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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

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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.

AN UNMET NEED

Despite recent advances, there are still critical needs to address in gastric/gastro-oesophageal (G/GEJ) cancers

 

In Singapore, for gastric cancers, 58.2% of patients were diagnosed at Stages III-IV, where the five-year age-standardised relative survival (ASRS) rate is below 40%1. 

The five-year ASRS rate for Stage IV diseases in Singapore is as low as 5%1,2, which is comparable to the overall global rate (≤10%)4

In Singapore, GC is the 8th most common cancer in men and the 10th most common cancer in women in Singapore population.3


In Singapore, mortality caused by GC is the 6th most common in men and the 7th most common in women.3


   

7th MOST DEADLY CANCER (WOMEN)
7th MOST DEADLY CANCER (WOMEN)

 

‡Locally advanced (stage II and III) and metastatic (stage IV) gastric/GEJ cancer per TNM staging classification as described in NCCN Guidelines®.4

Over 1 million new cases of G/GEJ cancers were diagnosed worldwide in 2020, making it the 5th most diagnosed cancer.5

 

An estimated 769,000 people died worldwide in 2020 due to G/GEJ cancers, making it the 4th most deadly cancer.5


 

4th most
4th most

As novel biomarkers emerge, they may reveal more opportunities to enhance care for advanced G/GEJ cancer

 

EMERGING BIOMARKERS

help identify previously undefined subsets of metastatic gastric (mG)/ gastroesophageal junction (GEJ) cancer patients:

  • CLDN18.2 (Claudin 18.2) , as a component of tight junctions, has a critical role in cell-to-cell epithelial adhesion and regulating selective barrier properties7-10
  • FGFR2b (fibroblast growth factor receptor 2b) is a splice variant of FGFR2, a transmembrane signalling pathway that intermediates diverse cellular behaviours and cellular processes, such as mitogenesis, differentiation, cell proliferation, angiogenesis, and invasion11,12

ESTABLISHED BIOMARKERS

are used to inform clinical decisions:

  • HER2 (human epidermal growth factor receptor 2) is associated with activation of downstream signalling that leads to uncontrolled cell-cycle progression, cell division and proliferation, motility,invasion, and adhesion13
  • MSI (microsatellite instability) is characterised by somatic alterations in microsatellite sequences that are associated with genomic instability11,14 MSI occurs when the DNA MMR system does not function appropriately14
  • 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 surveillance15


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

EMERGING BIOMARKERS

CLDN18.2:
IHC16

FGFR2b:
IHC, NGS17,18§||

Il IHC detects FGFR2b overexpression; NGS detects FGFR2 gene amplification by ctDNA.17,18

ESTABLISHED BIOMARKERS

PD-L1:
IHC4§¶

HER2:
IHC, ISH, NGS4,19§*

MSI/MMR:
PCR, NGS/IHC4§

IHC=immunohistochemistry; ctDNA=circulating tumour DNA; ISH=in situ hybridisation; MMR=mismatch repair; NGS=next generation sequencing;

§Expression utilises IHC and PCR tests;4,16,17 amplification utilises ISH and NGS tests.4,18,19

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.
 

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.13,21–23

 

EMERGING BIOMARKERS

CLDN18.216,21
(high expression)**

36%

FGFR2b22
(positive)

30%

** 2+/3+ staining by IHC in ≥75% of tumour cells.21

ESTABLISHED BIOMARKERS

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

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

 

HER213
(Positive)

22%

MSI25
(MSI-high)

4%

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 discoveries26–30

CLDN18.2
Claudin18.2

FGFR2b biomarker.

CLDN18.2

CLDN18.2 is an emerging biomarker that may help you learn more about your patients with advanced mG/GEJ cancer10,31



Claudins are a family of transmembrane proteins7,29:

Claudins are a major component of epithelial and endothelial tight junctions, which are involved in controlling the flow of molecules between cells.7,9

Claudins are present throughout the body, but two specific isoforms of CLDN18 are localised to certain tissue types7,29:

  • CLDN18.2 is the dominant isoform in normal, healthy gastric epithelial cells
  • CLDN18.1 is the dominant isoform in normal, healthy lung tissue

 

Preclinical studies have shown that CLDN18.2 may become more exposed and accessible to antibodies as gastric tumours develop.7,32,33

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.7,9,33

It functions to regulate selective barrier properties and contributes to cell-to-cell epithelial adhesion.7–10

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.7,32,33

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.7,32


Although not present in healthy tissues beyond gastric epithelial cells, CLDN18.2 may be overexpressed in oesophageal, pancreatic, lung, and ovarian tumours as well.7

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 36% of mG/GEJ patients are CLDN18.2 positive (high expression).21

  • High expression: 2+/3+ IHC staining in ≥75% of tumour cells21
  • Among locally advanced and mG/GEJ cancer biomarkers, CLDN18.2+ is highly prevalent
  • Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers16

 

Few patients with 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.

  • In a real-world, mono-institutional study,* CLDN18.2+ (high expression) were also positive for the following biomarkers:21



* 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.

 

CLDN18.2 is expressed in both diffuse-type tumours and intestinal-type tumours.16

FGFR2b
fibroblast growth factor receptor 2b

FGFR2b biomarker.

