Stomach Cancer Biomarkers

Microsatellites are short, repeated strings of DNA. Changes called mutations within microsatellites cause microsatellite instability.⁷

MSI-H ⁷

A cancer described as ‘microsatellite instability-high, or ‘MSI-H’ ( “MSI high”), contains a high number of mutations in its microsatellites. Scientists within laboratories can test for microsatellite mutations in a tumor sample, and if this testing shows mutations in 30% or more microsatellites, the cancer is called MSI-H.

Our body’s cells naturally age and get damaged, and so are constantly creating their own younger replacements. To do this, cells must make a copy of their complete set of DNA. This copying process is called replication. When DNA is copied to make a new cell, mistakes can occur. Cells usually correct these mistakes and go on to make healthy copies of themselves.

However, MSI-H cells seem to have a weakness (or deficiency) in their ability to correct mistakes that happen when their DNA is copied to make a new cell.

About 4% of gastric cancers and GEJ cancers can be MSI-H. Knowing whether cancer is MSI-H may help plan the best treatment; this subgroup of tumors tends to be very sensitive to immunotherapy checkpoint inhibitors including anti-PD1/PDL1 and anti-CTLA4 therapies.

Of note:

• MSI-H is caused by dMMR, which stands for ‘mismatch repair deficiency’. In some cancers, mismatch repair genes and proteins can end up being wrong or working incorrectly through gene changes (mutations, deletion, or other mistakes), resulting in a lack of ability to properly correct mistakes in DNA replication. Consequently, abnormal (odd) gene mutations and proteins in the cancer cells become a permanent problem, causing these cells to multiply quickly and invade other tissues.
• Tumors that are not MSI-H are called microsatellite stable or MSS.
• You might see MSI-H described as MSI-H/dMMR. MSI-H/dMMR.

MSI-H tumors tend to highly express a protein called PD-L1.

PD-L1 ⁸

PD-L1 ( “P.D.L.1”) is a protein found on various cells in our body, including some cancer cells.

PD-1 (“P.D.1”) is a protein expressed on T cells, a type of immune cell.

PD-L1 naturally binds to PD-1 on T cells. When PD-L1 and PD-1 bind, this interaction ‘turns off’ T cells, which can then no longer kill other cells, including cancer cells. We say that PD-1 and PD-L1 binding puts the “brakes” on our body’s immune response to whatever cell expresses PD-L1, whether it be a normal cell (it puts the brakes on autoimmunity) or on cancer cells (it helps cancer cells evade our immune system).

Anticancer drugs called immune checkpoint inhibitors are used to block either PD-1 or PD-L1 and stop these two proteins from binding. When PD-1 and PD-L1 cannot bind, the “brakes” on the immune system are released, and T cells are free to kill the target cell, in this case, cancer cells.¹⁵

Gastric cancer cells sometimes make quite a lot of PD-L1, especially MSI-H/dMMR tumors.

A laboratory will measure the amount of PD-L1 in a patient’s tumor sample. The higher the amount, the more PD-L1 “positive” that cancer is. The laboratory then gives that cancer a score called a PD-L1 “combined positive score” (CPS). From now on, this will be referred to simply as the “PD-L1 score”. The laboratory ranks the cancer as having a PD-L1 score greater than 1 (>1), a PD-L1 score greater than 5 (>5), or a PD-L1 score greater than 10 (>10). The more PD-L1 that is made, the higher the PD-L1 score.

The higher the PD-L1 score, the better chance that an immune checkpoint inhibitor will work. Numerous studies have repeatedly shown that immune checkpoint inhibitors in the setting of tumors with low/negative PD-L1 scores are not effective.

TMB ⁹

TMB  stands for ‘tumor mutation burden”. This is the total number of mutations (changes) found in the DNA of cancer cells. The number is reported as “mutations per megabase” or “mut/Mb.” A high TMB score is generally greater than or the same as 10 mut/Mb. MSI-H tumors are ‘hypermutated’ and have very high TMB scores. However, some tumors that are not MSI-H (called MSS, or microsatellite stable) also have high TMB scores. Some studies suggest that the higher the TMB score, the higher the chance that immunotherapy checkpoint inhibitors will be effective.

NTRK¹⁰

For NTRK (“entrek”), we talk about NTRK gene fusions (“entrek jean fyoo-zhuns”). In a gene fusion, pieces of genes from 2 different areas join together in an unusual way. In the NTRK gene fusion (often simply called an NTRK fusion), a piece of the NTRK gene joins with another piece of gene. NTRK fusions lead to unusual (abnormal) TRK ( “trek”) proteins, and these abnormal proteins can cause cancer cells to grow.

Although generally rare, NTRK fusions can be found in stomach cancer (<1% of all gastroesophageal cancers). If a tumor contains an NTRK fusion, patients usually respond very well to NTRK-targeted therapy.