Molecular variations in regions of the upper GI tract may guide cancer treatments

By Liz Meszaros, MDLinx
Published July 9, 2017

Key Takeaways

Gene mutations in the various regions of the upper digestive tract may, in the future, help tailor cancer treatment according to the location of the cancer, concluded researchers in their study presented at the European Society for Medical Oncology, in Barcelona, Spain.

Researchers sought to assess the molecular variations between small bowel adenocarcinomas (SBAs), right-sided colon cancers (RT-Colon), and gastroesophageal cancers (GEC).

“Our study was undertaken primarily because SBAs are greatly understudied, as well as increasing in incidence nationwide, and we wanted to determine what may make them unique,” said principal researcher Mohamed E. Salem, MD, assistant professor of medicine, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. “We really didn’t have good data on SBAs so we’ve been treating the tumors as if they were colon cancers and we really need to start treating them based on their unique properties.”

They included 4,278 tumors, comprised of 531 SBAs, 1,073 RT-Colon, and 2,674 GEC, which they assessed via NextGen sequencing, protein expression, and gene amplification. Using somatic nonsynonymous missense mutations, they calculated tumor mutational loads (TML)—often a marker for tumor response to immunotherapy, and conducted analyses using Fisher’s exact testing.

Dr. Salem and colleagues found that the most frequently mutated genes in SBAs included TP53 (51%), KRAS (49%), APC (26%), SMAD4 (12%), PIK3CA (8%), BRAF (6%), and others. When comparing SBA mutations with RT-Colon and GEC mutations, they found varying frequencies in many genes. But researchers found that SBAs were more similar to colon than to gastric cancers.

In GECs, they found a 2-fold higher level of PD-L1 expression—a marker for immunotherapy responsiveness, compared with RT-Colon. This difference in PD-L1 expression was not nearly significant, however, between GEC and SBA tumors. Typically, the higher the PD-L1 level, the better response cancer will have to certain immunotherapies.

“With this study, we now have what I think is one of the biggest datasets on SBAs,” said Dr. Salem. “Previously, investigators studying the colon found very unique differences between the left and ride sides, and our study therefore took advantage of those findings by exploring the differences between ride-sided colon cancers and SBAs. We now see a continuum of molecular changes that occur as these regions of the digestive tract transition from one area to the other.”

Future steps, according to Dr. Salem, will include correlating their findings with treatment outcomes retrospectively, as well as a clinical trial to assess the best treatments for SBA patients.

This study was supported by Georgetown Lombardi’s Ruesch Center for the Cure of Gastrointestinal Cancer.

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