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18-08-2011 | Gastroenterology | Article

Gastric cancer subtype predicts survival, chemotherapy response


Free abstract

MedWire News: Researchers have identified two intrinsic genetic subtypes of gastric cancer (GC) that respond differently to certain chemotherapy regimens, thus setting the possibility of tailored treatment in the future.

The findings are of importance, given that the majority of GC patients are treated with similar regimens showing different levels of success.

"Our study is the first to show that a proposed molecular classification of GC can identify genomic subtypes that respond differently to therapies, which is crucial in efforts to customize treatments for patients," said lead study author Patrick Tan (Duke-National University of Singapore).

Tan and team analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes, which were validated in primary tumors from 521 patients in four independent cohorts. Genetic subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers. In addition, in vitro sensitivity to 5-fluorouracil, cisplatin, and oxaliplatin was assessed.

Gene expression profiling revealed distinct patterns of expression that were indicative of two intrinsic genomic subtypes (G-INT and G-DIF). In 64% of cases, the genetic subtypes validated the Lauren histopathologic classifications for GC, while genomic profiling distinguished subtypes where Lauren's classification could not.

Validation of findings among primary tumors showed that the intrinsic subtypes, but not subtypes based on Lauren's classification, were prognostic of survival.

"It was quite reassuring to us that the genomic subtypes were associated with Lauren's system," said Tan. "There is a general assumption in the field that intestinal and diffuse gastric cancers (as classified by Lauren) represent two very different version of gastric cancer, and now genomic data confirms this."

G-INT cell lines were found to be significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin compared with G-DIF lines. Furthermore, intrinsic subtypes were associated with increased survival time following adjuvant, 5-fluorouracil-based therapy in patients.

"The exact mechanistic reasons for this difference are currently unclear, and this is an area that we're actively working on," commented Tan, adding that the research team is working to find subtype-specific molecular vulnerabilities to drugs.

Writing in the journal Gastroenterology, the team says the findings suggest that, in addition to patient prognosis, the intrinsic subtypes could be used to guide treatment selection.

However, the findings should be interpreted with caution until results from a follow-up phase II study comparing clinical outcomes in patients allocated to oxaliplatin or cisplatin based on their genomic profile is complete.

By Ingrid Grasmo

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