Four Distinct Subtypes of Gastric Cancer Found

Adam Bass, MD

Gastric cancer is comprised of 4 distinct molecular subtypes of disease, each representing a unique opportunity for new drug development, according to a paper published in Nature by The Cancer Genome Atlas (TCGA).

The study evaluated the molecular composition of 295 primary gastric adenocarcinomas using 6 different molecular analysis platforms that utilized DNA and RNA sequencing and protein arrays. The 4 main subtypes that emerged in the study were Epstein—Barr virus (EBV)-positive, microsatellite unstable, genomically stable, and chromosomal instable. Within each of these subtypes, the study identified distinct molecular targets for future drug development, including PD-L1 and PD-L2 amplification in EBV-positive tumors. Moreover, tumors with chromosomal instability expressed amplification of tyrosine kinase receptors.

“A key advance with this project is that we have identified and developed a much more useful classification system to find groups of gastric cancer that have distinct molecular features, and at the same time, we also identified key targets to pursue in different groups of patients,” lead investigator Adam Bass, MD, from the Harvard Medical School and Dana-Farber Cancer Institute, said in a press release. “This will provide a strong foundation for categorizing the disease and for doing so in a way in which we can develop clinical trials based on some of the critical molecular alterations that are driving different classes of cancers.”

In the analysis, the EBV-positive subtype of gastric cancer represented the most actionable subtype identified. Approximately 10% of tumors fell into this category, with nearly 80% harboring a protein-changing alteration in PIK3CA. This finding suggests susceptibility to a PI3 kinase inhibitor, the researchers suggested.

In July, the PI3K delta inhibitor idelalisib gained approval in combination with rituximab as a treatment for patients with chronic lymphocytic leukemia.

Additionally, several other PI3K inhibitors are in development. A phase I study exploring the investigational PI3K inhibitor BYL719 in combination with the Hsp90 inhibitor AUY922 is currently enrolling patients with metastatic gastric cancer (NCT01613950).

The study also found higher levels of the JAK2 gene in patients with the EBV-positive subtype, suggesting that certain gastric cancers could be susceptible to JAK2 inhibitors, such as ruxolitinib. However, at this point, studies are not currently examining JAK2 inhibition in this disease type. An earlier study did explore AZD1480 in patients with gastric cancer; however, development of this compound was discontinued (NCT01219543).

Amplifications in PD-L1/2 in the EBV-positive subtype indicate that checkpoint inhibitors directed toward these ligands could be effective. A phase I study is investigating the PD-L1 inhibitor MPDL3280A in patients with solid tumors or hematologic malignancies. Patients with gastric cancer will be enrolled in this study, although it is not specifically looking for the EBV-positive subtype (NCT01375842).

The chromosomally unstable category represented the largest subtype, with these tumors generally being located in the areas between the stomach and esophagus. Bass noted that these tumors “have a striking number of genomic amplifications of key cancer-promoting genes.”

Roughly 20% of tumors fell into the microsatellite unstable category, or those with malfunctions in DNA repair mechanisms. Additionally, 20% of tumors fell into the genomically stable category, with approximately 30% of these tumors having alterations in the RHOA pathway.

“These tumors are especially deadly because of their ability to metastasize rapidly and because we lack effective therapies,” Bass said regarding the genomically stable subtype. “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.”

The NCI and the National Human Genome Research Institute, which are run by the National Institutes of Health (NIH), manages TCGA. In a press release concerning the results, the director of the NIH characterized the EBV findings as groundbreaking.

“This study reinforces the value of the approach we are using to study genomic diversity and similarity among tumors of many different cancer types,” NCI director Harold Varmus, MD, said in a release. “Only such a systematic analysis could have yielded observations about the association between EBV and several provocative molecular characteristics.”