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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, 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 2b; HER2=human epidermal growth factor receptor 2b; MSI=microsatellite instability; PD-L1=programmed death-ligand 1.

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 gastric
cancer (mGC) survive 5 years post diagnosis.1,2*

*US SEER 18 areas (2011–2017), distant stomach cancer.1,2

6% 5-year survival rate of mGC in the US.

IN THE UNITED STATES

In 2022, it is estimated that nearly 26,400 new cases of G/GEJ cancers will be diagnosed in the US, of which 62% will likely be advanced† stage disease.1,2

In the US, patients with advanced disease at diagnosis will likely have a poor outcome, as less than 50% receive second-line therapy for mGC.3,4

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

AROUND THE WORLD

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

In 2018, the global overall 5-year survival rate was
approximately ≤10% in mGC.6

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) , 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 signaling pathway that intermediates diverse cellular behaviors 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 signaling that leads to uncontrolled cell-cycle progression, cell division and proliferation, motility, invasion, and adhesion13
  • MSI (microsatellite instability) is characterized by somatic alterations in microsatellite sequences that are associated with genomic instability11,14
  • PD-L1 (programmed death-ligand 1) can bind to the immune checkpoint receptor PD-1 (programmed death cell protein 1) which allows tumors to escape immune surveillance15

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

 

EMERGING BIOMARKERS

CLDN18.2:
IHC16

FGFR2b:
IHC,ctDNA17‡

‡FGFR2b overexpression can be determined by IHC; FGFR2 gene amplification can be determined by ctDNA.17

 

ESTABLISHED BIOMARKERS

PD-L1:
IHC4§

HER2:
IHC, ISH, NGS4,18||

MSI/MMR:
PCR, NGS/IHC4

IHC=immunohistochemistry; ctDNA=circulating tumor DNA; ISH=in situ hybridization; NGS=next generation sequencing; PCR=polymerase chain reaction.
§Varying diagnostic assays.19

||Other ISH methods (FISH=fluorescent ISH; SISH=silver ISH; CISH=chromogenic ISH; DDISH=dual-color dual-hapten ISH).18




Emerging biomarkers are highly prevalent among mG/GEJ biomarkers.
 

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.13,20-22

EMERGING BIOMARKERS

CLDN18.220
(high expression)

36%

FGFR2b21
(positive)

30%

2+/3+ IHC staining in ≥75% of tumor cells.20

 

ESTABLISHED BIOMARKERS

PD-L122,23
(Variable due to multiple factors)#

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

HER213
(Positive)

22%

MSI24
(MSI-high)

4%

CPS=combined positive score.

#PD-L1 prevalence of PD-L1 at various CPS thresholds is still being explored. Data are from a randomized controlled trial and a real-world retrospective medical records study.22,23

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 cancer10,25



Claudins are a family of transmembrane proteins7,26:

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 localized to certain tissue types7,26:

  • 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 tumors develop.7,27,28

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.7,9,28

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

EXPOSED TO ANTIBODIES IN TUMORIGENESIS

 

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

 

Malignant transformation leads to polarity disruptions and structure loss.27,28 As a result, CLDN18.2 may be more exposed and accessible to antibodies.7,27,28

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 tumor site and metastatic disease.7,27


CLDN18.2 may be expressed when tumors develop in esophageal, pancreatic, lung, and ovarian tissues as well.7

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



While approximately 70% of 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).20

  • High expression: 2+/3+ IHC staining in ≥75% of tumor cells20
  • Among mG/GEJ biomarkers, CLDN18.2+ is highly prevalent
  • Detecting CLDN18.2 can be accomplished by standard IHC staining methods, as with many other biomarkers16

 

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

  • In a real-world mono-institutional study, CLDN18.2+ (high expression) samples were also positive for the following biomarkers20*:




*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.20

 

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

  • Tumors with diffuse histology, as seen in the US and other Western countries, are associated with a poorer prognosis than those with intestinal histology29

FGFR2b
(fibroblast growth factor receptor 2b)

FGFR2b gastric cancer biomarker

FGFR2b

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

 

FGFR signaling contributes to tumor progression by enhancing angiogenesis and proliferation.11

