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Proof-of-Concept Study Finds Feasibility, Not Clinical Utility of Gastric Cancer Genomic Classifier

NEW YORK (GenomeWeb) – Even though the authors of a new study were unable to establish the clinical utility of the gastric cancer genomic classifier they were evaluating, they said their results still showed that gene expression profiling could help guide treatment.

A team of researchers led by the National University of Singapore's Patrick Tam sought to assess whether previously reported intrinsic gene expression signatures could help tailor gastric cancer treatment. In Gastroenterology in 2011, the team reported on its finding of two gastric cancer subtypes with distinct gene expression patterns that were associated with chemotherapy response and patient survival.

In their new study, the researchers examined whether those intrinsic gene expression signatures could predict chemotherapy benefit. As they reported in Clinical Cancer Research yesterday, they found no demonstrable clinical utility of this classifier. However, a metabolic classifier they also examined looked promising.

"Importantly, this proof-of-concept study demonstrated that prospective gene-expression profiling to guide treatment selection is feasible and can yield potentially actionable results with a reasonable turnaround timeframe," Tam and his colleagues wrote in their paper.

The previously reported intrinsic gene expression signature — which is based on 171 genes — divides gastric cancers into two groups: G-intestinal (G1) or G-diffuse (G2). In their earlier work, the researchers found that G1 cell lines were more sensitive to oxaliplatin and 5-fluorouracil, while G2 cell lines were more sensitive to cisplatin and 5-fluorouracil.

In their new '3G' trial, the researchers enrolled 81 patients with advanced gastric cancer and used the classifier to divvy them up into a G1 group, a G2 group, or a third group, dubbed G3, that couldn't be assigned to one of the others. They placed 48 patients in G1 group, 21 in G2, and 12 in G3. This, the researchers noted, shows genomic profiling and stratification was successful for 86 percent of patients and took a median seven working days.

Thirty of the G1 patients were treated using oxaliplatin plus S-1 (SOX) chemotherapy, while the rest were treated with cisplatin plus S-1 (SP) chemotherapy. All the G2 patients, meanwhile, were treated with SP chemotherapy and the G3 patients with SOX chemotherapy.

However, none of the groups met the researchers' goal of a 70 percent response rate. Instead, they reported response rates of 44.8 percent for the G1-SOX group, 8.3 percent for the G1-SP group, 26.7 percent for G2-SP, and 55.6 percent for G3-SOX. This, they said, did not predict a differential benefit from oxaliplatin or cisplatin.

And while the higher response rate of the G1-SOX as compared to G1-SP seems to support some clinical utility for their genomic classifier, the researchers noted that, contradictorily, patients in the G1-SP group had longer median progression-free survival.

Why there are these conflicting endpoints remains to be examined, the researchers said, though they noted it could be due to chance. They added that the 8.3 response rate in the G1-SP group was "peculiar" and lower than expected. They also noted that initial data on the classifier was from in vitro proliferation assays and suggested that that might not translate to survival rates.

Tam and his colleagues also retrospectively tested two other published genomic signatures developed in Asian populations. One — reported by some of the same researchers in 2013 in Gastroenterology — showed that patients with metabolic subtypes, as opposed to mesenchymal or proliferative subtypes, had longer progression-free and overall survival.

The other classifier, based on the Asian Cancer Research Group's work, did not appear to have any ability to predict outcomes from chemotherapy treatment.

Still, the researchers said they've "shown that genomic profiling to guide chemotherapy selection in the advanced gastric cancer setting is feasible, even though our data does not support our
genomic classifier," though the metabolic classifier does warrant further study.

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