Stomach Cancer: How Immunotherapy and Targeted Therapy are Changing Treatment

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The approval of a targeted therapy and an immunotherapy drug for some patients with advanced stomach cancer reflects recent new approaches to this difficult-to-treat cancer that hasn’t had many therapeutic advances in recent years.

Stomach cancer, uncommon in the United States but a leading cause of cancer death globally, causes few definitive symptoms in early stages and is usually diagnosed too late for curative therapy. The main treatment for stomach cancer is surgery to remove the tumor, combined with chemotherapy, which can be given before or after surgery. Radiation therapy may also be used in combination with surgery or chemotherapy.

Investigators led by Dana-Farber's Adam Bass, MD, led to the identification of four subtypes of stomach cancers.

Investigators led by Dana-Farber’s Adam Bass, MD, led to the identification of four subtypes of stomach cancers.

Unlike many other types of cancer, stomach cancer research has seen few developments leading to precision therapies that can home in on molecular weak points to halt or shrink tumors. One such therapy, approved in 2010, targets a protein, HER2, that is over-expressed on the surface of about 20 to 25 percent of stomach cancers. The drug trastuzumab (Herceptin) was approved for use with chemotherapy in patients with HER2-overexpressing metastatic cancer of the stomach or gastroesophageal junction – the area where the stomach and esophagus meet. Other drugs that target HER2, such as lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumab emtansine (Kadcyla), are now being studied in clinical trials.

Immunotherapy drugs, which help the patient’s immune system seek out and destroy tumor cells, have proven very effective for some patients with advanced melanoma, non-small cell lung cancer, kidney cancer, and other cancer types. In September 2017, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) for people with certain advanced cancers of the stomach or the gastroesophageal junction.

The approval applies to patients with advanced cancers, called adenocarcinomas, that have come back or continued to grow after having at least two previous treatments. The cancer cells must also test positive for the PD-L1 protein, which allows some cells to escape attack by the immune system. The FDA also approved a new lab test to check these cancers for the PD-L1 protein and determine whether the patient is likely to benefit from cancer drugs known as immune checkpoint inhibitors.

Pembrolizumab has also been approved to treat any type of tumor that is so-called MSI-High, meaning its cells exhibit microsatellite instability. A small percentage of stomach cancers have this characteristic.

In an effort to diagnose stomach cancer earlier, researchers are looking at known risk factors, such as mutations that run in certain families that increase the risk of the disease, although these are rare.

The strongest known risk factor for stomach cancer is infection with the H. pylori bacterium, which is found in about 50 percent of the world’s population. H. pylori infection causes chronic inflammation and increases the risk of developing ulcers and stomach cancer. However, most people whose stomachs harbor the bug don’t develop cancer.

Studies are being conducted to see whether antibiotic treatment of people who are chronically infected by H pylori will help prevent stomach cancer. Some studies have found that treating this infection may prevent precancerous stomach abnormalities, but more research is needed.

Another research effort, which has led to the identification of four subtypes of stomach cancers, highlights the complexity of the disease, and may eventually lead to more precise treatments. Investigators led by Adam Bass, MD, reported that analysis of 295 samples of stomach cancers revealed four groups that had distinct features and types of molecular alterations.

Bass, who directs the Center for Esophageal and Gastric Cancer at Dana-Farber, says that grouping the cancers this way will help researchers enroll patients in clinical trials that test drugs aimed at targeting their specific stomach cancer subtype.

Learn more about treatment for stomach cancer from Dana-Farber’s Center for Esophageal and Gastric Cancer.

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