Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer.

BACKGROUND

Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC).

PATIENTS AND METHODS

Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes.

RESULTS

In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42-0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39-0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36-3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06-1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis.

CONCLUSIONS

Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC.