Stomach Cancer Biomarkers
List of Biomarkers
Tried and tested (established) biomarkers are used to assist in clinical decision-making.5
HER2 6 (“her” 2); is a protein involved in normal cell growth. However, cancer cells can have larger than normal amounts of HER2. These larger amounts of HER2 can cause cells to grow more quickly and spread to other parts of the body.
Cancer cells that have a large amount of HER2 are called HER2 positive. Around 22% of gastric cancers are HER2-positive. HER2-positive tumors are treated with anti-HER2 targeted therapies.
Cancer cells that have only a small amount of HER2 are called HER2 negative. HER2-negative tumors do not benefit from anti-HER2 targeted therapies.
Testing a tumor (cancer) sample for amounts of HER2 (positive or negative) is standard upon a new diagnosis of stage IV gastric or GEJ cancer as it can help plan treatment.
*HER2 can also be called c-erbB-2, HER2/neu, human EGF receptor 2, and human epidermal growth factor receptor 2.
Microsatellite instability (MSI)
Microsatellites are short, repeated strings of DNA. Changes called mutations within microsatellites cause microsatellite instability.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.
- 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 ( “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 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.
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.
Biomarker Associated Treatments Overview
The way that physicians use biomarkers to guide patient treatment is shown below.
HER2 testing should be done at the time of diagnosis or as soon as possible before treatment.
For patients with HER2-positive cancer, trastuzumab is usually given along with chemotherapy as the first line of attack. Pembrolizumab can also be added to this first therapy course, but patients seem not to benefit much unless a PD-L1 score is 10 or higher (see PD-L1 and MSI below).
If the first line of attack with trastuzumab + chemotherapy does not work, fam-trastuzumab deruxtecan-nxki is the next (second) line of attack. Fam-trastuzumab deruxtecan-nxki is trastuzumab linked with a drug that blocks DNA copying in cancer cells and kills them. Fam-trastuzumab deruxtecan-nxki is called an “antibody-drug conjugate”)
As the first line of attack, patients with HER2-negative cancers are treated with a chemotherapy regimen—combined with nivolumab if the patient tumor has the required PD-L1 score. Go to PD-L1 below.
A different chemotherapy regimen is usually used in the next (second) line of attack.
PD-L1 and MSI/MMR testing should be done along with HER2 at the time of diagnosis or as soon as possible before treatment.
HER2-negative status often pairs with higher tumor PD-L1 levels (amounts).
Preferred first-line treatments for patients with HER2-negative gastric cancer include nivolumab combined with chemotherapy for tumors with a PD-L1 score of 5 or more. Nivolumab may also be helpful for tumors with a PD-L1 score of less than 5 if it looks like the patient has very few treatment options. This could be talked over with the treating physician.
Treatment with pembrolizumab/nivolumab is based on testing for MSI/MMR, PD-L1, or high tumor mutation burden (TMB)
PD-L1 and MSI/MMR testing should be done along with HER2 at the time of diagnosis or as soon as possible before treatment. MSI-H tumors should receive checkpoint inhibitor with either nivolumab or pembrolizumab, with or without chemotherapy (discussion with the oncologist regarding this decision is necessary)
If a patient fails their first therapy and their tumors are MSI-H/dMMR, and immunotherapy treatment has not yet been used for whatever reason, then treatment with pembrolizumab or dostarlimab (another PD-1 antibody) is recommended
If a patient fails their first therapy and their tumors are TMB-high (greater than or the same as 10 mut/Mb), pembrolizumab treatment is an option
If a patient fails their first therapy and their tumors are NTRK fusion-positive, entrectinib or larotrectinib are treatment options.
A lot still needs to be learned about how biomarkers can be used in cancer care and how they can be tested. Researchers are trying to fill those gaps using lab studies and clinical trials.
The following biomarkers and treatments are worth keeping an eye on and might be tested if you decide to enroll in a clinical trial.
Claudin 18.2 (CLDN18.2)
Claudins are proteins that keep in check the flow of molecules between cells. One of these proteins, claudin 18.2, is found in the healthy stomach mucosa (a moist protective stomach lining). However, it seems that claudin 18.2 is involved in some gastric cancer formation and growth. Between 14% and 87% of gastric cancers have this protein, and around 35% of metastatic gastric/GEJ cancers produce it in large quantities.
