Oncotarget

Research Papers:

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

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

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Oncotarget. 2019; 10:5510-5522. https://doi.org/10.18632/oncotarget.27140

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Abstract

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

Correspondence to:

Sanjay Goel,email: [email protected]

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.


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