FGFR2b: An Emerging Stomach Cancer Biomarker

A biomarker refers to any biological characteristic found in your tissues or bodily fluids that can be measured and evaluated objectively. Examples of biomarkers used in clinical practice include your blood pressure and heart rate.

Biomarkers serve as indicators of normal or abnormal processes, conditions, or diseases, such as cancer. In oncology, biomarkers can come in the form of proteins, nucleic acids (DNA and RNA) and many other biological molecules derived from your blood, urine, saliva, and tumor tissues.

These biomarkers are typically involved in the formation of cancer or are released due to the presence of the disease. Testing for cancer biomarkers in your blood or tissue samples can reveal important information about the cancer you’ve been diagnosed with, which can then be used to determine the most effective treatment options for you. Therefore, biomarker testing plays a critical role in guiding the next steps of your cancer journey. This article will explore an emerging biomarker called FGFR2b and how it relates to gastric cancer detection and potential treatment.

Fibroblast growth factor receptor 2 (FGFR2) belongs to the FGFR family of genes. It provides the instructions to produce its corresponding protein FGFR2. This protein is predominantly expressed in epithelial cells which are cells that cover the internal and external surfaces of our skin, blood vessels, and body cavities. FGFR2 functions as a transmembrane receptor tyrosine kinase which means that it is embedded in the cell membrane of epithelial cells, with parts of the protein protruding out into the extracellular environment as well as the inside of the epithelial cell itself.

FGFR2 becomes activated when its partner protein fibroblast growth factor (FGF) binds to the extracellular portion of the receptor. This sets off a cascade of signals between multiple proteins within the epithelial cell, which culminates in the promotion of various cellular processes. These include cell growth and survival, the formation of new blood vessels (angiogenesis), cell migration and invasion. Altogether, these processes can lead to cancer formation if they are not regulated.

One variant of the FGFR2 protein is the FGFR2 isoform III beta (FGFR2b), which is the isoform that was found to be overexpressed in roughly 30% of people with advanced gastric cancers.

Overproduction of FGFR2b proteins can be attributed to genomic aberrations of the FGFR2 gene. This includes mutations (alterations) in the gene itself and increased copies of the FGFR2 gene present in your genome (gene amplification). When these genomic abnormalities occur, the FGFR2 signaling cascade is continuously activated, leading to uncontrolled cell growth, tumor angiogenesis and other processes contributing to cancer formation.

FGFR2b overexpression has not only been observed in primary gastric tumors, but also in secondary tumors that have spread to metastatic sites or nearby lymph nodes. This suggests that FGFR2b may have a vital role in tumor progression and metastasis in stomach (or gastric) cancers.

Diagnosing FGFR2b-positive gastric cancers

FGFR2b-positive cancers are those where the tumor cells overexpress FGFR2b. Diagnosing FGFR2b-positive gastric cancers starts with biomarker testing which are also commonly known as molecular testing or tumor profiling. These comprehensive tests can be carried out on your tumor tissues to detect whether your tumor cells express large amounts of FGFR2b proteins or if there are multiple copies of the FGFR2 gene in your genome.

The molecular techniques that can be used to measure expression levels of FGFR2b protein or certain genetic alterations of the FGFR2 gene are called immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), respectively. Meanwhile, FGFR2 gene amplification can be measured using next generation sequencing (NGS). It is important to note that FGFR2b protein overexpression can occur in the absence of FGFR2 gene amplification. On top of that, NGS analysis can be more costly and time consuming. For these reasons, IHC and/or FISH are the conventional approach for testing of aberrations in the protein or genetic expression of FGFR2b as they are more rapid and cost-efficient as well.

> Learn more about the types of biomarker tests performed for gastric cancer

As FGFR2b overexpression is frequently seen in metastatic sites and lymph node tissue, both primary and secondary gastric cancer tissues should be examined for FGFR2b-positivity.

Determining FGFR2b levels in gastric cancers

IHC method is routinely used in clinic to determine the expression levels of FGFR2b in the tumor samples. Results of IHC testing are reported on a scale from 0 to 3+. The higher the number, the greater the amount of FGFR2b protein expressed.

• 0: FGFR2b is not expressed by the cells. The tumor is FGFR2b-negative.
• 1+: Low to moderate levels of FGFR2b expression. The tumor is FGFR2b-negative.
• 2+: Moderate to strong levels of FGFR2b expression. The tumor is FGFR2b-positive.
• 3+: Strong levels of FGFR2b expression. The tumor is FGFR2b-positive.

Targeting FGFR2b for cancer treatment

Its involvement in a variety of cancers has prompted scientists to look at FGFR2b as a potential therapeutic target. As of now, there are no FGFR2b inhibitors approved for use in gastric cancer. However, studies have shown that a promising new drug called bemarituzumab (anti-FGFR2b), when combined with chemotherapy, is able to improve survival in people with advanced gastric/GEJ tumors that were FGFR2b-positive and HER2-negative.

Bemarituzumab is a monoclonal antibody that works by attaching to FGFR2b proteins found on the surface of the cancer cells and in turn, interferes with the binding and activation of the FGFR2b.This disrupts the downstream signaling cascade of FGFR2b and inhibits the cancer-promoting processes associated with FGFR2.

Although bemarituzumab is still in Phase III clinical trials, scientists are speculating that this novel FGFR2 inhibitor may transform the treatment of FGFR2b-positive advanced gastric cancers.

FGFR2b as a biomarker in gastric cancer

Researchers have found that FGFR2b protein overexpression is associated with more advanced cancer stages and poorer patient outcomes, such as worse overall survival. Recent clinical trial findings have also shown that the higher the proportion of tumor cells overexpressing FGFR2b, the greater the response to targeted therapy using bemarituzumab and chemotherapy in gastric cancer patients.

For these reasons, FGFR2b has been identified as an emerging prognostic and predictive biomarker in gastric cancer. However, more research needs to be done on this unique molecular target before it cements itself as an established gastric cancer biomarker.