New Classification of Gastric Cancer Spurs Targeted Therapy

Zosia Chustecka

July 24, 2014

To date, gastric cancer has been treated with a one-size-fits-all approach, without too much success: it is the third leading cause of cancer deaths worldwide. This may change in the future, as the identification of 4 new subtypes of gastric cancer should spur research into a more personalized approach with targeted agents.

"We hope these results will facilitate the development of clinical trials to explore therapies in defined sets of patients, ultimately improving survival of this deadly disease," write the researchers.

The study, conducted as part of The Cancer Genome Atlas Project (TCGA), was published online July 23 in Nature, and was highlighted in a press release from the Dana-Farber Cancer Institute in Boston.

"This is a landmark report from TCGA proposing a new molecular classification that adds to the depth of knowledge about pathophysiology of gastric cancer and, more importantly, identifies subclasses that should be treated differently," said Alok Khorana MD, director of the gastrointestinal malignancies program at the Cleveland Clinic. He was not involved in the study and was approached for comment.

This is "yet another advance in precision medicine as we move away from clinical/anatomic classification of tumors," he told Medscape Medical News. " Identification of "druggable" targets is a key finding of this report and could potentially lead drug development."

However, Dr. Khorana cautioned that validation of this classification system in future studies is important, as is identifying the distribution of various subclasses across geographic regions (e.g., Asia vs North America).

Clinically Useful New Classification System

There is already some classification of gastric cancer, the researchers write.

For instance, the Lauren classification divides adenocarcinomas into intestinal and diffuse types, while the World Health Organization divides gastric cancer into papillary, tubular, mucinous (colloid), and poorly cohesive carcinomas.

However, these existing classification systems "have little clinical utility," and there is an urgent need for robust classifiers that can guide patient therapy.

"We clearly converged on 4 groups of gastric cancer with distinct features and classes of molecular alterations," commented corresponding author Adam Bass, MD, director for translational research at the Center for Esophageal and Gastric Cancer at Dana-Farber, in a statement.

The team collected tumor tissue and blood samples from 295 patients with primary gastric adenocarcinoma who had not been treated with either chemotherapy or radiation. The tissue specimens were analyzed with different molecular analysis technologies, and computational analysis of the large amount of resulting data showed up 4 distinct subtypes, as follows:

  • About half of the samples were tumors described as "chromosomally unstable," with cancer cells that contained a jumble of extra or missing pieces of genes and chromosomes. Dr. Bass said these tumors "have a striking number of genomic amplifications [extra copies] of key cancer-promoting genes" for which targeted therapies exist or are in development. He also noted that this subtype of tumor is frequently found in the junction between the stomach and the esophagus, and that this type of gastric cancer has been dramatically increasing in the United States.

  • About 20% were tumors in which malfunctioning DNA repair mechanisms cause a high rate of mutations, many of them leading to potential activation of cancer-related signaling proteins that can be targeted with novel precision drugs.

  • About 10% were tumors containing the Epstein–Barr virus, along with mutations in the PIK3CA gene pathway, extreme DNA hypermethylation, and extra copies of the programmed death ligand PD-L1 and PD-L2 genes. These results suggest that inhibitors of the PI3K pathway could have great utility in these cancers, Dr. Bass commented. In addition, the findings of elevated levels of PD-L1 and PD-L2, key regulators of the immune response, suggest that emerging immunotherapy agents should be tested in these patients.

  • The remaining 20% of tumors was termed "genomically stable," as they lacked the molecular features of the other 3 types. These tumors mostly fell into an already established class of gastric cancer known as diffuse-type tumors, which are "especially deadly because of their ability to metastasize rapidly and because we lack effective therapies," said Dr. Bass. In about 30% of these tumors (i.e., about 7% of the total samples), the team identified a novel set of genomic alterations in a pathway called the RhoA signaling pathway. "This finding result opens up an entirely new line of research to allow us to investigate what underlies this deadly form of gastric cancer and to ultimately develop new therapies," he added.

The study was supported by the Intramural Research Program and research grants from the National Institutes of Health. Dr. Khorana reports serving as a speaker for sanofi-aventis, Eisai, and Roche; receiving research grants from Leo Pharma and Eisai; and serving as a consultant for sanofi-aventis, Bristol-Myers Squibb, Johnson & Johnson, Isis Pharmaceuticals, Daiichi-Sankyo, and Boehringer-Ingelheim.

Nature. Published online July 23, 2014. Abstract

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