MSI-High Gastric Cancer: Prognosis and Treatment

Gastric cancer, a disease originating in the stomach lining, is not a single entity. It can be categorized into different types based on its molecular makeup, which helps guide treatment choices. One subtype is MSI-High gastric cancer, which has distinct biological origins and implications for patient care and future outcomes.

Defining MSI-High in Gastric Cancer

Our cells contain short, repetitive DNA sequences called microsatellites. The DNA Mismatch Repair (MMR) system functions as a proofreader, correcting errors when DNA copies itself, and is particularly active in these prone-to-error regions. When the MMR system is faulty, or deficient (dMMR), it fails to correct replication errors.

As a result, the lengths of these microsatellite tracts can change as insertions or deletions accumulate, a condition termed Microsatellite Instability (MSI). The designation “MSI-High” (MSI-H) signifies a large number of unstable microsatellites, pointing to a deficient MMR system. This is distinct from tumors that are Microsatellite Stable (MSS) or have low instability (MSI-L), where the MMR system is functional. This breakdown in DNA repair is a key process in the development of these cancers, leading to a high rate of genetic mutations.

Identification and Prevalence

Determining a tumor’s MSI status is a standard part of its molecular workup. One common technique is a Polymerase Chain Reaction (PCR)-based test, which amplifies specific microsatellite markers from the tumor’s DNA to see if they have changed in length compared to normal tissue.

Another approach is Immunohistochemistry (IHC), which assesses the MMR proteins directly. It uses antibodies to detect the presence of the main MMR proteins:

• MLH1
• MSH2
• MSH6
• PMS2

The absence of one or more of these proteins indicates a deficient MMR system and correlates with an MSI-High status. Next-Generation Sequencing (NGS) panels are also increasingly used and can report MSI status concurrently with other genetic information.

MSI-High status occurs in approximately 9% to 20% of gastric cancers. This frequency is influenced by factors like cancer stage and geography, with MSI-High tumors seen more often in older patients and in the lower part of the stomach (antrum).

Unique Features and Outlook

MSI-High gastric cancers are frequently located in the stomach’s antrum and are of the intestinal type according to the Lauren classification. Histologically, they may show features like mucus, signet ring cells, or a medullary growth pattern characterized by solid sheets of cells.

A defining feature of many MSI-High tumors is the presence of a dense infiltration of immune cells, known as tumor-infiltrating lymphocytes (TILs). This immune reaction is triggered by the high number of mutations in the cancer cells, which makes them appear foreign to the immune system.

The prognosis for patients with localized MSI-High gastric cancer is often more favorable compared to those with MSS tumors. However, some research suggests that MSI-High tumors may derive less benefit from certain standard chemotherapy drugs, like 5-fluorouracil (5-FU), when used after surgery, though this is a complex area of ongoing research.

Targeted Therapies and Immunotherapy Response

The development of immunotherapy has been a significant advance in treating MSI-High gastric cancer. Drugs called immune checkpoint inhibitors have shown high effectiveness. These drugs, including PD-1 and PD-L1 inhibitors like pembrolizumab and nivolumab, work by releasing the natural brakes on immune cells, allowing them to attack cancer cells more effectively.

MSI-High tumors respond well to immunotherapy because of their genetic makeup. The faulty DNA repair system leads to thousands of mutations, causing cancer cells to produce abnormal proteins called neoantigens. These neoantigens act as flags, making the tumor cells highly visible to the immune system, and checkpoint inhibitors amplify this existing immune recognition.

This connection has led to regulatory approvals for checkpoint inhibitors based on the MSI-H biomarker itself, regardless of the cancer’s origin. In metastatic gastric cancer, immunotherapy has improved outcomes for patients with MSI-High tumors, showing high response rates and prolonged survival compared to traditional chemotherapy.

Hereditary Connections and Implications

While many MSI-High gastric cancers arise sporadically, a portion are linked to an inherited condition known as Lynch syndrome. Lynch syndrome, also called Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is caused by a germline mutation in an MMR gene (MLH1, MSH2, MSH6, or PMS2) that is present in all cells and can be passed down through families.

A diagnosis of an MSI-High gastric cancer should prompt consideration of Lynch syndrome, and genetic counseling and germline testing can determine if the cancer is part of this hereditary syndrome. Confirming Lynch syndrome means the patient has an increased lifetime risk for other cancers, including colorectal, endometrial, and ovarian, which necessitates lifelong surveillance.

A diagnosis also has implications for the patient’s relatives, who can undergo cascade testing to see if they carry the mutation. This allows at-risk individuals to pursue preventive measures and enhanced screening protocols to manage their own cancer risks. This hereditary form is distinct from the more common sporadic cases, which are often caused by the silencing of the MLH1 gene through a process confined to the tumor itself.