Stomach Cancer: How Immunotherapy and Targeted Therapy are Changing Treatment


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.

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.

Shape matters


Unlocking the keys to H. pylori’s helical structure may lead to better antibiotic drugs for diseases from ulcers and stomach cancer to diarrhea and cholera

SEATTLE — May 27, 2010 — The bacterium Helicobacter pylori, which lives in the human stomach and is associated with ulcers and gastric cancer, is shaped like a corkscrew, or helix. For years researchers have hypothesized that the bacterium’s twisty shape is what enables it to survive – and thrive – within the stomach’s acid-drenched environment, but until now they have had no proof.

For the first time, researchers at Fred Hutchinson Cancer Research Center have found that, at least when it comes to H. pylori’s ability to colonize the stomach, shape indeed matters. Microbiologist Nina Salama, Ph.D., and colleagues report their findings May 28 in Cell.

Salama and colleagues are the first to demonstrate that the bug’s helical shape helps it set up shop in the protective gelatin-like mucus that coats the stomach. Such bacterial colonization – present in up to half of the world’s population – causes chronic inflammation that is linked to a variety of stomach disorders, from chronic gastritis and duodenitis to ulcers and cancer.

“By understanding how the bug colonizes the stomach, we can think about targeting therapy to prevent infection in the first place,” said Salama, the paper’s corresponding author and an associate member of the Human Biology Division at the Hutchinson Center. The paper’s first author, Laura K. Sycuro, Ph.D., conducted this work while a student in the University of Washington/Fred Hutchinson Cancer Research Center Molecular and Cellular Biology graduate program. She is now a postdoctoral research associate in the Hutchinson Center’s Clinical Research Division.

Specifically, the researchers discovered a group of four proteins that are responsible for generating H. pylori’s characteristic curvature. Using a mouse model, they found that laboratory-engineered mutant strains of H. pylori that are deficient in these proteins fail to twist properly and, consequently, are unable to colonize the stomach.

“Having these mutant strains in hand allowed us to test whether the helical shape is important for H. pylori infection, and it is,” Salama said. “All of our mutants had trouble colonizing the stomach and were out-competed by normal, helical-shaped bugs.” Interestingly and somewhat puzzlingly, the H. pylori mutants retained their ability to propel themselves through a thick, mucus-like gel in a petri dish even though they were unable to establish infection in stomach colonization experiments.

The researchers also discovered a novel mechanism by which these proteins drive the organism’s shape, in essence acting like wire cutters on a chain-link fence to strategically snip certain sections, or crosslinks, of the bacterium’s mesh-like cell wall.  “The crosslinks preserve the structural integrity of the bacterial wall, but if certain links are cleaved or relaxed by these proteins, it allows the rod shape to twist into a helix,” Salama said.

Mutant forms of H. pylori that lack these proteins are misshapen, ranging from rods to crescents, which hampers their ability to bore through or colonize the stomach lining.

“We found that the bacteria that lost their normal shape did not infect well, and so we know that if we inhibit normal shape we can slash infection rates,” Salama said.

Other disease-inducing bacteria that have these proteins include Vibrio cholerae, a comma-shaped bug that causes cholera, and the curved to helical rod-shaped Campylobacter jejuni, which is the leading cause of bacterial diarrhea in developed countries.

“The fact that we found proteins that act on the cell wall of H. pylori that seem to be important for bacterial survival and that these proteins are found in other pathogens with similar shapes makes them a possible drug target for a number of bacterial diseases,” she said.

H. pylori is contagious, but its exact transmission route is unknown. While more than 80 percent of those infected will remain asymptomatic, an estimated 10 percent to 15 percent will develop related diseases such as ulcers and/or stomach cancer. About 70 percent of stomach cancers are associated with H. pylori infection.

The current treatment for H. pylori infection in those diagnosed with peptic ulcers is a combination of proton-pump inhibitors to reduce gastric acid secretion paired with antibiotics to eradicate the bug. The treatment is not always effective, however, due to the prevalence of antibiotic resistance.

“H. pylori infection is hard to treat. There are no vaccines. Right now the only treatment is eradication therapy, and we are running out of tricks because of resistance to essentially all current antibiotics,” Salama said.

The bug was first characterized in the early 1980s by Australian researchers Barry J. Marshall and Robin Warren, who in 2005 received the Nobel Prize in physiology or medicine for their discovery. Prior to their finding, the prevailing theory was that most stomach ulcers and gastritis were caused by spicy food or stress.

In addition to helical rods or spirals, bacterial species come in a wide variety of highly conserved shapes that range from spheres and rods to crescents and stars. They can be found on and within animals and plants – and indeed wherever life exists, from deep in the Earth’s crust to the oceans and forests – and they play a key role in regulating the environment. In humans, which harbor 10 times more bacterial cells than human cells, bacteria not only cause diseases ranging from strep throat to pneumonia, but they also perform a host of helpful duties, from aiding digestion to making vitamins that the human body alone cannot produce.

“We are a consortium. We depend on them as they depend on us,” Salama said.

source: Fred hutinson’s cancer center

Comparison of the once-daily levofloxacin-containing triple therapy with the twice-daily standard triple therapy for first-line Helicobacter pylori eradication: a prospective randomised study.


Simple compound of Helicobacter pylori eradication therapy may improve drug compliance of patients. The aims of this study were to compare the efficacy and tolerability of a simple combination containing levofloxacin 7-day once-daily with standard twice-daily triple therapy.
PATIENTS AND METHODS: This was a prospective, randomised, open-label trial. A total of 189 consecutive patients diagnosed with peptic ulcer and H. pylori infection were enrolled. Patients were randomly divided into two groups: LEC group–levofloxacin 500 mg, esomeprazole 40 mg and clarithromycin 500 mg once daily for 7 days; AEC group–amoxicillin 1 g, esomeprazole 40 mg and clarithromycin 500 mg twice daily for 7 days.
RESULTS: There were 90 patients in the LEC group and 99 patients in the AEC group. By intention-to-treat and per-protocol analysis, the H. pylori eradication rate was 78.9% [71/90; 95% confidence interval (CI), 70.3-87.5%] and 83.5% (71/85; 95% CI, 75.5-91.6%) respectively, in the LEC group; and 74.8% (74/99; 95% CI, 66.0-83.5%) and 86.0% (74/86; 95% CI, 78.6-93.5%) respectively, in the AEC group. The incidence and tolerability of side effects were similar between these two groups.
CONCLUSION: The efficacy and tolerability of once-daily levofloxacin-containing triple therapy are equal to those of the standard twice-daily triple therapy in this study. However, none of the treatment regimens evaluated achieved enough eradication efficacies to be considered as a recommendable first-line treatment.