A New Gastric Cancer Subtype Responds to 5-FU

Megan Brooks

September 04, 2013

Researchers have identified a third subtype of gastric adenocarcinoma that preferentially responds to 5-fluorouracil (5-FU). They've named it the metabolic subtype.

"One of the features that makes gastric cancer so lethal is that it arises from many genetic alterations, creating differences in how the tumors respond to therapies," senior researcher Steve Rozen, PhD, director of the Centre for Computational Biology at the Duke–National University of Singapore (NUS) Graduate Medical School, said in a statement.

"What our study has shown is that there are actually 3 distinct molecular classifications that appear to be biologically and therapeutically meaningful," he explained.

The study was published in the September issue of Gastroenterology.

The other 2 subtypes — mesenchymal and proliferative — largely coincide with the diffuse and intestinal subtypes, respectively, described in the Lauren classification, write Emily S. Turner and Jerrold R. Turner, MD, PhD, from the University of Chicago, in an accompanying editorial.

"Metabolic is definitely a third subtype that seems to be separate from the types Lauren characterized 40 years ago," Dr. Turner told Medscape Medical News.

Matching Tumors to Treatment

The prognosis for patients with gastric cancer remains poor. The 5-year survival rate is less than 30% in the United States, Dr. Rozen and colleagues write. Despite differences in tumor characteristics and the way they respond to treatments, patients often receive a "one-size-fits-all" treatment approach, they note.

There is an "urgent need for improved classification of gastric cancer that provides insight into the biology of the tumors that might help predict treatment response," coauthor Patrick Tan, MD, PhD, from the cancer and stem cell biology program at Duke–NUS, said in a statement.

The researchers analyzed 248 gastric tumors using microarray-based gene-expression profiling and identified 3 distinct subtypes: proliferative, metabolic, and mesenchymal.

Tumors of the proliferative subtype are characterized as having high levels of genomic instability, a mutation in the TP53 tumor suppressor gene, and hypomethylation, they report.

Notably, patients with the metabolic subtype benefited preferentially from 5-FU treatment, the researchers report. In addition, metabolic-subtype cell lines were more sensitive than other cell lines to 5-FU.

They note that the preferential sensitivity of metabolic-subtype gastric cancers to 5-FU probably stems from the significantly lower expression of both thymidylate synthase and dihydropyrimidine dehydrogenase in this subtype than in the other 2 subtypes.

Gastric tumors of the mesenchymal subtype resemble cancer stem cells and, consistent with this, are preferentially sensitive to PI3K/AKT/mTOR inhibitors, the researchers found.

They validated their observations in an independent set of 70 gastric tumors.

"Regarding HER2, we have not had the data to look at this systematically at the protein level, but the genomic site of this gene is most often amplified in the proliferative subtype," Dr. Rozen told Medscape Medical News.

"If confirmed in future studies, the classification of gastric cancers reported here could guide development of therapies tailored to the molecular subtypes," Zhengdeng Lei, PhD, from the cancer and stem cell biology program at the Duke–NUS Centre for Computational Biology, said in a statement.

The fact that the researchers identified 3 gastric cancer subtypes "based on a small number of marker genes" is noteworthy, Dr. Turner said. "The potential advance is that in 2 cases they think they have evidence that it will reflect chemosensitivity. That's important because gastric cancer is typically detected at a late stage and has a very short survival," he told Medscape Medical News.

Toward Personalized Treatment

Dr. Rozen emphasized that this new classification "is not yet ready for use in patients."

Dr. Turner agrees that the team's observations have to be confirmed, but said that it's "very likely" this research could have treatment implications down the road.

"In terms of diagnosis, we are moving much more toward ancillary molecular studies. What is happening in pathology departments around the world is that traditional histopathology, instead of being the sole diagnostic procedure, is the first step. Based on what is found there, molecular studies and other ancillary analyses can be selected to choose treatments more wisely," he said.

This study and similar reports "represent new hope for personalized therapy of gastric adenocarcinoma," write the editorialists. "Finding ways to apply this information to identify tumor subsets and develop molecularly tailored, individualized therapies will require creative thinking in this era of evidence-based, cost-effective medicine."

The study was supported by the Duke–NUS Signature Research Programs, with funding from the Singapore Agency for Science, Technology, and Research (A*STAR); the Singapore Ministry of Health; the Singapore National Medical Research Council; the Singapore National Research Foundation and Ministry of Education; and the Singapore Biomedical Research Council. The study authors report that a patent application covering the gene-expression-based classification of gastric adenocarcinoma has been filed by Exploit Technologies Pte, Ltd, a technology transfer arm of A*STAR. The editorialists have disclosed no relevant financial relationships.

Gastroenterology. 2013;145:505-508, 554-565. Editorial, Abstract

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