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.
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.
CLDN18.2
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
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
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
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
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
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
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
* 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
FGFR2b
FGFR2b is a receptor tyrosine kinase that has a role in normal cell development42
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
Biomarker | Biomarker | Prevalence overlap | Reference |
---|---|---|---|
FGFR2b | CLDN18.2 | Unknown* | Presently unavailable* |
FGFR2b | PD-L1+ | Unknown† | Presently unavailable† |
FGFR2 | HER2 (3+) | 0.3% | Su 201447 |
FGFR2b | MSI/MMR | Unknown‡ | 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.
HER2
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
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*
Biomarker | Biomarker | Prevalence overlap | Reference |
---|---|---|---|
HER2 | CLDN18.2 | 12-15% | Pellino 2021,21 Pellino 2019,51 Baek 201952 |
HER2 | PD-L1+ | 7.4% | Angell 201853 |
HER2 | MSI | 11.1% | Angell 201853 |
HER2 | FGFR2 | 0.3% | Su 201447 |
* IHC/ISH should be considered first, followed by additional NGS testing as appropriate.17
MSI
MSI expression is associated with genomic instability and increased susceptibility to tumour development.9
Microsatellites are repeated sequences of nucleotides in DNA.12
MICROSATELLITE STABLE TUMOUR
TUMOUR WITH HIGH MSI/MMRd
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
Biomarker | Biomarker | Prevalence overlap | Reference |
---|---|---|---|
dMMR | CLDN18.2 | 15% | Pellino 202121 |
MSI | PD-L1+ | 53.2% | Angell 201853 |
MSI | HER2 (3+) | 4.2% | Angell 201853 |
MSI/MMR | FGFR2b | Unknown* | 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
PD-L1 (programmed death-ligand 1) is a transmembrane protein that may be expressed on various tumour cells and/or immune cells.58
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
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
Biomarker | Biomarker | Prevalence overlap | Reference |
---|---|---|---|
PD-L1 (CPS ≥1) | CLDN18.2 | 28% | Pellino 202121 |
PD-L1 (CPS ≥5 | CLDN18.2 | 20% | Pellino 202121 |
PD-L1+ | HER2 (3+) | 3.2% | Angell 201853 |
PD-L1+ | MSI | 53.2% | Angell 201853 |
PD-L1 | FGFR2 | Unknown* | 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
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
Biomarker testing provides more insight into mG/GEJ cancer as more biomarkers are being discovered:
*IHC/ISH should be considered first, followed by additional NGS testing as appropriate.17
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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