  • MSI can be detected via PCR-based molecular testing and NGS
  • MMR protein expression can be analysed via IHC
  • There is variable overlap of MSI/MMR and other gastric cancer biomarkers; overlap of deficient MMR (dMMR) and CLDN18.2 is minimal
Biomarker Biomarker Prevalence overlap Reference
dMMRCLDN18.215%Pellino 202121
MSIPD-L1+53.2%Angell 201853
MSIHER2 (3+)4.2%Angell 201853
MSI/MMRFGFR2bUnknown*Presently unavailable*

*A PubMed search using the search terms (gastric cancer) AND (FGFR2) AND (MSI) produced seven articles, none of which included information pertaining to the prevalence overlap of these two biomarkers. A search using the search terms (gastric cancer) AND (FGFR2) AND (MMR) produced two articles, neither of which included information pertaining to the prevalence overlap of these two biomarkers.

 

PD-L1
programmed death-ligand 1

PD-L1 gastric cancer biomarker

PD-L1

Amongst biomarkers in mG/GEJ cancer, PD-L1 is one of the more recent to be utilised in clinical decision-making30

 

PD-L1 (programmed death-ligand 1) is a transmembrane protein that may be expressed on various tumour cells and/or immune cells.58

  • When bound to PD-1, PD-L1 acts as a T-cell inhibitory molecule, leading to immune cell evasion and subsequent tumour cell survival58
  • PD-L1 expression has been detected in various tumours, including lung, colon, ovarian and gastric cancers59
  • However, the cellular process of expression may not always be the same throughout the body20

    • Various studies have shown discordant levels of PD-L1 in the primary tumour versus metastatic lesions20
    • Expression levels may also vary during disease progression as PD-L1 is impacted by changes in immune response20

As the key regulator of immune tolerance and immune exhaustion, expression of PD-1 is tightly controlled: on naïve T-cells, PD-1 is only expressed in a low basal level; initial immune stimulation can induce PD-1 expression on T-cells, B-cells, macrophages and dendritic cells (see figure below). 60

  • PD-L1 overexpression in GC patients with EBV+ is primarily caused by:

    • Amplification of the CD274 gene encoding PD-L1, which increases gene copy number and leads to up-regulation of mRNA expression; methylation of the gene promoter suppresses its transcription and interferon (IFN)-γ-mediated signalling via activation of interferon regulatory factor 3 (IRF3) (see figure below)61–63

    NORMAL CELL


In normal tissues, PD-1/PD-L1 binding prevents an excessive immune response and protects tissue from damage through the induction of immune tolerance.60

      GASTRIC CANCER CELL

 



In gastric cancer, CD274 focal amplification and IFN-γ-mediated signalling can lead to PD-L1 overexpression and T-cell exhaustion.60,61

Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials: 67-73% CPS ≥1, 29-31% CPS ≥5 and 16-18% CPS ≥1023,24*†

*Study population was limited to 592 patients with locally advanced or mG/GEJ cancer who experienced disease progression after first-line therapy with a platinum and fluoropyrimidine.23

†Study analysed 56 specimens from therapy-naïve biopsies from German patients with primarily non-metastatic gastric adenocarcinoma.24

 

 

  • 5-year survival rates of patients with and those without PD-L1-positive tumours were 48.9% and 80.7%, respectively64
  • Analysis of 56 gastric carcinoma slides found 27.3% of cases were PD-L1 negative (CPS <1), 43.6% with low PD-L1 expression (CPS ≥1 to <5), 12.7% moderate (CPS ≥5 to <10) and 16.4% strong expression (CPS ≥10)24
  • The variations in prevalence may be due to several factors, such as tumour heterogeneity and clinical trial methodology (including differences in patient population, staining techniques, scoring algorithms and diagnostic assays)20,27
  • When evaluating the relationship between PD-L1 at two positivity thresholds, data suggest there is limited overlap with CLDN18.2 and HER2 with overlap higher with HER2
Biomarker Biomarker Prevalence overlap Reference
PD-L1 (CPS ≥1)CLDN18.228%Pellino 202121
PD-L1 (CPS ≥5CLDN18.220%Pellino 202121
PD-L1+HER2 (3+)3.2%Angell 201853
PD-L1+MSI53.2%Angell 201853
PD-L1FGFR2Unknown*Presently unavailable*

*A PubMed search using the search terms (gastric cancer) AND (FGFR2) AND (PD-L1) produced five articles, none of which included information pertaining to the prevalence overlap of these two biomarkers.

