Immunotherapy for Gastric Cancer — You May Be Eligible But There are Considerations

“Patients certainly need to ask [their] doctor if they would be a candidate for immunotherapy,”  Dr. Alan Lima Pereira, a medical oncologist at Moffitt Cancer Center in Tampa, Florida, tells SurvivorNet.

“The test to check that is really easy. It’s kind of old and cheap test that we do at the biopsy that gave the diagnosis of cancer to the patient. We do not need to biopsy again.”

How Does Immunotherapy Work?

Normally, white blood cells find and destroy abnormal cells, but cancer cells learn to hide from them so they can continue growing and spreading. Immunotherapy drugs find the cancer cells in their hiding places by blocking proteins that shield them. Once the cancer cells are uncovered, the immune system can do its job properly.

Because these drugs zero in on cancer cells while leaving much of the surrounding healthy tissue alone, they tend to be less toxic compared to traditional chemotherapy or radiation therapy which bombard both cancerous and healthy cells. Immunotherapy can also provide a longer-lasting response by training the immune system to recognize and remember cancer cells, potentially reducing the risk of the cancer coming back.

The approach can be life-changing — and possibly even life-saving — for many patients.

Immunotherapy is Not for Everyone

“There are certain patients with preexisting autoimmune conditions such as severe rheumatoid arthritis or autoimmune hepatitis, where the risk of giving immunotherapy and over-activation [of] their immune system outweighs the benefit that you may receive from this treatment,” Dr. Nicholas J. Hornstein, medical oncologist at Northwell Cancer Institute in Manhattan, tells SurvivorNet.

“In terms of the anti-cancer component, patients who have autoimmune diseases that are on active treatment for those diseases may not have benefit from anti PD-L1 therapies due to the fact that their autoimmune diseases will be exacerbated and worsened by the treatment.”

How Do I Know if I Should Get Immunotherapy?

Molecular profiling utilizes various tests — one of which is next generation sequencing — to generate a genomic profile for the cancer, as well as identify important biomarkers that can define diagnosis, prognosis, and predict response to treatment.

This should be part of discussions between you and your healthcare team after a cancer diagnosis.

Next-generation sequencing is a super advanced tool that has changed how we study genes. It’s like a modern toolbox used by scientists to quickly and affordably read the instructions of an organism’s DNA or RNA. This has helped researchers read a lot of genetic information quickly — so they can understand entire sets of genes, find differences in genes, and study how genes work.

NGS has various names, which can be a bit puzzling. NGS is the same as next-generation testing, comprehensive genomic profiling, broad molecular profiling or high-throughput sequencing. It is also commonly referred to as molecular testing.

NGS isn’t a particular test for a specific type of cancer. Instead, it’s a group of tests or a technique that searches for all the genetic changes in a tumor’s genes.

Gastric Cancer Specific Testing

Chemotherapy, which attempts to kill all fast-growing cells in the body, has been the backbone of gastric cancer treatment for many years. However, treatment methodologies are changing. These advances involve testing your cancer for the presence of genetic mutations, or molecular features, which might be targets for relatively new medications. For some people, these medications are extending life in remarkable ways.

“If the patient’s tumor has a specific generic alteration called microsatellite instability, nowadays we can use immunotherapy for these patients,” Dr. Pereira explains.

According to NCCN guidelines, if metastatic gastric cancer is documented or suspected, it’s mandatory to perform HER2, PD-L1, CLDN18.2, and microsatellite testing (if not done previously).

HER2 Testing

The human epidermal growth factor receptor 2 (HER2) is a receptor on the surface of almost all the cells in our body, and it is one of the many receptors responsible for the communication between the cells to promote their growth, division, repair, and survival.

In other words, HER2 is one of the many receptors that help cells grow and divide when the timing is right. An error in the HER2 gene is something that doctors can look for when deciding how to treat advanced gastric cancer, as well as several other cancers. The frequency of HER2 overexpression in gastric and gastroesophageal cancer ranges from 4.4% to 53%, with a mean of 18%.

“Targeted drugs” like Enhertu or Herceptin directly seek out and bind to HER2 proteins to effectively slow down or stop the growth of the cancer. Because it avoids harming healthy tissue surrounding the cancer, it can have fewer side effects compared to traditional chemotherapy.

Microsatellite Instability in Gastric Cancer

Around 5% of gastric cancers have deficiency in mismatch repair (dMMR), the biologic footprint of which is microsatellite instability high (MSI-H).

Sometimes in cancer cells, the ability to correct DNA replication errors is disrupted by the mutation of mismatch repair (MMR) genes. When the MMR system is defective, it silences specific proteins (MLH1, MSH6, PMS2, MSH2), whose job it is to correct occasional replication errors. Thus, a mismatch repair deficiency (dMMR) allows errors to accumulate due to the lack of repairs and the accumulation of errors is known as high microsatellite instability (MSI-H).

There are two kinds of laboratory tests for this biomarker, both involve a tissue sample (biopsy) of the tumor. Depending on the method used, an abnormal result is called either microsatellite instability high or mismatch repair deficient (dMMR).

Patients who harbor this mutations, could be eligible to drugs such as nivolumab (brand name Opdivo) or pembrolizumab (brand name Keytruda).

PD-L1 Testing

“Patients who benefit from immunotherapy usually have cancer cells that express certain targets. This is known as a PD-L1 expression score, which tends to be above 1%,” Dr. Hornstein tells SurvivorNet.

PD-1, referred to as programmed cell death 1, is a protein that is found on the outer surface of cells in your immune system. PD-L1, referred to as programmed cell death ligand, is on the outer layer of some normal blood cells, as well as some cancer cells.

When PD-1 binds to PD-L1, this puts the brakes on the immune system and can prevent immune cells from attacking and killing cells. Normally, this acts as a braking mechanism to prevent our immune systems from becoming overactive and going somewhat haywire by attacking our normal cells. Cancer cells can take over or override this innate mechanism, preventing cancer cells from dying.

Claudin 18.2 Testing

“An evolving therapeutic target is something called something called claudin 18.2. It is a protein that’s tested in the tumor. If it is expressed, there is now a drug [that] — together with chemotherapy — can target that protein,” Dr. Sofya Pintova, a Gastrointestinal Medical Oncologist at Mount Sinai Hospital in New York City, tells SurvivorNet.

Vyloy is a specialized medication designed for adults with locally advanced or metastatic gastric cancer. Metastatic, or advanced, cancer means that the disease has spread to distant parts of the body and cannot be removed by surgery.

This treatment is specifically for patients whose tumors test positive for a protein called claudin 18.2 and are negative for HER2 (human epidermal growth factor receptor 2).

Questions to Ask Your Doctor

If you or a loved one has been diagnosed with gastric cancer and you’re curious about whether you would benefit from immunotherapy, consider asking your doctor some or all of the following questions:

• Should I have next-generation sequencing testing?
• Do you need both the tissue sample and blood samples for NGS testing?
• Do I have any genetic mutation that would change the course of my treatment?
• Is my gastric cancer HER2 positive or negative?
• Should I have MSI-High Testing?
• Am I eligible to receive targeted therapy? What about immunotherapy?

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