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Discover Claudin18.2,
 a novel biomarker in the advanced gastric cancer landscape.

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

 

Exploring biomarker advancements starts here.
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WELCOME TO

The Gastric Cancer Landscape

SELECT A BIOMARKER BELOW

CLDN18.2=Claudin18.2; FGFR2b=fibroblast growth factor receptor 2, isoform IIIb; 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/gastroesophageal junction (G/GEJ) cancers

 

In the United States, approximately 6% of patients with metastatic G/GEJ cancer survive 5 years post diagnosis.1,2*†

Approximately 6% 5-year survival rate of metastatic gastric/gastroesophageal junction (mG/GEJ) cancer in the US.

*US SEER 22 areas (2013-2019), gastric and esophageal cancers, distant stage.1,2

†SEER data do not have a separate classification for GEJ apart from esophageal cancer; therefore, true GEJ projections are unknown.2

IN THE UNITED STATES

In 2023, an estimated 26,500 new cases of gastric cancer (62% advanced‡ stage) and ~21,600 new cases of esophageal† cancer (72% advanced‡ stage) will be diagnosed in the US.1-3

In the US, patients with advanced disease at diagnosis will likely have a poor outcome,4,5 and less than 50% will receive second-line therapy for mG/GEJ cancer.6§

‡Locally advanced (stage II and III) and metastatic (stage IV) gastric/GEJ cancer per tumor node metastases (TNM) staging classification as described in NCCN Guidelines.4,5

§Data from a retrospective analysis of electronic medical records of 3850 eligible G/GEJ/esophageal adenocarcinoma patients that underwent first-line therapy and were alive at 45 days after completion of first-line therapy.6

TNM=tumor node metastases.

AROUND THE WORLD

Over 1.6 million new cases of gastric and esophagealII cancers were diagnosed worldwide in 2020, making them the 5th and 7th most diagnosed cancers, respectively.7

An estimated 1.3 million people died worldwide in 2020 due to gastric and esophagealII cancers, making them the 4th and 6th most deadly
cancers, respectively.7

 

IIBased on GLOBOCAN 2020 data for gastric and esophageal cancers. GLOBOCAN data do not have a separate classification for GEJ apart from esophageal cancer; therefore, true GEJ projections are unknown.7

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 patients:

  • CLDN18.2 , as a component of tight junctions, has a role in the regulation of permeability, barrier function, and polarity of epithelial layers8-10
  • FGFR2b is a splice variant of FGFR2, a transmembrane signaling pathway that intermediates diverse cellular behaviours and processes, such as mitogenesis, differentiation, cell proliferation, angiogenesis, and invasion11,12

ESTABLISHED BIOMARKERS

are used to inform clinical decisions:

  • HER2 is associated with activation of downstream signaling that leads to uncontrolled cell-cycle progression, cell division and proliferation, motility, invasion, and adhesion13
  • MSI is characterized by the accumulation of mutations in microsatellite DNA sequences leading to genomic instability.11,14 MSI occurs when the DNA MMR system does not function appropriately14
  • PD-L1 can bind to the immune checkpoint receptor PD-1 (programmed death cell protein 1) which allows tumors to escape immune surveillance15

CLDN18.2=Claudin18.2; FGFR2b=fibroblast growth factor receptor 2, isoform IIIb; HER2=human epidermal growth factor receptor 2; MMR=mismatch repair; MSI=microsatellite instability; PD-L1=programmed death-ligand 1.

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 advanced G/GEJ cancer16



Claudins are a family of transmembrane proteins8:

Claudins are a major component of tight junctions, which are involved in controlling the flow of molecules between cells.8,9

Claudins are present throughout the body, but two specific isoforms of CLDN18 are localized to certain tissue types8,17:

  • CLDN18.2 is the dominant isoform in normal gastric tissue and is often retained in malignant transformation
  • CLDN18.1 is the dominant isoform in normal and malignant lung tissue

 

Preclinical data have shown that CLDN18.2 may become more exposed
 as gastric tumors develop.8,16

CONFINED IN HEALTHY TISSUE

CLDN18.2 confined in healthy tissue.
CLDN18.2 confined in healthy tissue.

In normal gastric mucosa, CLDN18.2 is typically buried within tight junctions8,16

RETAINED AND EXPOSED IN MALIGNANT TRANSFORMATION

CLDN18.2 retained and exposed during malignant transformation.
CLDN18.2 retained and exposed during malignant transformation.

CLDN18.2 is often retained during malignant transformation.

CLDN18.2 may be more exposed when cell polarity disruptions and structure loss occur.8,16,18

MAINTAINED IN METASTATIC PROGRESSION

CLDN18.2 maintained in metastatic progression.
CLDN18.2 maintained in metastatic progression.

CLDN18.2 may also be localized in lymph node metastases of gastric adenocarcinoma as well as other distant metastatic sites.8,19-21

The information provided above is based on the current understanding of data.

