HER2/neu (serum)

HER2/neu Overview

HER2/neu, also known as ERBB2, is a gene that codes for a protein called human epidermal growth factor receptor 2. This protein is a receptor on the surface of breast cells, gastric cells, and other cells, and is involved in cell growth, division, and repair. When the HER2 gene is amplified or the HER2 protein is overexpressed, it can lead to uncontrolled cell growth, a hallmark of cancer. HER2/neu is an important biomarker in several cancers, most notably breast cancer and gastric cancer, influencing prognosis and guiding targeted therapy decisions.

While tissue-based testing (immunohistochemistry and FISH) is the gold standard for assessing HER2 status, soluble fragments of the HER2 extracellular domain can be shed into the bloodstream, allowing for serum HER2/neu (sHER2) testing. This serum marker can provide complementary information, particularly for monitoring disease progression and treatment response.

HER2/neu Biology and Function

The HER2/neu gene is located on chromosome 17 and encodes a 185-kDa transmembrane glycoprotein. It is a member of the epidermal growth factor receptor (EGFR) family, which also includes EGFR (HER1/ErbB1), HER3 (ErbB3), and HER4 (ErbB4).

These receptors play a critical role in cellular signal transduction pathways that regulate cell growth, survival, adhesion, migration, and differentiation. HER2 is unique among the family members as it lacks a direct ligand-binding domain but acts as a preferred dimerization partner for other activated HER receptors. Upon dimerization, the receptor complex initiates downstream signaling cascades, such as the PI3K/Akt/mTOR pathway and the Ras/MAPK pathway, which promote cell proliferation and survival.

Overexpression or amplification of the HER2 gene leads to an increased number of HER2 receptors on the cell surface, resulting in constitutive activation of these signaling pathways, driving uncontrolled cell growth and making the cancer more aggressive.

Indications for HER2/neu Testing

HER2/neu testing is primarily indicated for patients diagnosed with:

1. Breast Cancer:
   • All newly diagnosed invasive breast cancers should be tested for HER2 status to determine prognosis and eligibility for HER2-targeted therapies (e.g., trastuzumab, pertuzumab, T-DM1).
   • Recurrent or metastatic breast cancer should also undergo HER2 retesting, as HER2 status can change over time or with treatment.
2. Gastric and Gastroesophageal Junction Adenocarcinoma:
   • Patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma should be tested for HER2 overexpression to identify candidates for HER2-targeted therapy (e.g., trastuzumab).
3. Other Cancers (Investigational/Emerging):
   • HER2 overexpression or amplification is being investigated in other cancer types, including colorectal cancer, lung cancer, ovarian cancer, and endometrial cancer, for potential therapeutic targeting.

While tissue biopsy remains the gold standard for initial diagnosis, serum HER2/neu testing can be used for monitoring purposes, particularly in metastatic settings where repeat biopsies may be challenging.

HER2/neu in Breast Cancer

Approximately 15-20% of breast cancers are classified as HER2-positive. These cancers tend to be more aggressive, grow faster, and are more likely to recur than HER2-negative tumors. However, the development of HER2-targeted therapies has significantly improved the prognosis for patients with HER2-positive breast cancer.

• Prognosis: Before targeted therapies, HER2-positive breast cancer was associated with a worse prognosis. Now, with effective treatments, outcomes have dramatically improved.
• Treatment: HER2-targeted drugs, such as trastuzumab (Herceptin), pertuzumab (Perjeta), and trastuzumab emtansine (Kadcyla), specifically block the HER2 protein, inhibiting cell growth and inducing tumor cell death. These therapies are a cornerstone of treatment for HER2-positive breast cancer in both early and advanced stages.

Accurate assessment of HER2 status (either amplification of the gene or overexpression of the protein) is crucial for guiding treatment decisions.

HER2/neu in Gastric Cancer

HER2 overexpression occurs in about 15-20% of gastric and gastroesophageal junction (GEJ) adenocarcinomas. Similar to breast cancer, HER2-positive gastric cancer is also associated with a more aggressive disease course.

