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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.
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
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
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
EMERGING BIOMARKERS
help identify previously undefined subsets of mG/GEJ cancer patients:
ESTABLISHED BIOMARKERS
are used to inform clinical decisions:
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
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:
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
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
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
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
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
When evaluating the relationship between CLDN18.2 and other biomarkers, data suggests there is limited overlap.
*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
FGFR2b
FGFR signaling contributes to tumor progression by enhancing angiogenesis and proliferation.11
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
HER2
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
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*
*IHC/ISH should be considered first, followed by additional NGS testing as appropriate.4
MSI
MSI is associated with genomic instability and increased susceptibility to tumor development.11
Microsatellites are repeated sequences of nucleotides in DNA.14
MSI-H has been reported in 4% of mG/GEJ cancers.24
Detection of MSI is typically assessed with various methods.4
PD-L1
PD-L1 (programmed death-ligand 1) is a transmembrane protein that may be expressed on various tumor cells and/or immune cells.35
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
PD-L1 expression is detected using IHC.4
SUMMARY
NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer (NCCN Guidelines®) support using biomarkers to help map the path forward for patients.4
The NCCN Guidelines® recommend:
Biomarker testing provides more insight into mG/GEJ cancer as more biomarkers are discovered.
*IHC/ISH should be considered first, followed by additional NGS testing as appropriate.4
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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