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This site is intended for Australian Healthcare Professionals.

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DISCOVER HOW

established and 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=Claudin18.2; 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 gastric cancers


The 5-year survival rate of gastric cancer in Australia is 38%.1

 

Map
Map


In Australia, approximately 2,500 new cases of stomach cancer are diagnosed each year, with around 1,100 deaths.1
 

 

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

EMERGING BIOMARKERS

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

  • CLDN18.2 (Claudin 18.2) 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 properties2–5
  • 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 invasion6,7

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 adhesion6,8
  • MSI (microsatellite instability) is characterised as somatic alterations in microsatellite sequences that are associated with genomic instability6,9
  • 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 surveillance10

Most emerging and established biomarkers can be detected by using standard, widely accepted assays such as IHC

 

EMERGING BIOMARKERS

CLDN18.2:
IHC11*

FGFR2b:
IHC, NGS12,13*†

ESTABLISHED BIOMARKERS

PD-L1:
IHC14–17*‡

HER2:
IHC, ISH, NGS14–17*§

MSI/MMRd:
PCR, NGS/IHC14–16*

IHC=immunohistochemistry; ctDNA=circulating tumour DNA; ISH=in situ hybridisation; MMRd=mismatch repair deficient; NGS=next generation sequencing; PCR=polymerase chain reaction.

* Expression utilises IHC and PCR tests;11,14–16 amplification utilises ctDNA, ISH and NGS tests.13–17
† IHC detects FGFR2b overexpression; NGS detects FGFR2 gene amplification by ctDNA.13,14
‡ Varying diagnostic assays.18
§ Other ISH methods (FISH=fluorescent ISH; SISH=silver ISH; CISH=chromogenic ISH; DDISH=dual-colour dual-hapten ISH).17



Emerging biomarkers are highly prevalent among mG/GOJ biomarkers.
 

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.8,19–21

 

EMERGING BIOMARKERS

CLDN18.211,19,22
(high expression)‖¶

33–38%

FGFR2b20
(positive)

30%

‖ 2+/3+ staining by IHC in ≥70% of tumour cells. Includes locally advanced unresectable or mG/GOJ adenocarcinoma.11

High expression: 2+/3+ IHC staining in ≥75% of tumour cells.19

 

ESTABLISHED BIOMARKERS GLOBAL PREVALENCE RATES

PD-L121,23
(variable due to multiple factors)**

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

 

HER2
(Positive)

22%8

MSI
(MSI-high)

4-6%24

CPS=combined positive score; mG/GOJ=metastatic gastric/gastro-oesophageal junction.

**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.21,23

 

Timeline of targetable biomarker discoveries25–29

Timeline of targetable biomarker discoveries
Timeline of targetable biomarker discoveries

In 2021, ASCO recognised molecular profiling in gastrointestinal cancer as Advance of the Year.30

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/GOJ cancer 5,31

 

Claudins are a family of transmembrane proteins:2,28

Claudins are a major component of epithelial and endothelial tight junctions, which are involved in controlling the flow of molecules between cells.2–4

Claudins are present throughout the body, but two specific splicing isoforms of CLDN18 are localised to certain tissue types:2,28

  • CLDN18.2 is the dominant isoform in normal, healthy gastric epithelial cells2,28
  • CLDN18.1 is the dominant isoform in normal, healthy lung tissue2,28

 

Preclinical studies have shown that CLDN18.2 may become more exposed and accessible to antibodies as gastric tumors develop.2,32,33

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.2,4,33

It functions to regulate selective barrier properties and contributes to cell-to-cell epithelial adhesion.2–5

EXPOSED IN TUMOURIGENESIS

 

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


Malignant transformation leads to polarity disruptions and structure loss.32,33 As a result, CLDN18.2 may be more exposed and accessible to antibodies.2,32,33

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.2,32


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

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

While approximately 70% of locally advanced and mG/GOJ cancers express CLDN18.2 (at any level), recent studies have shown approximately 38% of mG/GOJ patients are CLDN18.2 positive (high expression).19,22

Detecting the presence of CLDN18.2 identifies a previously undefined patient population
Detecting the presence of CLDN18.2 identifies a previously undefined patient population
  • High expression: 2+/3+ IHC staining in ≥75% of tumour cells19
  • Among locally advanced and mG/GOJ cancer biomarkers, CLDN18.2+ is highly prevalent22
  • Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers11

 

Few patients with locally advanced or mG/GOJ cancer who are CLDN18.2+ (high expression*) also test positive for other biomarkers.19

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

  • In a real-world, mono-institutional study,† CLDN18.2+ samples were also positive for the following biomarkers:19


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



* High expression levels of CLDN18.2: 2+ and 3+ intensity in ≥75% tumour cells.19
† Study population was limited to 350 Caucasian patients with mG/GOJ cancer, of which 117 patients had high expression of CLDN18.2. FGFR2b was not evaluated in this study.