• Prognosis: HER2-positive gastric cancer patients may have a poorer prognosis without targeted therapy.
• Treatment: Trastuzumab, in combination with chemotherapy, has been shown to improve survival in patients with HER2-positive advanced gastric or GEJ adenocarcinoma, making HER2 testing a standard practice for these patients.

The pattern of HER2 expression can be heterogeneous in gastric cancer, making tissue sampling and interpretation important.

Serum HER2/neu Testing

The HER2/neu protein has an extracellular domain (ECD) that can be shed from the surface of tumor cells and circulate in the bloodstream. This soluble form is referred to as serum HER2/neu (sHER2) or HER2 ECD.

• Mechanism: Cleavage of the extracellular domain can occur naturally or be enhanced by metalloproteinases produced by tumor cells.
• Clinical Utility: Serum HER2/neu levels can be elevated in patients with HER2-overexpressing tumors, particularly in metastatic settings.
• Advantages:
  • Non-invasive: A simple blood test, avoiding the need for repeat biopsies.
  • Monitoring: Useful for monitoring disease progression, recurrence, and response to therapy, especially in advanced breast and gastric cancers.
  • Predictive Value: In some cases, elevated sHER2 levels may indicate a higher tumor burden and poorer prognosis, and a decrease in sHER2 levels can correlate with treatment response.
• Limitations:
  • Sensitivity: Not all HER2-positive tumors shed sufficient amounts of sHER2 into the bloodstream to cause elevated levels, so sHER2 testing alone is not sufficient for initial diagnosis.
  • Correlation: While generally correlated, sHER2 levels do not always perfectly reflect tissue HER2 status.
  • Specificity: Mild elevations can occur in some benign conditions, though significant elevations are highly suggestive of cancer.

Serum HER2/neu is primarily used as a monitoring tool in patients with known HER2-positive metastatic disease, especially when tissue re-biopsy is not feasible.

Interpreting Serum HER2/neu Levels

Reference ranges for serum HER2/neu can vary between laboratories, but generally:

• Normal Range: Typically less than 15 ng/mL (or equivalent U/mL).
• Elevated Levels: Levels above the upper limit of normal, particularly significantly elevated levels (> 15 ng/mL, or higher thresholds depending on the assay), suggest the presence of HER2-overexpressing cancer.
• Monitoring Treatment:
  • A decrease in sHER2 levels during targeted therapy (e.g., trastuzumab) can indicate a positive response to treatment.
  • A rise in sHER2 levels may suggest disease progression or recurrence.
• Prognostic Value: Higher baseline sHER2 levels can be associated with a greater tumor burden and a less favorable prognosis in metastatic breast cancer.

It is important to interpret sHER2 results in conjunction with clinical context, imaging studies, and tissue HER2 status. Serum HER2/neu is not recommended as a standalone diagnostic test for primary HER2 status but serves as a valuable adjunct for monitoring.

Frequently Asked Questions (FAQ)

References

1. National Cancer Institute (NCI). (n.d.). HER2 (Human Epidermal Growth Factor Receptor 2). NCI Dictionary of Cancer Terms. Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-terms/def/her2
2. American Society of Clinical Oncology (ASCO) & College of American Pathologists (CAP). (2018). Guideline for HER2 Testing in Breast Cancer. Journal of Clinical Oncology, 36(20), 2095-2111.
3. Rüschoff, J., Hanna, W., Bilous, M., et al. (2012). HER2 testing in gastric cancer: a practical approach. Modern Pathology, 25(11), 1545-1559.
4. Maurer, M., Cirkel, S., & Harbeck, N. (2019). Clinical utility of serum HER2 as a biomarker in breast cancer. Translational Oncology, 12(10), 1279-1286.
5. Diemer, D., & Esteva, F. J. (2020). HER2 in Breast Cancer: From Pathogenesis to Targeted Treatment. In: J. R. Harris et al. (Eds.), Diseases of the Breast (6th ed.). Wolters Kluwer. (General reference for HER2 in breast cancer).
6. Bang, Y. J., Van Cutsem, E., Feyereislova, A., et al. (2010). Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. The Lancet, 376(9742), 687-697.