Excision repair cross-complementing group-1 (ERCC1) induction kinetics and polymorphism are markers of inferior outcome in patients with colorectal cancer treated with oxaliplatin
PDF | Full Text | How to cite
Metrics: PDF 924 views | Full Text 1723 views | ?
Devika Rao1, Atrayee Basu Mallick1,*, Titto Augustine2, Cecilia Daroqui1, Jeeshan Jiffry2, Amartej Merla1, Imran Chaudhary1, Raviraja Seetharam1, Arjun Sood1, Srikanth Gajavelli1, Santiago Aparo1,2, Lakshmi Rajdev1,2, Andreas Kaubisch1,2, Jennifer Chuy1,2, Abdissa Negassa3, John M. Mariadason4, Radhashree Maitra1,2 and Sanjay Goel1,2
1 Department of Medical Oncology, Montefiore Medical Center, Bronx, New York, USA
2 Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
3 Department of Epidemiology and Biostatistics, Albert Einstein College of Medicine, Bronx, New York, USA
4 Gastrointestinal Cancers Program and Oncogenic Transcription Laboratory, Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Melbourne, Australia
* Currently at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
|Sanjay Goel,||email:||[email protected]|
Keywords: oxaliplatin; colorectal cancer; ERCC1; FOLFOX; resistance
Received: April 24, 2019 Accepted: July 17, 2019 Published: September 17, 2019
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.