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Next-generation sequencing identified mutations that affect panitumumab response
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WASHINGTON, D.C.—The use of a new next generation sequencing technology may help researchers identify gene mutations that will help alter or predict a patient’s response to the monoclonal antibody panitumumab, according to the results of a retrospective analysis of phase-3 data presented today at the American Association for Cancer Research 101st Annual Meeting in Washington, D.C.
“We believe this establishes a proof of principle that you can use next generation sequencing within a phase-3 trial setting,” said David M. Reese, MD, executive medical director in medical sciences and head of oncology early development at Amgen.
KRAS gene mutations have been established as a biomarker for a lack of response to anti-epidermal growth factor receptor antibodies in colorectal cancer. In this study, Reese and colleagues investigated whether gene mutations, other than the KRAS mutation, alter colorectal cancer response to panitumumab(Vectibix, Amgen).
“This would allow us to see if we can further refine the population of patients who would potentially benefit from the antibodies,” said Reese, who presented the results. The researchers used the Roche 454 pyrosequencing technology to examine the mutations.
The analysis used banked patient tumor samples from a randomized, phase-3 study of panitumumab. Tumor samples from 288 patients were tested for mutations in nine genes: KRAS (exon 3), BRAF, NRAS, AKT1, CTNNB1, EGFR, PIK3CA, PTEN and TP53.
Overall, about eight genes were evaluable per patient. Researchers identified more than one mutation in 109 tumors; 20 tumors had more than one mutation in a single gene.
In addition, two tumor samples yielded KRAS and BRAF mutations, suggesting that the presence of these mutations together is not always mutually exclusive, which has been previously reported, according to Reese.
Results of the mutation study indicated that KRAS mutations in codon 61 occurred in about 2.5% of tumors; 5% of patients had NRAS mutations and about 7.5% had BRAF mutations.
“The mutation rates in most of the rest of the genes are consistent to what has been reported in the rest of the literature, and in fact, we regarded that as an important check on the internal validity of the experiment,” Reese said
The results indicated that patients with KRAS mutations had no beneficial effect from panitumumab, whereas those patients with wild-type KRAS did.
Among those patients with wild-type KRAS, BRAF mutations were not predictive of PFS, and NRAS mutations appeared to behave in a similar fashion to KRAS mutations, in that patients with these mutations appeared not to benefit from panitumumab, Reese said.
“None of the other genes appeared to be predictive of outcomes,” he said. KRAS, including codon 61, and potentially mutations in NRAS appear to predict resistance to panitumumab. Further investigation in larger studies is required to determine the predictive value of BRAF mutations.” – by Leah Lawrence
For more information:
- Reese DM. #LB-174. Presented at: AACR 101st Annual Meeting; April 17-21, 2010; Washington, D.C.
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