FGFR2b

FGFR2b is an emerging biomarker that introduces another way to identify a subset of patients with advanced G/GEJ cancer12


FGFR signalling has a key role in many biological processes, but it also offers important information about how cancer may develop.35,36

  • FGFR2 (Fibroblast growth factor receptor 2) is a receptor tyrosine kinase that has a role in normal cell development36
  • The splice variant FGFR2b is expressed in various types of epithelial cells where tumours may begin to grow (including pancreatic, breast, endometrial, cervical, lung, and colorectal cancers)36,37
  • FGRF2b may be associated with higher T stage (size of the tumor and any spread into nearby tissue) and higher N stage (extent of nodal metastasis)35,3B

 

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


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

 

Detecting FGFR2b can be done with the following tests17,18:

  • FGFR2b overexpression using IHC17
  • FGFR2 gene amplification using ctDNA by NGS17,18

 

HER2
human epidermal growth factor receptor 2

HER2 biomarker.

HER2

HER2 was the first biomarker used to guide clinical decisions in advanced mG/GEJ cancer11



HER2 (human epidermal growth factor receptor 2) is a receptor-tyrosine kinase that is overexpressed and/or amplified in mG/GEJ cancer.11

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

  • Studies have shown HER2 is present in several cancers, including colorectal, ovarian, prostate, lung, gastric and gastro-oesophageal tumours19
  • When HER2 is overexpressed and/or amplified, it can lead to uncontrolled cell growth and tumorigenesis13:

    • However, the mechanisms that lead to gene amplification remain largely unknown39

 

HER2 positivity has been reported in 22% of advanced G/GEJ cancers.13


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. 4,13,19*

  • Guidelines recommend starting with IHC and following with ISH methods when expression is 2+ (equivocal)4

    • ISH methods include fluorescent in situ hybridisation (FISH), silver in situ hybridisation (SISH), chromogenic in situ hybridisation (CISH), dual-colour dual-hapten in situ hybridisation (DDISH)4,19
  • Positive (3+) or negative (0 or 1+) IHC results do not require further testing via ISH4


*IHC/ISH should be considered first, followed by additional NGS testing as appropriate.4

MSI
microsatellite instability

MSI biomarker.

MSI

MSI/MMR is an established biomarker that can be found in a broad range of solid tumour types,including mG/GEJ cancer14



MSI is associated with genomic instability and increased susceptibility to tumour development.11

Microsatellites are repeated sequences of nucleotides in DNA.14

  • Microsatellite instability (MSI) is caused when the DNA mismatch repair (MMR) system does not function appropriately14:

    • This loss prevents normal repair and correction of DNA, allowing mismatches to occur14
    • The MMR proteins are the most frequently mutated genes in cancer14
  • Tumors with ≥30% expression of unstable microsatellites are referred to as MSI-high (MSI-H), while tumors with 10-29% expression are considered MSI-low11
  • MSI is found most often in colorectal cancer, gastric cancer, and endometrial cancer, but it may also be found in many other types of cancer14

 


MSI-H has been reported in 4% of advanced G/GEJ cancers.25




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

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

PD-L1
programmed death-ligand 1

PDL1 biomarker.

PD-L1

Amongst biomarkers in mG/GEJ cancer, PD-L1 is one of the more recent to be utilised in clinical decision-making28



PD-L1 (programmed death-ligand 1) is a transmembrane protein that may be expressed on various tumor cells and/or immune cells.40

  • When bound to PD-1, PD-L1 acts as a T-cell inhibitory molecule, leading to immune cell evasion and subsequent tumor cell survival40
  • PD-L1 expression has been detected in various tumors, including lung, colon, ovarian, and gastric cancers41
  • 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 tumor vs metastatic lesions20

 

Prevalence of PD-L1 has been reported for several positivity thresholds throughout various studies23,34*†:


*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.24
†Study analysed 56 specimens from therapy-naïve biopsies from German patients with primarily non-metastatic gastric adenocarcinoma.23

 

  • The variations in prevalence may be due to several factors, such as tumor heterogeneity and clinical trial methodology (including differences in patient population, staining techniques, scoring algorithms, and diagnostic assays)20,42
  • Expression levels may also vary during disease progression, as PD-L1 is impacted by changes in immune response20

PD-L1 expression is detected using IHC.4

SUMMARY

Initial panels that include biomarker testing help to create a more complete patient profile and lead to more informed decisions

 

Guidelines for mG/GEJ cancer support the use of biomarkers to help support using biomarkers to help map the path forward for patients.4,43

  • CSCO Guidelines include the use of immunohistochemistry (IHC) and in situ hybridisation (ISH) to detect clinically relevant biomarkers43
  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend biomarker testing at diagnosis, and comprehensive biomarker testing4


Biomarker testing provides more insight into advanced mG/GEJ cancer as more biomarkers are discovered.

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

    • IHC can detect CLDN18.2, FGFR2b, HER2, MMR, PD-L1,4,16,17
    • In mG/GEJ cancer, other testing methods can be utilised to detect certain biomarkers, for example: NGS for FGFR2, ISH/NGS for HER2,* and PCR/NGS for MSI4,17-19

      • **IHC/ISH should be considered first, followed by additional NGS testing as appropriate.4

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

    • 36% of mG/GEJ patients were CLDN18.2 positive (high expression)21
    • 30% of mG/GEJ cancers displayed FGFR2b positivity22
  • Prevalence of established biomarkers have been reported throughout various studies as:

    • HER2 positivity in 22% of advanced G/GEJ cancers13
    • MSI-H in 4% of mG/GEJ cancers25
    • 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.

To submit a question or for any other queries, please contact jason.tang@astellas.com or click here to contact our Medical Information Team.

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REFERENCES

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  25. 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.
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