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

2019-09-17

Rao, Devika

Mallick, Atrayee Basu

Augustine, Titto

Daroqui, Cecilia

Jiffry, Jeeshan

Merla, Amartej

Chaudhary, Imran

Seetharam, Raviraja

Sood, Arjun

Gajavelli, Srikanth

Aparo, Santiago

Rajdev, Lakshmi

Kaubisch, Andreas

Chuy, Jennifer

Negassa, Abdissa

Mariadason, John M

Maitra, Radhashree

Goel, Sanjay

ERCC1

FOLFOX

colorectal cancer

oxaliplatin

resistance

Journal Article

0000-0001-9123-7684

10.18632/oncotarget.27140

ERCC1, 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). Western 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. ERCC1 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). ERCC1 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.

link

Oncotarget 2019; 10(53): 5510-5522

Oncotarget