  • FGFR2 (fibroblast growth factor receptor 2) is a receptor tyrosine kinase that has a role in normal cell development30
  • 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).30,31
  • 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)12,32

 

FGFR2b positivity has been observed in 30% of mG/GEJ cancers.21


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

 

Detecting FGFR2b overexpression can be done with the following tests.17

  • FGFR2b overexpression by IHC
  • FGFR2 gene amplification by ctDNA

 

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 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.18

  • Studies have shown HER2 is present in several cancers, including colorectal, ovarian, prostate, lung, gastric, and gastroesophageal tumors18
  • 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 unknown33

 

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 the intestinal type.4,13,18*

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

    • ISH methods include fluorescent in situ hybridization (FISH), silver in situ hybridization (SISH), chromogenic in situ hybridization (CISH), dual-color dual-hapten in situ hybridization (DDISH)4,18
  • 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 gastric cancer biomarker

MSI

MSI is an established biomarker that can be found in a broad range of solid tumor types, including mG/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) represents phenotypic evidence that the DNA mismatch repair (MMR) system is not functioning normally14:

    • 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 mG/GEJ cancers.24




Detection of MSI 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)

PD-L1 gastric cancer biomarker

PD-L1

Among biomarkers in mG/GEJ cancer, PD-L1 is one of the more recent to be utilized in clinical decision-making34



PD-L1 (programmed death-ligand 1) is a transmembrane protein that may be expressed on various tumor cells and/or immune cells.35

  • When bound to PD-1, PD-L1 acts as a T-cell inhibitory molecule, leading to immune cell evasion and subsequent tumor cell survival35
  • PD-L1 expression has been detected in various tumors, including lung, colon, ovarian and gastric cancers36
  • However, the cellular process of expression may not always be the same throughout the body19

    • Various studies have shown discordant levels of PD-L1 in the primary tumor vs metastatic lesions19

 

Prevalence of PD-L1 has been reported for several positivity thresholds throughout various studies: 67-73% CPS ≥1, 29-31% CPS ≥5, and 16-18% CPS ≥10.22,23*+

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

+Study analyzed 56 specimens from therapy-naive biopsies or post-neoadjuvant treatment from German patients with primarily non-metastatic gastric adenocarcinoma.22

 

 

  • 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)19,37
  • Expression levels may also vary during disease progression, as PD-L1 is impacted by changes in immune response19

PD-L1 expression is detected using IHC.4

SUMMARY

Initial diagnostic panels that include biomarker testing may help provide a more comprehensive patient profile and lead to more informed clinical decisions

 

NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer (NCCN Guidelines®) support using biomarkers to help map the path forward for patients.4

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


The NCCN Guidelines® recommend:

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


Biomarker testing provides more insight into 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, PD-L1, HER2, MMR4,16,17
    • Other testing methods often focus on specific biomarkers (ctDNA for FGFR2, ISH/NGS for HER2,* and PCR/NGS for MSI)4,17,18

      • *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)20
    • 30% of mG/GEJ cancers observed FGFR2b positivity21
  • Prevalence of established biomarkers have been reported throughout clinical trials as:

    • HER2 positivity in 22% of advanced mG/GEJ cancers13
    • MSI-H in 4% of mG/GEJ cancers24
    • PD-L1 at several positivity thresholds: 67-73% CPS ≥1, 29-31% CPS ≥5, and 16-18% CPS ≥1022,23



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

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  4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed 01-12-2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  5. 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.
  6. Casamayor M, Morlock R, Maeda H, Ajani J. Targeted literature review of the global burden of gastric cancer. Ecancermedicalscience 2018;12:883. Published (Epub) 11-26-2018.
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LINKS TO OTHER WEBSITES. Solely as a convenience to you, Astellas may provide links on this Site to other websites that are not maintained by or under the control of Astellas. If you use these links, you will leave this Site. Please remember that linked sites are not necessarily Astellas's sites, and the information could change without Astellas's knowledge. Third-party linked sites and their contents should not be attributed to Astellas (or any of its affiliated companies) in any manner. Astellas has not attempted to verify the truth or accuracy of any third-party sites or content contained on any third-party sites and does not make any representations or warranties about such sites or the content of such sites. If you decide to access any of the third-party sites linked to this Site, you do so entirely at your own risk. In the event Astellas endorses a particular organization, Astellas will clearly state its endorsement next to any link to that organization.

