ASCO 2014 Report: Genetic SNP appears to be predictive of utility of cetuximab in metastatic colorectal cancer

by Bruce Sylvester – The presence of the single nucleotide polymorphism (SNP) rs895374, located in UbcH7, an E2 ligase conducting neddylation of HECT E3 ligases involved in EGFR degradation, is independently predictive of the patient-specific utility of cetuximab treatment in metastatic colorectal cancer.

Researchers reported this finding in a poster presentation at ASCO 2014.

“We have previously reported that rs895374 correlates with progression free survival (PFS) in patients (n=108) treated with cetuximab in two phase II studies of further-line treatment,” the authors noted. “The aim of this study was to validate the predictive value of rs895374 in an independent cohort of cetuximab treated patients with a cetuximab-free chemotherapy arm serving as negative control,” they said.

The investigators isolated genomic DNA from tissue samples of 455 patients (median age 64 years, male 64.2%) treated in first-line with either FOLFIRI cetuximab (n=218) or FOLFIRI bevacizumab (n=237) enrolled in the FIRE-3 trial (NCT00433927).

The cetuximab arm served as validator of prior results, and the bevacizumab arm served as negative control arm to confirm the predictive value of rs895374.

The researchers reported that the minor allele A was associated with shorter progression-free survival in the FOLFIRI + cetuximab validation cohort, (10.5 months vs. 8.2 months; logrank p=0.005; HR 0.66 (0.47-0.89)).

In the FOLFIRI plus bevacizumab arm, they found no difference in progression-free survival (10.3 months versus 10.5 months, logrank p=0.85; HR 1.03 (0.77-138)).

The presence of rs895374 was not associated with tumor response or median overall survival.

The authors concluded that the predictive value of rs895374 for the utility of cetuximab treatment was validated by this study, but no prognostic value was established.

“This is the first report proving that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with metastatic colorectal cancer. As the process of EGFR recycling is an important mechanism of cetuximab resistance, novel anti-EGFR antibodies like Sym004 may overcome resistance mechanisms by preventing EGFR recycling,” they added.

Citation: 2014 ASCO Annual Meeting; General Poster Session, Gastrointestinal (Colorectal) Cancer; Abstract Number 3571