HER2: A 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, genetic material like 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. Therefore, testing for cancer biomarkers in your blood or tissue samples can reveal important details about the cancer you’ve been diagnosed with.

Human epidermal growth factor receptor 2 (HER2) is a protein encoded by the ERBB2 gene. Normally, HER2 regulates processes such as cell growth and survival, which are needed to maintain healthy tissues and organs in your body. However, when a mutation (change or alteration) arises in the ERBB2 gene located in your gastric mucosa cells, it can cause extra copies of the mutated ERBB2 in your genome. This phenomenon is known as gene amplification, which in turn results in overexpression of HER2 protein by the cells.

Other members of the HER protein family, like HER1, are activated when bound to their corresponding partner proteins called ligands. However, HER2 does not have its own ligand. Instead, when overexpressed and present at very high concentrations on the cell surface, HER2 proteins are able to bind to each other and subsequently become activated. Constitutively activated HER2 proteins then continuously send signals that promote cell growth and survival and inhibit cell death. Hence, HER2 acts as an oncogene in the context of stomach (gastric) cancer as its overexpression drives uncontrolled cell division and ultimately, the development into cancer.

Approximately 22% of advanced or metastatic stomach (gastric) cancer cases carry a mutation in the ERBB2 encoding for HER2 proteins. These cases are called HER2-positive gastric cancers. HER2 overexpression is more frequently observed in intestinal-type gastric adenocarcinomas rather than the diffuse-type. It is also more common in low-grade tumors where the tumor cells are well to moderately differentiated. Low-grade tumors are slow-growing in nature and its tumor cells can look similar to normal, healthy tissues under a microscope.

Diagnosing HER2-positive gastric cancers

HER2-positive gastric cancers can be diagnosed via molecular testing or tumor profiling which are comprehensive tests carried out on your tumor tissues to determine whether it overexpress HER2 proteins or if your cancer cells carry the ERBB2 gene mutation, respectively.

The two molecular techniques commonly used are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC measures the amount of HER2 proteins expressed on the surface of the cancer cells, while FISH detects gene amplification based on the number of copies of ERBB2 gene in the cancer cells. IHC is usually the preferred approach for HER2 screening compared to FISH which is more labor intensive. However, both techniques may sometimes be used to obtain a more definite result.

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

Determining HER2 levels in gastric cancers

Results of IHC testing are reported on a scale from 0 to 3+. The higher the number, the greater the amount of HER2 protein expressed.

• 0 or 1+: Level of HER2 expression is normal. The tumor is HER2-negative.
• 2+: There is HER2 overexpression, but a FISH test is needed to confirm the HER2 status.
• 3+: Level of HER2 expression is higher than normal. The tumor is HER2-positive.

Meanwhile, FISH test results are reported as negative or positive.

• Negative: Levels of ERBB2 gene in the cancer cells are normal. The tumor is HER2-negative.
• Positive: There are at least four copies of ERBB2 gene in the cancer cells. The tumor is HER2-positive.

Targeting HER2 for cancer treatment

Trastuzumab is a monoclonal antibody drug developed to target HER2-positive gastric cancers. This drug works by attaching to HER2 receptor proteins found on the surface of cancer cells. This interaction blocks growth-stimulating signals propagated from HER2 proteins, thereby stopping the cancer cells from growing and dividing uncontrollably.

Trastuzumab is the first molecular targeted agent approved for use as a form of standard treatment in gastric cancer. The combination therapy of trastuzumab in conjunction with chemotherapy showed survival benefit over chemotherapy alone and hence, became the first-line treatment for HER2-positive metastatic gastric adenocarcinomas.

HER2 as a biomarker in gastric cancer

Because HER2 status alone does not affect your survival or the course of your condition if you have gastric cancer, it is not a prognostic biomarker. However, overexpression of HER2 is associated with a better response to cancer treatments like targeted therapy and chemotherapy. It is also linked to longer survival in advanced gastric cancer patients who have undergone HER2-targeted therapy. For these reasons, HER2 has been established as an important predictive biomarker in gastric cancer. As such, it is standard procedure to carry out HER2 IHC or FISH on tissue biopsies from patients with advanced or metastatic gastric cancer. This allows clinicians to identify patients with HER2 overexpression and thus, are more likely to respond to targeted therapy with trastuzumab.