Abstract
BackgroundERCC1, a component of nucleotide excision repair pathway, is known to repair DNA breaks induced by platinum drugs. We sought to ascertain if ERCC1 expression dynamics and a single nucleotide polymorphism (SNP) rs11615 are biomarkers of sensitivity to oxaliplatin therapy in patients with colorectal cancer (CRC).MethodsWestern blot and qPCR for ERCC1 expression was performed from PBMCs isolated from patients receiving oxaliplatin-based therapy at specified timepoints. DNA was also isolated from 59 biorepository specimens for SNP analysis. Clinical benefit was determined using progression free survival (PFS) for metastatic CRC.ResultsERCC1 was induced in PBMC in response to oxaliplatin in 13/25 patients with mCRC (52%). Median PFS with ERCC1 induction was 190d compared to 237d in non-induced patients (HR 2.35, CI 1.005-5.479; p=0.0182). ERCC1 rs11615 SNP analysis revealed that 43.3% harbored C/C, 41.2%-T/C and 15.5%-T/T genotype. Median PFS was significantly lower with C/C or T/C (211 and 196d) compared to T/T (590d; p=0.0310).ConclusionsERCC1 was induced in a sub-population of patients undergoing oxaliplatin treatment, which was associated with poorer outcome, suggesting this could serve as a marker of oxaliplatin response. C/C or C/T genotype in ERCC1 rs11615 locus decreased benefit from oxaliplatin.
Highlights
The platinum group of cancer chemotherapeutic agents includes cisplatin, its analog carboplatin, and oxaliplatin, only oxaliplatin is effective in the treatment of colorectal cancer (CRC)
Excision repair cross complementing group 1 (ERCC1) was induced in peripheral blood mononuclear cells (PBMC) in response to oxaliplatin in 13/25 patients with mCRC (52%)
ERCC1 rs11615 single nucleotide polymorphism (SNP) analysis revealed that 43.3% harbored C/C, 41.2%-T/C and 15.5%-T/T genotype
Summary
Western blot and qPCR for ERCC1 expression was performed from PBMCs isolated from patients receiving oxaliplatin-based therapy at specified timepoints. Clinical benefit was determined using progression free survival (PFS) for metastatic CRC
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