DISCLAIMER OF WARRANTIES. THIS SITE, INCLUDING ANY INFORMATION, SERVICES, OR MATERIAL MADE AVAILABLE ON OR THROUGH THIS SITE, IS PROVIDED ON AN "AS IS" AND "AS AVAILABLE" BASIS. TO THE MAXIMUM EXTENT PERMITTED BY LAW, ASTELLAS EXPRESSLY DISCLAIMS ALL WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING WITHOUT LIMITATION ANY WARRANTY OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, OR NONINFRINGEMENT. FURTHERMORE, ASTELLAS DOES NOT WARRANT THE ACCURACY OR COMPLETENESS OF ANY INFORMATION ON THIS SITE AND MAY MAKE CHANGES TO THE INFORMATION, SERVICES, OR MATERIAL MADE AVAILABLE ON OR THROUGH THIS SITE AT ANY TIME WITHOUT PRIOR NOTICE TO USERS OF THIS SITE. INFORMATION AT THIS SITE THAT IS PERIODICALLY UPDATED MAY NOT BE CURRENT AT THE MOMENT YOU VISIT THIS SITE AND MAY CONTAIN ERRORS. ASTELLAS MAKES NO WARRANTY THAT THE SITE WILL MEET YOUR REQUIREMENTS; THAT THE SITE WILL BE UNINTERRUPTED, TIMELY, SECURE, OR ERROR-FREE; THAT MESSAGES OR REQUESTS WILL BE DELIVERED; THAT DEFECTS WILL BE CORRECTED; OR THAT THIS SITE IS FREE OF VIRUSES OR OTHER HARMFUL COMPONENTS. ASTELLAS MAKES NO WARRANTY REGARDING ANY GOODS OR SERVICES PURCHASED OR OBTAINED THROUGH THE SITE OR ANY TRANSACTIONS ENTERED INTO THROUGH THE SITE. YOU ASSUME THE ENTIRE RISK AS TO THE RESULTS AND PERFORMANCE OF THE SITE AND ANY GOODS OR SERVICES PURCHASED THEREFROM.

LIMITATION OF LIABILITY. IN NO EVENT WILL ASTELLAS BE LIABLE FOR ANY DAMAGES WHATSOEVER. THIS INCLUDES BUT IS NOT LIMITED TO DIRECT, INDIRECT, INCIDENTAL, PUNITIVE, AND CONSEQUENTIAL DAMAGES (INCLUDING, WITHOUT LIMITATION, THOSE RESULTING FROM LOST PROFITS, LOST DATA, OR BUSINESS INTERRUPTION) ARISING OUT OF THE USE, INABILITY TO USE, OR THE RESULT OF USE OF THIS SITE, ANY WEBSITES LINKED TO THIS SITE, THE MATERIALS OR INFORMATION CONTAINED ON ANY OR ALL SUCH SITES, OR ANY MATERIALS, PRODUCTS, OR SERVICES OFFERED ON THIS SITE OR SITES LINKED TO THIS SITE, WHETHER BASED ON WARRANTY, CONTRACT, TORT, OR ANY OTHER LEGAL THEORY AND WHETHER OR NOT ADVISED ON THE POSSIBILITY OF SUCH DAMAGES. IN NO EVENT WILL ASTELLAS, ITS SUPPLIERS, OR ANY OTHER PARTY INVOLVED IN CREATING, PRODUCING, OR DELIVERING THIS SITE BE LIABLE TO YOU IN ANY MANNER WHATSOEVER FOR ANY DECISION MADE OR ACTION OR NONACTION TAKEN BY YOU IN RELIANCE UPON INFORMATION PROVIDED THROUGH THIS SITE. APPLICABLE LAW MAY NOT ALLOW THE EXCLUSION OR LIMITATION OF INCIDENTAL OR CONSEQUENTIAL DAMAGES, SO THE ABOVE LIMITATION OR EXCLUSION MAY NOT APPLY TO YOU.

THIS SITE IS INTENDED FOR US AUDIENCES ONLY. Access to and use of this Site is subject to the above terms and conditions. This Site was developed and is maintained by Astellas. Information, copy, and claims are intended only for the residents of the United States.