HER2 Positive Gastric Cancer
HER2 positive gastric cancer is a distinct type of stomach cancer that produces high levels of a protein called HER2, making it grow faster than other types. This discovery has led to new targeted treatments that can help patients live longer.
Table of contents
- What is HER2 Positive Gastric Cancer?
- How Common is This Type of Cancer?
- Understanding the HER2 Protein
- Detection and Testing
- First-Line Treatment Options
- Second-Line Treatment Options
- Survival and Prognosis
- Ongoing Research and Future Treatments
What is HER2 Positive Gastric Cancer?
HER2 positive gastric cancer is a specific type of stomach cancer where cancer cells produce too many copies of a protein called HER2 (human epidermal growth factor receptor 2). This protein is found on the surface of all cells and normally helps control cell growth. However, when cancer cells have too much HER2 protein, they grow and divide much faster than normal cells, causing the cancer to spread more quickly[1].
This type of cancer can occur in the stomach itself or at the gastroesophageal junction (GEJ), which is the area where the tube that carries food from your mouth (the esophagus) meets the stomach[2]. The discovery that HER2 plays a role in gastric cancer has created a new way to classify and treat this disease[1].
How Common is This Type of Cancer?
About 15% to 20% of all gastric cancers are HER2 positive[6][13]. However, the percentage varies depending on where the cancer is located. When the cancer develops specifically at the gastroesophageal junction, about 30% of cases are HER2 positive. In contrast, when the cancer is located in other parts of the stomach, only about 15% of cases test positive for HER2[2].
Overall, gastric cancer is a major health concern worldwide, ranking as the fifth most common cancer globally and the fourth leading cause of cancer deaths[1]. In the United States, approximately 43,280 new cases of stomach and esophageal cancer are diagnosed each year[5].
Understanding the HER2 Protein
HER2 is a protein that sits on the surface of cells and belongs to a family of proteins called the epidermal growth factor receptor (EGFR) family. This family includes four related proteins: HER1 (also called EGFR), HER2, HER3, and HER4[6]. These proteins work together to send signals that tell cells when to grow and divide.
In HER2 positive cancer, the gene that makes HER2 protein is amplified, meaning there are too many copies of it. This causes the cancer cells to produce excessive amounts of HER2 protein on their surface. When this happens, the growth signals become overactive, causing cancer cells to multiply rapidly and making the disease more aggressive[1][6].
Detection and Testing
Testing for HER2 is done on a sample of the tumor tissue, usually obtained through a biopsy (a procedure where a small piece of tissue is removed for examination)[4]. The testing is performed in specialized laboratories using approved methods.
There are two main ways to test for HER2. One method looks at how many copies of the HER2 gene are present, while another method measures how much HER2 protein is on the cell surface. The results are reported using a scoring system. Tumors are considered HER2 positive if they score as “IHC 3+” (meaning a high amount of protein) or “IHC 2+/ISH+” (meaning a moderate amount of protein confirmed by a second test)[4][10].
Healthcare providers use tests approved by regulatory authorities to ensure accurate results. Proper testing is essential because it determines whether a patient can receive HER2-targeted treatments[4].
First-Line Treatment Options
When HER2 positive gastric cancer is first diagnosed as advanced or has spread to other parts of the body, the main treatment combines chemotherapy with a targeted drug called trastuzumab (also known by the brand name Herceptin). Trastuzumab is a monoclonal antibody, which is a specially designed protein that attaches to the HER2 protein on cancer cells and stops them from growing[7][9].
A major clinical trial called ToGA, completed in 2010, showed that adding trastuzumab to chemotherapy helped people with HER2 positive gastric cancer live longer than those who received chemotherapy alone. This was the first major improvement in treatment for gastric cancer in decades[2][7]. In this study, patients who received trastuzumab plus chemotherapy lived for a median of 13.5 months, compared to 11.0 months for those who received only chemotherapy[9].
More recently, doctors have begun adding an immunotherapy drug called pembrolizumab (Keytruda) to the combination of trastuzumab and chemotherapy. However, this combination works only for patients whose tumors also have high levels of another protein called PD-L1. About 85% of patients with HER2 positive gastric cancer have elevated PD-L1 levels. For these patients, adding pembrolizumab to trastuzumab and chemotherapy has led to meaningful improvements in how long they live without the cancer getting worse[2][7].
Second-Line Treatment Options
When the cancer continues to grow despite initial treatment with trastuzumab, patients may be offered a different type of HER2-targeted therapy called trastuzumab deruxtecan (also known as T-DXd or by the brand name Enhertu). This drug is an antibody-drug conjugate, which means it combines a targeted antibody with a chemotherapy drug. The antibody finds and attaches to HER2 positive cancer cells, and then delivers the chemotherapy directly into those cells[6][13].
Clinical trials have shown that trastuzumab deruxtecan is effective as a second-line treatment. In a study called DESTINY-Gastric04, patients who received trastuzumab deruxtecan lived for a median of 14.7 months, compared to 11.4 months for patients who received standard chemotherapy. This represents an improvement of about 3 months in survival[20].
Trastuzumab deruxtecan has been approved in more than 65 countries for use in patients with HER2 positive gastric cancer who have already received trastuzumab-based treatment[6][10].
Survival and Prognosis
The outlook for patients with HER2 positive gastric cancer depends on many factors, including how advanced the cancer is when it is first found and how well it responds to treatment. For stomach cancer in general, when the disease has spread to distant parts of the body, the 5-year survival rate is about 5% to 10%[10][15].
However, survival rates vary significantly based on the stage of the cancer. For cancer that is still localized only in the stomach, about 70% of patients survive for 5 years. When the cancer has spread to nearby lymph nodes or structures, this rate drops to 32%. For cancer that has spread to distant organs, only about 5% of patients survive for 5 years[15].
The introduction of HER2-targeted treatments has improved outcomes for patients with HER2 positive gastric cancer. Before these treatments were available, patients typically lived less than one year after diagnosis with advanced disease. With current treatments, survival has improved, though the disease remains challenging to treat[13].
Ongoing Research and Future Treatments
Researchers continue to study new ways to treat HER2 positive gastric cancer. Several approaches are being investigated in clinical trials[1][6]:
- New HER2-targeted antibody-drug conjugates with different designs and delivery systems
- Drugs that block HER2 in different ways, such as pertuzumab, which prevents HER2 from pairing with other growth factor receptors
- Combinations of multiple HER2-targeted drugs used together
- Using HER2-targeted treatments earlier in the disease, including before surgery in patients whose cancer has not yet spread
- Combining HER2-targeted drugs with immunotherapy drugs to help the immune system fight the cancer
One ongoing trial called DESTINY-Gastric05 is testing whether trastuzumab deruxtecan, when combined with chemotherapy and immunotherapy, can be used as a first-line treatment instead of trastuzumab. This trial is evaluating whether this approach can help patients live longer while potentially reducing some of the side effects associated with standard chemotherapy[10].
Despite these advances, challenges remain. Not all patients with HER2 positive gastric cancer respond to treatment, and most patients who initially benefit from HER2-targeted drugs eventually develop resistance, meaning the drugs stop working. Understanding why this happens and finding ways to overcome resistance are major focuses of current research[5][6].
