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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; Impact Journals LLC; Volume: 10; Issue: 53 Linguagem: Inglês

10.18632/oncotarget.27140

1949-2553

Devika Rao, Atrayee Basu Mallick, Titto Augustine, Cecilia Daroqui, Jeeshan Jiffry, Amartej Merla, Imran Chaudhary, Raviraja N. Seetharam, Arjun B. Sood, Srikanth Gajavelli, Santiago Aparo, Lakshmi Rajdev, Andreas Kaubisch, Jennifer Chuy, Abdissa Negassa, John M. Mariadason, Radhashree Maitra, Sanjay Goel,

DNA Repair Mechanisms

// Devika Rao 1 , Atrayee Basu Mallick 1 , * , Titto Augustine 2 , Cecilia Daroqui 1 , Jeeshan Jiffry 2 , Amartej Merla 1 , Imran Chaudhary 1 , Raviraja Seetharam 1 , Arjun Sood 1 , Srikanth Gajavelli 1 , Santiago Aparo 1 , 2 , Lakshmi Rajdev 1 , 2 , Andreas Kaubisch 1 , 2 , Jennifer Chuy 1 , 2 , Abdissa Negassa 3 , John M. Mariadason 4 , Radhashree Maitra 1 , 2 and Sanjay Goel 1 , 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 Correspondence to: Sanjay Goel, email: sgoel@montefiore.org Keywords: oxaliplatin; colorectal cancer; ERCC1; FOLFOX; resistance Received: April 24, 2019 Accepted: July 17, 2019 Published: September 17, 2019 ABSTRACT Background 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). Methods 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. Results 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). Conclusions 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.