Using massively parallel gene sequencing technology, researchers were able to identify specific genetic mutations that appear to be predictive of response to a drug commonly administered for metastatic colorectal cancer.
Using massively parallel gene sequencing technology, researchers were able to identify specific genetic mutations that appear to be predictive of response to a drug commonly administered for metastatic colorectal cancer. The analysis involved banked patient tumor samples from a previous phase 3 trial and merits further investigation in larger studies, Marc Peeters, MD, PhD, said at the American Association for Cancer Research annual meeting in Washington.
Dr Peeters and colleagues examined tumor samples from 288 patients who had taken part in a trial of panitumumab, a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). Through massively parallel gene sequencing-an approach that allows investigators to read genetic code more quickly than previous DNA sequencing technologies-they analyzed the samples for mutations in nine genes: KRAS (exon 3), NRAS, BRAF, PIK3CA, PTEN, AKT1, EGFR, beta-catenin (CINN1B), and TP53.
Panitumumab (Vectibix, Amgen) and best supportive care together significantly improved progression-free survival (PFS) in patients who had KRAS wild-type tumors versus best supportive care alone, but had no apparent effect on those with KRAS mutant tumors. The same held true with the NRAS gene: Patients with NRAS wild-type tumors had improved PFS, while those with NRAS mutant tumors did not appear to benefit in the same way.
The 9 genes included in this analysis were chosen because they are known to be mutated in colorectal cancer,” said Dr Peeters, an oncologist at Antwerp University Hospital in Belgium. “All 9 genes are either direct or indirect components of the EGFR signaling pathway. The fact that mutations in KRAS and NRAS were associated with lack of response to panitumumab is not surprising.”
Dr Peeters added that while NRAS mutations occur relatively infrequently, “based on this analysis, they might appear to serve as a predictive biomarker. However, further investigation is required to determine their predictive value.”
The study yielded a higher-than-expected rate of simultaneous mutation of KRAS and either BRAF or NRAS. Again, Dr Peeters said additional investigation will be needed to establish whether BRAF mutations have any predictive value.
According to a news release issued by Amgen, other retrospective analyses of trials in metastatic colorectal cancer have not shown a treatment benefit for panitumumab in patients whose tumors had KRAS mutations in codon 12 or 13, and therefore use of the agent is not recommended in patients with those mutations.
The researchers believe that this is the first time that massively parallel sequencing has been used to analyze tumor samples from a phase 3 clinical trial. Dr Peeters called the technology a “quantum leap beyond the methods that were used to sequence the first human genomes in the 1990s.”
Sequencing produced data for an average of 7.85 genes per patient, with the data completeness for each gene ranging from 84% to 99%. A total of 109 tumors among the 288 samples had >1 mutant gene, and 20 had >1 mutation in a single gene.