 

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Summary

SUMMARY

MDT working: Optimisation of biomarker testing

 

The European Society for Medical Oncology (ESMO) guidelines on the diagnosis and treatment of gastric cancer recommend screening for HER2, PD-L1 and MSI-H/dMMR.18

In the US, guidelines for mG/GEJ cancer support the use of biomarkers to help map the path forward for patients:17

  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend biomarker testing at diagnosis and comprehensive biomarker testing17


Biomarker testing provides more insight into mG/GEJ cancer as more biomarkers are being discovered:

  • Standard IHC staining methods can detect a wide range of emerging and established biomarkers

    • IHC amongst others, can detect CLDN18.2, FGFR2b, HER2, MMR and PDL-114,15,17
    • In mG/GEJ cancer, other testing methods often focus on specific biomarkers, for example: NGS for FGFR2b, ISH/NGS for HER2* and PCR/NGS for MSI15–17,19

      • *IHC/ISH should be considered first, followed by additional NGS testing as appropriate.17

  • In clinical trials, biomarker testing has revealed a high prevalence of emerging biomarkers

    • 36% of mG/GEJ cancer patients were CLDN18.2 positive (high expression)21
    • 30% of mG/GEJ cancer patients with Epstein-Barr virus–positive (EBV+) have FGFR2b positivity22
  • Prevalence of established biomarkers have been reported throughout clinical trials as:

    • HER2 positivity in 22% of advanced G/GEJ cancers11
    • MSI-H in 4% of mG/GEJ cancers26
    • PD-L1 at several positivity thresholds: 67–73% CPS ≥1, 29–31% CPS ≥5 and 16–18% CPS ≥1023,24



As biomarker research continues, it expands our view of the patient population, reveals more information about the mG/GEJ cancer landscape, and helps inform clinical decisions.

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REFERENCES

1. Casamayor M, Morlock R, Maeda H, Ajani J. Targeted literature review of the global burden of gastric cancer. Ecancermedicalscience 2018;12:883. eCollection 2018.

2. Larønningen S, Ferlay J, Beydogan H, et al (2022). NORDCAN: Cancer Incidence, Mortality, Prevalence and Survival in the Nordic Countries, Version 9.2 (23.06.2022). Association of the Nordic Cancer Registries. Cancer Registry of Norway. Available from: https://nordcan.iarc.fr/en/dataviz/survival_table?sexes=2. Accessed 14-10-2022

3. Global Cancer Observatory, International Agency for Research on Cancer 2022. https://gco.iarc.fr/today/explore. Accessed 14-10-2022

4. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209-49.

5. Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res 2008;14(23):7624-34.

6. Dottermusch M, Krüger S, Behrens HM, et al. Expression of the potential therapeutic target Claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch 2019;475(5):563-71.

7. Coati I, Lotz G, Fanelli GN, et al. Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases. Br J Cancer 2019;121(3):257-63.

8. Li J, Zhang Y, Hu D, Gong T, Xu R, Gao J. Analysis of the expression and genetic alteration of CLDN18 in gastric cancer. Aging (Albany NY) 2020;12(14):14271-84.

9. Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World J Gastroenterol 2018;24(26):2818-32.

10. Ahn S, Lee J, Hong M, et al. FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod Pathol 2016;29(9):1095-103.

11. Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 2015;18(3):476-84.

12. Baudrin LG, Deleuze JF, How-Kit A. Molecular and computational methods for the detection of microsatellite instability in cancer. Front Oncol 2018;8:621.

13. Kawazoe A, Shitara K, Kuboki Y, et al. Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer. Gastric Cancer 2019;22(1):69-76.

14. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol 2021;32(5):609-19.

15. Catenacci DV, Tesfaye A, Tejani M, et al. Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design. Future Oncol 2019;15(18):2073-82.

16. Jogo T, Nakamura Y, Shitara K, et al. Circulating tumor DNA analysis detects FGFR2 amplification and concurrent genomic alterations associated with FGFR inhibitor efficacy in advanced gastric cancer. Clin Cancer Res 2021;27(20):5619-27.

17. National Comprehensive Cancer NetworkR. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesR): gastric cancer version 2.2022 (01-11-2022). https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed 14-10-2022.

18. Lordick F, Carneiro F, Cascinu S, et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2022; 33(10):1005-1020.

19. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol 2016;22(19):4619-25.

20. Meng X, Huang Z, Teng F, Xing L, Yu J. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev 2015;41(10):868-76.

21. Pellino A, Brignola S, Riello E, et al. Association of CLDN18 protein expression with clinicopathological features and prognosis in advanced gastric and gastroesophageal junction adenocarcinomas. J Pers Med 2021;11(11):1095.

22. Ooki A, Yamaguchi K. The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer 2021;24(6):1169-83.

23 Fuchs CS, Ozgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated PD-L1-KEYNOTE-061 trial. Gastric Cancer 2022;25(1):197–206.

24. Schoemig-Markiefka B, Eschbach J, Scheel AH, et al. Optimized PD-L1 scoring of gastric cancer. Gastric Cancer 2021;24(5):1115-22.

25. Shitara K, Van Cutsem E, Bang Y-J, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol 2020;6(10):1571–80.

26. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncol 2018;4(5):e180013. Erratum in: JAMA Oncol 2019;5(4):579.

27. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398(10294):27-40.

28. Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 1984;312(5994):513-6.

29. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260(5109):816-9.

30. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192(7):1027-34.

