Excision repair cross-complementing group-1 (ERCC1) induction kinetics and polymorphism are markers of inferior outcome in patients with colorectal cancer treated with oxaliplatin

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.

Genetic Variants in DNA Repair Pathways as Potential Biomarkers in Predicting Treatment Outcome of Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: A Systematic Review

“…Several ERCC1 SNPs have been evaluated for their association with treatment outcome of oxaliplatin in CRC patients ( Supplementary Material—Table S1 ). The most commonly investigated nucleotide polymorphism is rs11615 ( Stoehlmacher et al., 2004 ; Ruzzo et al., 2007 ; Liang et al., 2008 ; Martinez-Balibrea et al., 2008 ; Pare et al., 2008 ; Chang et al., 2009 ; Chua et al., 2009 ; Chen et al., 2010 ; Liang et al., 2010 ; Huang et al., 2011 ; Lamas et al., 2011 ; Farina Sarasqueta et al., 2011 ; Li et al., 2012 ; Kumamoto et al., 2013 ; Nishina et al., 2013 ; van Huis-Tanja et al., 2014 ; Zaanan et al., 2014 ; Rao et al., 2019 ). A total of 10 studies showed a significant association between this polymorphism and treatment outcome ( Stoehlmacher et al., 2004 ; Ruzzo et al., 2007 ; Martinez-Balibrea et al., 2008 ; Pare et al., 2008 ; Chang et al., 2009 ; Chua et al., 2009 ; Chen et al., 2010 ; Huang et al., 2011 ; Li et al., 2012 ; Rao et al., 2019 ).…”

“…The most commonly investigated nucleotide polymorphism is rs11615 ( Stoehlmacher et al., 2004 ; Ruzzo et al., 2007 ; Liang et al., 2008 ; Martinez-Balibrea et al., 2008 ; Pare et al., 2008 ; Chang et al., 2009 ; Chua et al., 2009 ; Chen et al., 2010 ; Liang et al., 2010 ; Huang et al., 2011 ; Lamas et al., 2011 ; Farina Sarasqueta et al., 2011 ; Li et al., 2012 ; Kumamoto et al., 2013 ; Nishina et al., 2013 ; van Huis-Tanja et al., 2014 ; Zaanan et al., 2014 ; Rao et al., 2019 ). A total of 10 studies showed a significant association between this polymorphism and treatment outcome ( Stoehlmacher et al., 2004 ; Ruzzo et al., 2007 ; Martinez-Balibrea et al., 2008 ; Pare et al., 2008 ; Chang et al., 2009 ; Chua et al., 2009 ; Chen et al., 2010 ; Huang et al., 2011 ; Li et al., 2012 ; Rao et al., 2019 ). Most studies, six out of 10, reported the mutant CC genotype to be the favorable genotype, with significantly better DFS, PFS, and OS ( Stoehlmacher et al., 2004 ; Chang et al., 2009 ; Chua et al., 2009 ; Chen et al., 2010 ; Huang et al., 2011 ; Li et al., 2012 ).…”

“…Both polymorphisms showed no significant association with treatment outcome. Moreover, two (Kassem et al, 2017;Rao et al, 2019) out of five (Basso et al, 2013;Li et al, 2014;Sfakianaki et al, 2019) studies based on mRNA or protein expression level of ERCC1 showed a significant association between low ERCC1 expression and prolonged PFS and OS.…”

Application of pharmacogenetics in oncology

“…The ERCC1 gene participates is the nucleotide excision pathway and is also connected with a gene specific repair which is realized by platinum containing anti-cancer drugs [27]. It has been found that high ERCC1 levels in patients with bladder cancer are associated with worse outcome [4,28].…”

Pharmacological Treatment of Patients with Metastatic, Recurrent or Persistent Cervical Cancer Not Amenable by Surgery or Radiotherapy: State of Art and Perspectives of Clinical Research

“…The excision repair cross-complement 1 (ERCC1) status appears to be a predictive and prognostic factor in this clinical setting. This nucleotide excision repair gene is involved in resistance to platinum compounds in different malignancies [103][104][105][106][107]. A study performed on 45 tissue samples from patients with recurrent or metastatic cervical cancer treated with CDDP + IFO with or without PTX, reported that high ERCC1 expression was an independent poor predictor of both PFS (HR = 2.473, 95% CI = 1.146-5.339) and OS (HR = 3.187, 95% CI = 1.346-7.546) [106].…”