 

CLDN18.2 is expressed in both diffuse-type tumours and intestinal-type tumours.4

  • Tumours with diffuse histology, more often seen in the UK, US and other Western countries, are associated with poorer prognosis than those with intestinal histology34,35

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/GOJ cancer7,20


FGFR2b is a receptor tyrosine kinase that has a role in normal cell development36

  • FGFR2b signalling plays a key role in many biological processes, but it also offers important information about how cancer may develop36,37
  • FGFR 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)7
  • FGFR2 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 grow29,38

 

FGFR2 amplification is significantly associated with FGFR2 receptor overexpression in gastric cancer39

NORMAL CELL

normal cell fgf ligand

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.40

GASTRIC CANCER CELL

gastric cancer cell fgf ligand

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.40

Detection of specific FGFR2 isoforms (e.g. FGFR2b) or FGF ligand overexpression may represent novel and enriching predictive biomarkers for gastric cancer40

FGFR2b positivity can be observed in 30% of mG/GOJ cancers.20

FGFR2b positivity can be observed in 30% of mG/GEJ cancers.22
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:13,14

  • FGFR2b overexpression using IHC12
  • FGFR2 gene amplification by ctDNA using NGS12,13

 

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 201441
FGFR2bMSI/MMRUnknown‡Presently unavailable‡

* A PubMed search using the search terms (gastric cancer) AND (FGFR2) AND (CLDN18.2) 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.

HER2
human epidermal growth factor receptor 2

HER2 gastric cancer biomarker

HER2

HER2 was the first biomarker used to guide clinical decisions in mG/GOJ cancer6

 

HER2 is a receptor-tyrosine kinase that is overexpressed and/or amplified in mG/GOJ cancer.6

HER2 is a proto-oncogene that is involved in signalling pathways, which leads to cell growth and differentiation.17

  • Since its discovery in breast cancer, studies have shown HER2 is present in several cancers, including colorectal, ovarian, prostate, lung, gastric and gastro-oesophageal tumours17
  • When HER2 is overexpressed and/or amplified, it can lead to uncontrolled cell growth and tumourigenesis8

    • However, the mechanisms that lead to gene amplification remain largely unknown42

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 controllable43

NORMAL CELL

her2 heterodimers

Normal cell with low HER2 protein receptor expression and few HER2 receptor heterodimers at the cell surface43

HER2+ CANCER CELL

her2 gene

HER2 is overexpressed and/or amplified, multiple HER2 receptor heterodimers are formed at the cell surface and cell signalling gets enhanced.43

When HER2 is overexpressed, multiple HER2 protein receptors are formed and cell signalling is promoted, which results in enhanced responsiveness to growth factors and malignant growth.43

 

HER2 positivity has been reported in 22% of advanced G/GOJ cancers.8

HER2 positivity has been reported in 22% of advanced G/GEJ cancers.10
HER2 positivity has been reported in 22% of advanced G/GEJ cancers.10


Detection of HER2 may be done with IHC, ISH methods and NGS, and is generally more associated with intestinal type tumours.8,14,17*

  • Guidelines recommend starting with IHC and following with ISH methods when expression is 2+ (equivocal)14

    • ISH methods include FISH, SISH, CISH and DDISH14,17
  • Positive (3+) or negative (0 or 1+) IHC results do not require further testing via ISH14



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


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 2021,19
Moran 2018,44
Schuler 201745
HER2PD-L1+7.4%Angell 201846
HER2MSI11.1%Angell 201846
HER2FGFR20.3%Su 201441



CISH=chromogenic ISH; DDISH=dual-colour dual-hapten ISH; FISH=fluorescent ISH; IHC=immunohistochemistry; ISH=in situ hybridization; NGS=next generation sequencing; SISH=silver ISH.

*IHC/ISH should be considered first, followed by additional NGS testing as appropriate.14

MSI
microsatellite instability

HER2 gastric cancer biomarker

MSI

MSI is an established biomarker that can be found in a broad range of solid tumour types, including mG/GOJ cancer9



MSI expression is associated with genomic instability and increased susceptibility to tumour development.6

Microsatellites are repeated sequences of nucleotides in DNA.9

  • MSI is caused when the DNA mismatch repair (MMR) system does not function appropriately9

    • This loss prevents normal repair and correction of DNA, allowing mismatches to occur9
    • The MMR proteins are the most frequently mutated genes in cancer9
    • Tumours with ≥30% expression of unstable microsatellites are referred to as MSI-high (MSI-H)6
  • MSI is found most often in colorectal cancers, but it has also been detected in many other types of cancer9
  • High level MSI gastric cancers exhibit distinct aggressive biologic behaviours and a gastric mucin phenotype47

 

The main mechanisms by which failure occurs in the MMR system are via genetic and epigenetic changes in h-MLH1 and h-MSH2, and less frequently in h-MSH6 and h-PMS248

MICROSATELLITE STABLE TUMOUR

micrsatellite cell

TUMOUR WITH HIGH MSI

tumor cell

MMRd=MMR deficiency.

