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Amgen Uses 454 in Search of New Biomarkers for Oncology Drug Response

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By Julia Karow

This story was originally published April 21.

Amgen said last week that it has used next-generation sequencing to analyze archival tumor samples in order to find new biomarkers that can predict response to a drug for metastatic colorectal cancer.

In the study, researchers from Amgen and academic collaborators used the Roche 454 Life Sciences platform to sequence nine genes in 320 tumor samples from a clinical trial of the EGFR inhibitor Vectibix. It represents one of the first applications of next-gen sequencing to characterize samples from a clinical trial.

"To our knowledge, this is the first time next-generation sequencing has been used to analyze tumor samples from a Phase 3 clinical trial and demonstrates how advancing technologies can be quickly applied to ongoing clinical research," said Marc Peeters of Antwerp University Hospital, the study's principal investigator, in a statement from Amgen.

The aim of the study was to investigate whether mutations in nine genes known to be altered in colorectal cancer can predict response to Vectibix, also known as panitumumab. Mutations in the KRAS gene are already known to predict poor response to the drug.

According to an abstract published as part of a presentation at the American Association for Cancer Research conference in Philadelphia last week, the archived tumor samples, which had previously been analyzed for KRAS exon 2 mutations, came from a randomized Phase 3 monotherapy clinical trial of metastatic colorectal cancer that compared panitumumab plus best supportive care to best supportive care alone.

The researchers used the 454 sequencer to search for mutations in the AKT1, BRAF, CTNNB1, EGFR, KRAS (exon 3), NRAS, PIK3CA, PTEN, and TP53 genes. These genes are either directly or indirectly involved in the EGFR signaling pathway.

In total, they amplified 43 exons and generated 1.26 gigabases of sequence data from 5.7 million sequence reads. Of the 320 samples, 288 yielded results for a mean of 7.85 genes per patient. The data were between 84 percent and 99 percent complete for each gene.

The researchers found mutations in all nine genes. Fifty tumors had more than one mutated gene, and 20 had more than one mutation in a single gene.

They concluded that "the superior sensitivity of 454 sequencing revealed unexpected genotypic complexity in many patient tumor samples."

Vectibix significantly improved progression-free survival in patients with KRAS wildtype tumors and had no effect on progression-free survival in patient with KRAS-mutant tumors.

In addition to KRAS, mutations in NRAS were also associated with a lack of response to Vectibix. Patients with KRAS and NRAS wildtype tumors receiving Vectibix had improved progression-free survival, whereas those with NRAS mutant tumors did not appear to benefit from Vectibix.

The researchers also found higher-than-expected rates of simultaneous mutation of KRAS and either BRAF or NRAS, though Amgen said larger studies are required to determine the predictive value of BRAF mutations.

Amgen has been using the 454 platform for about a year and a half in its Molecular Sciences group, in particular to support the company's oncology drug development (IS 4/20/2010).

According to Alex Parker, a principal scientist at Amgen who is also involved in the Vectibix study, the company analyzed up to 1,000 samples last year using the 454 platform and is planning to study "many more," both from completed and ongoing clinical trials.

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