New Gene Technology Assesses Nine Genes that may Predict Response to Panitumumab

Although KRAS gene mutation is a well-established biomarker for a lack of response to anti-epidermal growth factor receptor (anti-EGFR) antibodies in colorectal cancer, a study presented at the AACR 101st Annual Meeting 2010 sought to determine whether mutations in 9 genes known to be mutated in colorectal cancer, including AKT1, BRAF, CTNNB1, EGFR, KRAS (exon 3), NRAS, PIK3CA, PTEN, and TP53, could also predict response to Vectibix (panitumumab) in patients with metastatic colorectal cancer. The study, which was presented by Mark Peeters, MD, PhD, department of oncology, Antwerp University Hospital, Antwerpen, Belgium, used massively parallel, next-generation sequencing technology to investigate these genes in 288 banked tumor samples from the “408” trial, a randomized, Phase 3 trial that compared panitumumab plus best supportive care with best supportive care alone. “In addition to the excitement of this being among the first times this technology has been used in Phase 3 research, the superior sensitivity of next-generation sequencing revealed unexpected genotypic complexity in many patients,” said Peeters in a press statement.

For the 288 patient tumor samples, balanced between the two “408” trial treatment arms, a mean of 7.85 genes per patient was identified; data completeness for each gene ranged from 84% to 99%. More than one mutant gene was identified in 109 tumors, with 20 having more than one mutation is a single gene.

Peeters and colleagues identified mutations in 1 of 250 AKT1 (0.4%), 18 of 243 BRAF (7.4%), 5 of 256 CTNNB1 (2.0%), 3 of 280 EGFR (1.1%), 7 of 284 KRAS (exon 3; 2.5%), 14 of 282 NRAS (5%), 24 of 255 PIK3CA (9.4%), 15 of 272 PTEN (5.5%), and 167 of 277 TP53 (60.3%) genes. Panitumumab significantly improved progression-free survival (PFS) in those with KRAS wild-type (WT; exons 2+3) tumors (n = 153; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.28-0.56) and had no effect on PFS in patients with KRAS mutant (exons 2+3) tumors (MT; n = 124; HR, 1.03; 95% CI, 0.71-1.50). In patients with KRAS WT tumors, the effect of panitumumab compared with best supportive care alone on PFS for additional tumor genotypes were as follows: NRAS WT (n = 138; HR, 0.39; 95% CI, 0.27-0.56), NRAS MT (n = 11; HR, 1.94; 95% CI, 0.44-8.44); BRAF WT (n = 115; HR, 0.37;

95% CI, 0.24-0.55), and BRAF MT (n = 15; HR, 0.34; 95% CI, 0.09-1.24).

Although observed mutation rates in this study were consistent with previous reports in colorectal cancer, higher than expected rates of simultaneous mutation at KRAS and either BRAF or NRAS were observed. Further research is needed to determine the predictive value in BRAF mutations.

AACR ABSTRACT LB-174 (http://bit.ly/bPuERQ)