 

CLDN18.2 expression may also be observed in esophageal adenocarcinoma, pancreatic adenocarcinoma, non-small cell lung cancer, and ovarian mucinous adenocarcinoma.8

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

 

While approximately 70% of advanced G/GEJ cancers express CLDN18.2 (at any detectable amount),20* two recent studies have shown that approximately 38% of patients with locally advanced unresectable or mG/GEJ cancer are Claudin18.2 positive (≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining by IHC).22,23†

  • Among advanced G/GEJ biomarkers, CLDN18.2 is highly prevalent13,22-24
  • Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers22-25

*Data from a retrospective analysis of 350 Caucasian patients with advanced G/GEJ cancer.20
†Data from 2 global randomized Phase 3 studies: the first study included 2,403 assessable patients, of which 922 were CLDN18.2 positive; and a second study which included 2,104 assessable patients, of which 808 were CLDN18.2 positive.22,23
‡Any detectable amount: moderate to strong membranous CLDN18 staining by immunohistochemistry (IHC) in any percentage of tumor cells.20

CLDN18.2 is highly prevalent among biomarkers for advanced G/GEJ cancer.13,22-24

Biomarker prevalence estimates from select studies are reported below. Prevalence data can vary among studies due to tumor heterogeneity, differences in patient population, clinical trial methodology, and diagnostic assays used. Positivity thresholds also vary by study.13,22-24,26-28

EMERGING BIOMARKERS

CLDN18.222,23
(positive)§

38%

FGFR2b26||
(positive)

30%

§≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining by IHC.22,23
||FGFR2b positivity: FGFR2b overexpression (IHC 2+/3+ any amount of tumor cells) and/or FGFR2 gene amplification by ctDNA (NGS 1.5x increase in FGFR2).26

ESTABLISHED BIOMARKERS

PD-L124,27
(variable due to multiple factors)

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

HER213
(positive)

22%

MSI28
(MSI-high)

4%

CPS=combined positive score.
PD-L1 prevalence at various CPS thresholds is still being explored. Data are from a randomized controlled trial and a real-world retrospective medical records study.24,27

CLDN18.2 is detected via IHC, as is standard with many other biomarkers22-25

 

EMERGING BIOMARKERS

CLDN18.2:
IHC22,23

FGFR2b:
IHC, NGS (ctDNA)26#

#FGFR2b protein overexpression assessed by IHC; FGFR2 gene amplification assessed using ctDNA by NGS.26

 

ESTABLISHED BIOMARKERS

PD-L1:
IHC4,5**

HER2:
IHC, ISH, NGS4,5,25††

MMR/MSI:
IHC, PCR/NGS4,5‡‡

 

ctDNA=circulating tumor DNA; IHC=immunohistochemistry; ISH=in situ hybridization; NGS=next generation sequencing; PCR=polymerase chain reaction.
** Varying diagnostic assays.29
†† Other ISH methods (FISH=fluorescent ISH; SISH=silver ISH; CISH=chromogenic ISH; DDISH=dual-color dual-hapten ISH).25
‡‡ MMR assessed by IHC, MSI by PCR/NGS.4,5


IHC scoring for CLDN18 in G/GEJ cancer is performed based on membrane staining intensity and percent of positive tumor cells22,23,30

Membrane staining of tumor cells for "0 No Staining," "1+ Weak Staining," "2+ Moderate Staining," and "3+ Strong Staining."
Membrane staining of tumor cells for "0 No Staining," "1+ Weak Staining," "2+ Moderate Staining," and "3+ Strong Staining."

CLDN18.2 positivity is defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 staining by IHC.22,23

CLDN18.2 expression has been seen in both diffuse-type gastric tumors and intestinal-type gastric tumors.20

  • Tumors with diffuse histology, as seen in the US and other Western countries, are associated with a poorer prognosis than those with intestinal histology31

FGFR2b
(fibroblast growth factor receptor 2b, isoform lllb)

FGFR2b gastric cancer biomarker.

FGFR2b

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

 

FGFR2b participates in angiogenesis and cell proliferation through
FGFR signaling pathways.11,12

  • FGFR2 (fibroblast growth factor receptor 2) is a receptor tyrosine kinase that has a role in normal cell development32
  • The splice variant FGFR2b is expressed in various types of epithelial cells where tumors may begin to grow (including pancreatic, breast, endometrial, cervical, lung, and colorectal cancers)32,33
  • FGFR2b may be associated with higher T stage (size of the tumor and any spread into nearby tissue) and higher N stage (extent of nodal metastases)12,34

 

FGFR2b positivity has been observed in 30% of advanced G/GEJ cancers.26*


FGFR2b positivity: FGFR2b overexpression (IHC 2+/3+ any amount of tumor cells) and/or FGFR2 gene amplification by ctDNA (NGS 1.5x increase in FGFR2)
*Data from select studies.26

 

 

Detecting FGFR2b can be done with the following tests26:

  • FGFR2b overexpression using IHC
  • FGFR2 gene amplification using ctDNA by NGS

 

HER2
(human epidermal growth factor receptor 2)

HER2 gastric cancer biomarker.