Because somatic mutations in MSI gastric cancers 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 MLK348


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.49,50

PD-L1=programmed death-ligand 1.

 

MSI-H has been reported in 4% of mG/GOJ cancers.24

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

MSI-H=MSI-high.


Detection of MSI is typically assessed with various methods.14

  • MSI can be detected via PCR-based molecular testing and NGS
  • MMR protein expression can be analysed via IHC

MMRd=MMR deficiency.

 

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 202119
MSIPD-L1+53.2%Angell 201846
MSIHER2 (3+)4.2%Angell 201846
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 (MMRd) 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/GOJ cancer, PD-L1 is one of the more recent to be utilised in clinical decision-making14,27



PD-L1 is a transmembrane protein that may be expressed on various tumour cells and/or immune cells.51

  • When bound to PD-1, PD-L1 acts as a T-cell inhibitory molecule, leading to immune cell evasion and subsequent tumour cell survival51
  • PD-L1 expression has been detected in various tumours, including lung, colon, ovarian and gastric cancers52
  • However, the cellular process of expression may not always be the same throughout the body18

    • Various studies have shown discordant levels of PD-L1 in the primary tumour versus metastatic lesions18
    • Expression levels may also vary during disease progression as PD-L1 is impacted by changes in immune response18

As the key regulator of immune tolerance and immune exhaustion,

expression of PD-1 is tightly controlled:53

NORMAL CELL

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 tolerance53

GASTRIC CANCER CELL

gastric cancer cell

In gastric cancer, CD274 focal amplification and IFN-γ-mediated signalling can lead to PD-L1 overexpression and T-cell exhaustion.53,54

  • 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 above)53
  • PD-L1 overexpression in gastric cancer patients with Epstein-Barr virus-positive (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 above)54–56

*EBV+ gastric cancer is a distinct gastric cancer subtype defined by EBV infection.


Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials21,23*†

Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials23,25*†
Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials23,25*†
Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials23,25*†
Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials23,25*†
Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials23,25*†
Prevalence of PD-L1 has been reported for several positivity thresholds throughout clinical trials23,25*†

 

CPS=combined positive score.

*Study population was limited to 592 patients with locally advanced or mG/GOJ 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.21

 

  • 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)18,57
  • Expression levels may also vary during disease progression, as PD-L1 is impacted by changes in immune response18

PD-L1 expression is detected using IHC.14

 

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 202119
PD-L1 (CPS ≥5)CLDN18.220%Pellino 202119
PD-L1+HER2 (3+)3.2%Angell 201846
PD-L1+MSI53.2%Angell 201846
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.

Summary

SUMMARY

 

Initial diagnostic panels with biomarker testing may lead to more comprehensive patient profiles and informed clinical decisions


Guidelines

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.15,16

NICE recommend HER2 screening for metastatic oesophago-gastric adenocarcinoma.58

CLDN18.2 is a new predictive biomarker for locally advanced unresectable or metastatic gastric adenocarcinoma, but still requiring validation for assessment in a standardised immunohistochemistry (IHC) assay for clinical practice.53,54

FGFR2 amplification/overexpression is being investigated and its validation as a predictive biomarker in randomised controlled trials (RCTs) is awaited.53,54


Biomarker testing provides more insight into mG/GOJ 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 PD-L111,12,14
    • In mG/GOJ cancer, other testing methods often focus on specific biomarkers, for example: NGS for FGFR2b, ISH/NGS for HER2* and PCR/NGS for MSI13,14,17

*IHC/ISH should be considered first, followed by additional NGS testing as appropriate.¹⁴

 

 

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

    • 38% of mG/GOJ cancer patients were CLDN18.2 positive (high expression)22
    • 30% of mG/GOJ cancer patients with Epstein-Barr virus–positive (EBV+) have FGFR2b positivity20

 

  • Prevalence of established biomarkers have been reported throughout clinical trials as:

    • HER2 positivity in 22% of advanced G/GOJ cancers8
    • MSI-H in 4% of mG/GOJ cancers24
    • PD-L1 at several positivity thresholds: 67–73% CPS ≥1, 29–31% CPS ≥5 and 16–18% CPS ≥1021,23

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

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