Claudin 18.2 is exposed in an unusual way on gastric/GEJ cancer cells, making the claudin protein available for binding of targeted monoclonal antibodies. 11An antibody is a protein that binds and responds to another protein, in this case, the Claudin 18.2 biomarker protein on the cancer cell.
Claudin 18.2-directed monoclonal antibodies under study for gastric/GEJ cancers include zolbetuximab.12
In the global phase 3 SPOTLIGHT trial, NCT03504397, first-line treatment with zolbetuximab combined with mFOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) led to significantly longer survival in patients with Claudin 18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ cancer.13 An “antibody-drug conjugate” called CMG901 (a monoclonal antibody targeting Claudin 18.2 linked to a cancer-killing drug) is also being studied [NCT04805307].
Claudin 18.2 protein amounts are measured using IHC.
Fibroblast growth factor receptor 2 (FGFR2) is a member of the FGFR family of genes and proteins. The FGFR2 gene creates a protein that helps all cells grow and new blood vessels form.11
FGFR2b is an unusual form of FGFR2 called a “splice variant.” Unusually high amounts of FGFR2b lead to unusually high cell growth and blood vessel formation.14,15
A cancer with high amounts of FGFR2b is called “FGFR2b-positive.”
Bemarituzumab is an antibody against FGFR2b. Bemarituzumab, in combination with chemotherapy, was tested in patients who had advanced or metastatic gastric/GEJ tumors that were FGFR2b-positive and HER2-negative. Patients must have had tumors with at least 10% FGFR2b [ClinicalTrials.gov identifier NCT03694522].16
Around 80%-85% of patients with advanced gastric/GEJ cancers are HER2-negative, and about 30% of these patients are FGFR2b-positive. In these 30% HER2-negative/FGFR2b positive patients, bemarituzumab was beneficial.16
Amounts of FGFR2b protein are measured using IHC, and quantities of FGFR2b gene are measured by ctDNA sequencing (analysis) using NGS, for example.
A mucosal barrier (a thin wall of skin that produces mucus to protect the stomach) contains proteins called mucins.17 One mucin, MUC17, is made at higher than normal amounts in about 50% (half) of gastric/GEJ cancers, which are called MUC17 positive cancers. An ongoing trial is studying a type of immunotherapy called AMG 199 in patients with MUC17-positive gastric/GEJ cancers [ClinicalTrials.gov Identifier: NCT04117958].
Amounts of MUC17 are measured using IHC
- ACS. American Cancer Society. Cancer Facts & Figures 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf. Accessed 05-19-2023.
- Sung, H., et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71, 209-249 (2021).
- ACS. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/precision-medicine.html).
- ACS. https://www.cancer.gov/about-cancer/treatment/types/biomarker-testing-cancer-treatment.
- Ajani, J.A., et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 20, 167-192 (2022).
- 6. NCI. National Cancer Institute. NCI dictionary of cancer terms: HER2. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/her2.
- NCI. National Cancer Institute. NCI dictionary of cancer terms: Microsatellite Instability https://www.cancer.gov/publications/dictionaries/cancer-terms/def/microsatellite-instability.
- NCI. National Cancer Institute. NCI dictionary of cancer terms: PD-1 https://www.cancer.gov/publications/dictionaries/cancer-terms/def/pd-1.
- NCI. National Cancer Institute. NCI dictionary of cancer terms: TMB https://www.cancer.gov/publications/dictionaries/cancer-terms/def/tmb.
- NCI. National Cancer Institute. NCI dictionary of cancer terms: NTRK gene fusion https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ntrk-gene-fusion.
- Singh, P., Toom, S. & Huang, Y. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. Journal of Hematology & Oncology 10, 105 (2017).
- Sahin, U., et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol 32, 609-619 (2021).
- Kohei Shitara, Florian Lordick, Yung-Jue Bang, Peter C. Enzinger, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. J Clin Oncol 41, 2023 (suppl 4; abstr LBA292). DOI 10.1200/JCO.2023.41.4_suppl.LBA292
- NCI. National Cancer Institute. NCI dictionary of cancer terms: FGFR2 gene. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/fgfr2-gene.
- Ooki, A. & Yamaguchi, K. The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer 24, 1169-1183 (2021).
- Wainberg, Z.A., et al. Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT). Journal of Clinical Oncology 39, 160-160 (2021).
- Kufe, D.W. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 9, 874-885 (2009).