SCIENTIFIC BACKGROUND
Gastric cancer (GC) or stomach cancer is one of the most common malignancies and the 4th leading cause of cancer-related death. Men are affected twice as often as women. GC is a multifactorial disease in which both environmental and genetic factors can have an impact on its occurrence and development. The incidence rate of GC rises progressively with age; the median age at diagnosis is 70 years. However, approximately 10% of gastric carcinomas are detected at the age of 45 or younger.
Before cancer develops, pre-cancerous changes often occur in the inner lining (mucosa) of the stomach. These early changes rarely cause symptoms, so they often go undetected. Cancers starting in different sections of the stomach can cause different symptoms and tend to have different outcomes. The cancer’s location can also affect treatment options.
About 90-95% are adenocarcinomas. These cancers develop from the gland cells in the mucosa. There are two main types of stomach adenocarcinomas: intestinal and diffuse. The intestinal type tends to have a slightly better prognosis. The cancer cells are more likely to have certain gene changes that might allow for treatment with targeted-therapy. The diffuse type tends to grow and spread more quickly. It is less common than the intestinal type, and it tends to be harder to treat.
The prognosis of patients is mainly determined by the stage, but also by histology, general condition and comorbidity. In early and localized stages, the therapy is curative, in metastatic stages, palliative. Therapeutic modalities are mainly surgery and medical tumor therapy. Despite some progress in the last 10 years, cancer-specific mortality is very high, at 70%.
GENOMIC ALTERATIONS
If the cells have a certain amount of an immune checkpoint protein called PD-L1, treatment with an immune checkpoint inhibitor such as pembrolizumab (Keytruda) might be an option. For Patients with high levels of microsatellite instability (MSI-H) or with a high tumor mutational burden (TMB-H), treatment with an immune checkpoint inhibitor might be recommended. If the cells have changes in one of the NTRK genes, certain targeted drugs can be an option for treatment.
POSSIBLE THERAPIES
In some people with stomach cancer, the cancer cells have too much of a growth-promoting protein called HER2 on their surface. Cancers with increased levels of HER2 are called HER2-positive. Drugs like trastuzumab that target the HER2 protein can often be helpful in treating these cancers.
Adding trastuzumab to chemo can help some people with advanced, HER2-positive stomach cancer live longer than just chemo alone. This drug only works if the cancer cells have too much HER2, so samples of the cancer must be tested for HER2 before starting treatment. Several similar versions (called biosimilars) are now available as well, including Ogivri, Herzuma, Ontruzant, Trazimera, and Kanjinti.
Fam-trastuzumab deruxtecan (Enhertu) is an antibody-drug conjugate (ADC), which is a monoclonal antibody linked to a chemotherapy drug. In this case, the anti-HER2 antibody attaches to the HER2 protein on cancer cells, bringing the chemo directly to them. This ADC can be used by itself to treat advanced HER2-positive stomach cancer, typically after treatment with trastuzumab has been tried.
Ramucirumab is a monoclonal antibody that binds to a VEGF receptor. This keeps VEGF from binding to cells and telling them to make more blood vessels. This can help slow or stop the growth of some cancers. Ramucirumab is used to treat advanced stomach cancer, most often after at least one chemo drug (or combination) stops working.
A very small number of stomach cancers have changes in one of the NTRK genes. This causes them to make abnormal TRK proteins, which can lead to abnormal cell growth and cancer. Larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) are drugs that target the TRK proteins. These drugs can be used to treat advanced cancers with NTRK gene changes that are still growing despite other treatments.
GENE PANEL
19 genes: ATM, BMPR1A, BRCA1, BRCA2, CDH1, EGFR, ERBB2, MET, MLH1, MSH2, MSH6, NTRK1, NTRK2, NTRK3, PIK3CA, PMS2, RET, ROS1, SMAD4
TARGETED PANEL
NTRK1/2/3 fusion, MSI
