Single-nucleotide polymorphism (SNP) of excision repair cross complementation group 1 (ERCC1) in nasopharynx cancer (NPC): A companion biomarker study to Hong Kong NPC Study Group 0502 trial

Abstract

Background: Polymorphisms at ERCC1 has been linked to platinum sensitivity and treatment outcome. We hypothesized that ERCC1 SNP at codon 118 and C8092A is predictive of relapse free survival (RFS) in NPC, and correlates with ERCC1 protein/mRNA in paired tumor samples. Methods: 0502 is a multi-center prospective clinical trial to assess adjuvant chemotherapy in NPC pts with detectable plasma EBV-DNA (pEBV) following primary radiotherapy (RT) or cisplatin-RT (CRT) (NCT00370890). Eligible pts with biopsy proven NPC, AJCC stage IIB-IVB, no persistent locoregional disease or distant metastasis, ECOG 0-1, adequate organ function, were screened by pEBV at 6-8 weeks after completing RT/CRT. Post-RT pEBV -ve pts received no further treatment. pEBV +ve pts underwent work-up and randomization to adjuvant chemotherapy or observation. We tested our hypothesis using samples collected in the 0502 screening cohort. Primary endpoint is relapse free survival (RFS). ERCC1 genotyping was by TaqMan real time PCR. 450 pts is planned to detect a hazard ratio (HR) of 1.5 for the weaker ERCC1 SNP at 80% power and 2-side 5% alpha level. In subset with available tumor biopsies, we quantified ERCC1 protein expression by immunohistochemistry (IHC) or Western blot (WB) with mouse monoclonal antibody (clone 8F1), and ERCC1 mRNA by quantitative RT-PCR. Results: ERCC1 SNP was analyzed in peripheral blood lymphocytes from 478 pts. Median follow up was 3.61 years (90% C.I. 3.36-3.88). 31% pEBV +ve, 17% randomized. ERCC1 genotype distribution at codon 118: 54% CC, 39% CT, 7% TT; C8092A: 38% CC, 50% CA, 12% AA. There was no significant association of ERCC1 SNP with 3-year RFS or overall survival. No significant correlation was observed in ERCC1 SNP and tumor ERCC1 expression by IHC, WB or mRNA. In subset evaluated by ERCC1 IHC (n=79), pts with ERCC1+ve tumor (H-score > median) had worse RFS (HR 2.34, 95% C.I. 1.06-5.16, p=0.036). Multivariate analysis showed pEBV was the most significant adverse prognosticator for all clinical endpoints. Conclusions: We found no association of ERCC1 SNP with NPC survival. pEBV remained the most significant prognostic biomarker in NPC.