Abstract 4932: Excision repair cross-complementing group-1 (ERCC1) induction and polymorphism are markers of inferior outcome in patients with colorectal cancer treated with oxaliplatin
Authors: Rao Devika , Mallick Atrayee Basu , Augustine Titto , Daroqui Cecilia , Jiffry Jeeshan , Merla Amartej , Chaudhary Imran , Seetharaman Raviraja , Sood Arjun , Gajavelli Srikanth , Aparo Santiago , Rajdev Lakshmi , Kaubisch Andreas , Chuy Jennifer , Maitra Radhashree , Goel Sanjay 
Published: August 2019

Background: Oxaliplatin confers tumoricidal effect by forming platinum-DNA adducts and is an integral part of the treatment paradigm for patients with colorectal cancer (CRC). The nucleotide excision repair pathway (NERP) plays a crucial role in tissue resistance to the drug. We have previously demonstrated that ERCC1 (part of NERP) is an inducible gene in CRC cell lines on exposure to oxaliplatin, and high levels confer drug resistance. We aimed to translate these findings by using Peripheral Blood Mononuclear Cells (PBMC) as a surrogate and assess ERCC1 as a biomarker of sensitivity to oxaliplatin therapy. Additionally, we assessed prevalence of single nucleotide polymorphisms (SNP) and its relation to patient outcomes.

Methods: In consenting patients with CRC who received oxaliplatin, blood was sampled at 0, 2, 48 hours, and 14 days during any cycle of chemotherapy, and/or DNA from formalin fixed paraffin embedded (FFPE) tissue was isolated. ERCC1 gene expression was quantified by qPCR (quantitative real time polymerase chain reaction) and WB (western blotting). SNPs were analyzed through Sanger sequencing of DNA from blood or tissue. Clinical benefit from oxaliplatin was determined using the parameters of relapse free survival (RFS) for limited stage and progression free survival (PFS) for mCRC.

Results: 54 patients had serial blood sampled; 25 (46.3%) had mCRC and 1 was excluded due to mortality prior to therapy. 13 (52%) had an increase in ERCC1 expression from baseline, while 11 (48%) showed no change or decrease. Median PFS was 190 and 237 days respectively (log-rank test HR 2.35, CI 1.005-5.479; p = 0.0182). In the 29 patients with limited stage disease, 19 (65.5%) had an induction of ERCC. In these patients change in expression did not correlate with RFS. We did not find any significant correlation of PFS with baseline expression of ERCC1 in either group. SNP in rs11615 (AAT&gt;AAC, 97 samples) was assessed. 80/97 had stage 4 disease, with AAC in 69 (86.3%) patients. Median PFS was lower in patients with AAC than AAT (203 vs 684.5 days; log-rank test HR 2.4, CI 1.45-3.97, p=0.0045). On analysis of racial distribution, blacks had the highest prevalence of AAC (100%), followed by Hispanics (81.8%), persons of mixed race (76.9%) and whites (68.8%) (Fisher exact test p=0.0004).

Conclusions: We confirm our hypothesis that the ERCC1 gene is induced in vivo in a sub-population of patients on treatment with oxaliplatin. This induction can serve as a potential marker of drug-resistance in mCRC as evidenced by the significant difference in PFS. Additionally, presence of SNP is an independent marker of drug resistance, which has a significant pattern of distribution among various races. Analysis of a second SNP (rs3212986), also implicated in drug resistance, is underway.

Citation Format: Devika Rao, Atrayee Basu Mallick, Titto Augustine, Cecilia Daroqui, Jeeshan Jiffry, Amartej Merla, Imran Chaudhary, Raviraja Seetharaman, Arjun Sood, Srikanth Gajavelli, Santiago Aparo, Lakshmi Rajdev, Andreas Kaubisch, Jennifer Chuy, Radhashree Maitra, Sanjay Goel. Excision repair cross-complementing group-1 (ERCC1) induction and polymorphism are markers of inferior outcome in patients with colorectal cancer treated with oxaliplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4932.