31. Force J, Howie LJ, Abbott SE, et al. Early stage HER2-positive breast cancers not achieving a pCR from neoadjuvant trastuzumab- or pertuzumab-based regimens have an immunosuppressive phenotype. Clin Breast Cancer 2018;18(5):410–17.

32. Merok MA, Ahlquist T, Royrvik EC, et al. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol 2013; 24(5):1274–82.

33. Hashimoto I, Oshima T. Claudins and gastric cancer: An overview. Cancers 2022;14(2):290.

34. Niimi T, Nagashima K, Ward JM, et al. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol 2001;21(21):7380-90.

35. Matsunobu T, Ishiwata T, Yoshino M, et al. Expression of keratinocyte growth factor receptor correlates with expansive growth and early stage of gastric cancer. Int J Oncol 2006;28(2):307-14

36. Smith SM, Wachter K, Horward A, et al. Clinical cancera 2021: ASCO’s report on progress against cancer. J Clin Oncol 2021;39(10):1165–84.

37. Arnold A, Daum S, von Winterfeld M, et al. Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas. Clin Transl Oncol 2020;22(12):2357-63.

38. Rohde C, Yamaguchi R, Mukhina S, Sahin U, Itoh K, Türeci Ö. Comparison of Claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol 2019;49(9):870-6.

39. Türeci O, Sahin U, Schulze-Bergkamen H, et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol 2019;30(9):1487-95.

40. Bickenbach K, Strong VE. Comparisons of gastric cancer treatments: east vs. west. J Gastric Cancer 2012;12(4):262.

41. Lee JY, Gong EJ, Chung EJ, et al. The characteristics and prognosis of diffuse-type early gastric cancer diagnosed during health check-Ups. Gut Liver 2017;11(6):807–12.

42. Kurban G, Ishiwata T, Kudo M, Yokoyama M, Sugisaki Y, Naito Z. Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in human uterine cervical cancer. Oncol Rep 2004;11(5):987-91.

43. Katoh M. Cancer genomics and genetics of FGFR2 (Review). Int J Oncol 2008;33:233-237.

44. Azoury SC, Reddy S, Shukla V, Deng CX. Fibroblast growth factor receptor 2 (FGFR2) mutation related syndromic craniosynostosis. Int J Biol Sci 2017;13(12):1479-88.

45. Kim HS, Kim JH, Jang HJ, et al. Pathological and prognostic impacts of FGFR2 overexpression in gastric cancer: A meta-analysis. J Cancer 2019;10(1):20–7.

46. Hierro C, Alsina M, Sanchez M, et al. Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall? Ann Oncol 2017;28(6):1207–16.

47. Su X, Zhan P, Gavine P R, et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer 2014;110:967–75.

48. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 2008;19(9):1523–29.

49. Vicario R, Peg V, Morancho B, et al. Patterns of HER2 gene amplification and response to anti-HER2 therapies. PLoS One;10(6):e0129876.

50. Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol 2001;12(Suppl 1):S3–8.

51. Pellino A, Riello E, Nappo F, et al. Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives. World J Gastroenterol 2019 October 14; 25(38): 5773-5788

52. Baek JH, Park DJ, Kim GY, et al. Clinical Implications of Claudin18.2 Expression in Patients With Gastric Cancer. Anticancer Res 2019;39:6973-6979.

53. Angell H K, Lee J, Kim K-M, et al. PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer. OncoImmunology 2019;8(2):1544442.

54. Kim JY, Shin NR, Kim A, et al. Microsatellite instability status in gastric cancer: a reappraisal of its clinical significance and relationship with mucin phenotypes. Korean J Pathol 2013;47(1):28-35.

55. Velho S, Fernandes MS, Leite M, et al. Causes and consequences of microsatellite instability in gastric carcinogenesis. World J Gastroenterol 2014;20(44):16433–42.

56. Ratti M, Lampis A, Hahne JC, et al. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci 2018;75(22):4151–62.

57. Eso Y, Shimizu T, Takeda H, et al. Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol 2020;55(1):15–26.

58. Wu Y, Chen W, Xu ZP, Gu W. PD-L1 distribution and perspective for cancer immunotherapy-blockade, knockdown, or inhibition. Front Immunol 2019;10:2022.

59. Qing Y, Li Q, Ren T, et al. Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Devel Ther 2015;9:901-9.

60. Ghosh C, Luong G, Sun Y. A snapshot of the PD-1/PD-L1 pathway. J Cancer 2021;12(9):2735–46.

61. Nakano H, Saito M, Nakajima S, et al. PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms. Sci Reps 2021;11(1):1982.

62. Budczies J, Denkert C, Győrffy B, et al. Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types. BMC Med Genomics 2017;10(1):74.

63. Wang Y, Wang H, Yao H, et al. Regulation of PD-L1: Emerging routes for targeting tumor immune evasion. Front Pharmacol 2018;9:536.

64. Saito H, Kono Y, Murakami Y, et al. Highly activated PD-1/PD-L1 pathway in gastric gancer with PD-L1 expression. Anticancer Res 2018;38(1):107–12.