Targeted therapy is an important part of the comprehensive treatment of gastric cancer. Targeted therapy can be simply understood as “targeted blasting”, that is, drug treatment targeting some clear cancer-causing sites in gastric cancer cells to cause specific death of tumor cells without endangering surrounding normal cells. At present, which target is the main target of targeted gastric cancer treatment in China for “targeted blasting”? Our experts have issued a guiding document on molecular targeted therapy for HER2-positive advanced gastric cancer, and this article will also introduce the most important target of gastric cancer, Human Epidermalgrowth Factor Receptor 2 (HEGF 2), through the “3Ws”. In this article, the most important target for gastric cancer, the Human Epidermalgrowth Factor Receptor2 (HER2), is introduced through the “3Ws”.
What:What is HER2?
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In layman’s terms, HER2 is a receptor, a protein, on the surface of cells. In normal cells, HER2 is a dedicated “messenger” that transmits growth signals from outside the cell to inside the cell, promoting cell growth and division through signaling. Under normal circumstances, these “messengers” carry out their missions in an orderly manner in the body, allowing cells to “age” normally, complete their proliferation, apoptosis, and participate in vascular and lymphatic vessel renewal. However, when these “messengers” are provoked, they will become abnormally active and even do whatever they want in the body together with other partners (they can form dimer or heterodimer with other family members), thus causing abnormal activation of signaling pathways in tumor cells and leading to tumor development. The tumor cells are not only the most active, but also the most aggressive.
Who: Which patients need HER2 testing?
China’s guidelines for HER2 testing in gastric cancer (2016 version) state that the following patients should be tested for HER2.
- All patients with pathologically confirmed gastric cancer need to be tested for HER2; for patients with gastric cancer who have been seen but have not been tested for HER2, even if they missed the opportunity for early detection, the test should be performed as soon as possible, which may provide a whole new turnaround in the treatment of advanced gastric cancer.
- For lesions after neoadjuvant therapy and for recurrent or metastatic lesions, re-testing for HER2 is recommended if sufficient specimens are available. Foreign studies have demonstrated that for patients with gastric cancer with a negative initial HER2 status, testing for HER2 status after obtaining specimens again can increase the detection rate of positive HER2 by 5.7% to 8.7%, and in addition, studies have shown that neoadjuvant chemotherapy can affect the HER2 status of gastric cancer. Patients who were HER2-positive after retesting benefited from chemotherapy combined with targeted therapy to a similar extent as those who were initially tested HER2-positive.
Both specimens from gastroscopic biopsies and surgical specimens can be used for HER2 testing. Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the main methods used for HER2 testing. If the IHC result is 2 plus, further FISH testing is required, and if FISH is also positive, the diagnosis of HER2 positivity is confirmed.
Why: Why test for HER2?
HER2 status is important in relation to treatment options and prognosis for gastric cancer, so HER2 testing is needed for appropriate gastric cancer patients.
HER2 status determines benefit of targeted therapy
HER2 status has now been shown to be a clear predictor of efficacy for targeted trastuzumab therapy, which simply means that HER2 status directly determines whether a patient is suitable for targeted therapy, with HER2-positive patients with advanced gastric cancer benefiting from targeted trastuzumab therapy and negative patients not being suitable for targeted trastuzumab therapy.
In a milestone in the history of targeted therapy for gastric cancer, the ToGA study demonstrated for the first time that trastuzumab in combination with chemotherapy improved survival in patients with HER2-positive advanced gastric cancer, and that trastuzumab treatment in combination with standard chemotherapy extended median survival to 16.0 months from 11.8 months with standard chemotherapy in patients with HER2 expression of IHC2+/FISH+ or IHC3+. Further studies have shown that the level of HER2 gene amplification can be used to predict the sensitivity to trastuzumab therapy in patients with advanced gastric cancer, with higher levels of gene amplification associated with higher sensitivity to trastuzumab therapy.
Based on the results of this study, trastuzumab was the first targeted agent recommended by the National Comprehensive Cancer Network (NCCN) guidelines for advanced gastric cancer, and it was also recommended by the Chinese Society of Clinical Oncology (CSCO), the National Cancer Institute (NCI), and the National Cancer Institute (NCI). Oncology (CSCO), the U.S. Food and Drug Administration (FDA), and the European Commission (EC) for patients with primary HER2-positive metastatic gastric cancer and gastroesophageal junction cancer.
For patients with advanced gastric cancer, every additional treatment means an additional chance of survival, so it is common for doctors to test and evaluate a patient’s HER status to determine whether they are a candidate for targeted therapy.
HER2
HER2 may indicate prognosis in some cases
Often patients and families with gastric cancer see a positive HER2 and panic: “Does a positive HER2 mean a bad prognosis?” The prognosis based on HER2 alone is inappropriate, and there is a lack of evidence-based medical evidence. Several studies have shown that HER2 may be associated with poor prognosis in patients with early gastric cancer, but is not an independent prognostic factor for advanced gastric cancer; the earlier the stage of gastric cancer (e.g., stage I), the higher the risk of recurrence for HER2 positive versus HER2 negative patients. The prognosis is best for HER2-negative patients with intestinal gastric cancer and worst for HER2-positive patients with diffuse gastric cancer.
HER2 may correlate with clinicopathologic features
There are numerous studies on HER2 status and the clinicopathologic features of gastric cancer, with widely varying results. However, most studies have shown that the rate of HER2 positivity is higher in Lauren typed intestinal, highly differentiated gastric cancer than in diffuse, poorly differentiated gastric cancer; patients with lymphovascular invasion, lymph node metastases, and liver metastases have a higher rate of HER2 positivity. The study showed that HER2 status was not related to the depth of tumor infiltration and stage.
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The current study suggests that HER2 status may correlate with chemosensitivity in advanced gastric cancer, with HER2-positive gastric cancer having higher chemosensitivity than negative gastric cancer. HER2 status may also guide the screening of patients for benefit from postoperative adjuvant therapy for gastric cancer, and patients with HER2-negative gastric cancer may benefit more from postoperative adjuvant therapy.
The rate of HER2 positivity in Chinese gastric cancer patients is 12% to 13%, which means that 1 in 7 to 8 gastric cancer patients in China are HER2 positive. The awareness of HER2 testing among gastric cancer patients in China is generally low, resulting in many HER2-positive patients missing treatment opportunities. (Contributed by Yanwen Diao, Department of Medical Oncology, First Affiliated Hospital of China Medical University)