HER2

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



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

HER2 is a proto-oncogene that is involved in signaling pathways, which leads to cell growth and differentiation.25

  • Studies have shown HER2 is present in several cancers, including colorectal, ovarian, prostate, and lung tumors25
  • 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 unknown35

 

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



HER2 positivity: overexpression (IHC3+) and/or gene amplification (FISH-positive)
*Data from select studies.13


Detection of HER2 may be done with IHC, NGS, and ISH methods.4,5

  • Guidelines recommend starting with IHC; followed by ISH methods only when IHC expression is 2+ (equivocal)4,5

    • IHC/ISH should be considered first, followed by additional NGS testing as appropriate4,5
    • ISH methods include fluorescent in situ hybridization (FISH), silver in situ hybridization (SISH), chromogenic in situ hybridization (CISH), and dual-color dual-hapten in situ hybridization (DDISH)25
  • Positive (3+) or negative (0 or 1+) IHC results do not require further testing via ISH4,5
  • HER2 testing in gastric cancer differ from testing in breast cancer due to differences in tumor biology, intratumoral heterogeneity of HER2 expression, and incomplete membrane staining13,25
  • Overexpression or amplification of HER2 is more common in patients with intestinal histology13

MSI
(microsatellite instability)

MSI gastric cancer biomarker.

MSI

MSI is an established biomarker that can be found in a broad range of solid tumor types, including advanced G/GEJ cancer14



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

Microsatellites are repeated sequences of nucleotides in DNA.14

  • Microsatellite instability (MSI) is caused when the DNA mismatch repair (MMR) system is not functioning 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.28*

*Data from select studies.28




Detection of MSI and MMR is typically assessed with various methods.4,5

  • 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)

PD-L1 gastric cancer biomarker.

PD-L1

Among biomarkers in advanced G/GEJ cancer, PD-L1 is one of the more recent to be utilized in clinical decision-making36



PD-L1 (programmed death-ligand 1) is a transmembrane protein that may be expressed on various tumor cells and/or immune cells.37

  • When bound to PD-1, PD-L1 acts as a T-cell inhibitory molecule, leading to immune cell evasion and subsequent tumor cell survival37
  • PD-L1 expression has been detected in various tumors, including lung, colon, ovarian, and gastric cancers38
  • However, the cellular process of expression may not always be the same throughout the body39

    • Various studies have shown discordant levels of PD-L1 in the primary tumor vs metastatic lesions39

 

Prevalence of PD-L1 has been reported for several positivity thresholds throughout various studies24,27*:

PD-L1 prevalence at various CPS thresholds is still being explored. Data are from a randomized controlled trial and a real-world retrospective medical records study.24,27
*Data from select studies.24,27

 

  • 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)39,40
  • Expression levels may also vary during disease progression, as PD-L1 is impacted by changes in immune response39

PD-L1 expression is detected using IHC.4,5

CPS=combined positive score.

SUMMARY

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

 

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer and Esophageal and Esophagogastric Junction Cancers* support using biomarkers to help map the path forward for patients.4,5†

  • Biomarker testing has an important role in the diagnosis, classification, and molecular characterization of G/GEJ cancer
  • The implementation of molecular testing has had a significant impact on clinical practice and patient care


The NCCN Guidelines® recommend4,5:

  • Testing for all established biomarkers (HER2, MSI, PD-L1) at diagnosis if metastatic cancer is documented or suspected
  • The use of IHC/ISH/targeted PCR should be considered first, followed by additional NGS testing as appropriate

*In adenocarcinomas of unresectable locally advanced, locally recurrent or metastatic disease of esophageal and esophagogastric junction cancers.5
†This is a summary of relevant portions of the NCCN Guidelines. Please see the full NCCN Guidelines for Gastric Cancer and Esophageal and Esophagogastric Junction Cancers at NCCN.org.4,5


Biomarker testing provides more insight into advanced G/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, PD-L1, HER2, MMR4,5,22,23,26
    • Other testing methods often focus on specific biomarkers (ctDNA by NGS for FGFR2, ISH/NGS for HER2,‡ and PCR/NGS for MSI)4,5,26

      • ‡The use of IHC/ISH/targeted PCR should be considered first, followed by additional NGS testing as appropriate.4,5

  • According to recent studies, biomarker testing has revealed a high prevalence of emerging biomarkers

    • Approximately 38% of patients with locally advanced unresectable or mG/GEJ cancer were CLDN18.2 positive22,23
    • 30% of advanced G/GEJ cancers observed FGFR2b positivity26§
  • 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 advanced G/GEJ cancers28§
    • PD-L1 at several positivity thresholds: 67-73% CPS ≥1, 29-31% CPS ≥5, and 16-18% CPS ≥1024,27§

§Data from select studies. Prevalence data can vary among studies due to tumor heterogeneity, differences in patient populations, clinical trial methodology, and diagnostic assays used. Positivity thresholds may vary by study.13,24,26-28

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

Stay Up To Date

STAY INFORMED


 

REFERENCES

  1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: stomach cancer. https://seer.cancer.gov/statfacts/html/stomach.html. Accessed 04-24-2023.
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