The nucleotide excision repair (NER) pathway has been implicated as an important factor in modulating overall cancer survival and responsiveness to platinum based chemotherapy agents in a variety of tumor types. We have evaluated the role of genetic variation in a key gene of the NER pathway; the ERCC2 (XPD) A35931C Lys751Gln single nucleotide polymorphism (SNP). This SNP has been associated with reduced DNA repair capacity and has also been implicated in improving response to platinum based chemotherapy in a variety of tumors including squamous cell carcinoma of the head and neck (SCCHN) lung and colorectal cancer. Here we evaluated the role of this SNP on SCCHN survival in 539 Caucasian cases. The mean age of SCCHN diagnosis among these patients was 59.7 years. The overall follow-up time in months (mean±SD, range) was 27.3+24.1 (0.06-130.8) and the progression-free survival was 16.1+18.2 months (1.0-90.8). The most common (~30%) chemotherapy regimen included platinum-based therapy either alone or in combination. Our data do not implicate the ERCC2 polymorphism as a biomarker of overall survival, adjusted hazard ratio (adjusted for age, gender and stage) was 1.2 (95% CI 0.80-1.74). When the cases were classified into two groups, those treated with platinum and those treated with surgery alone, the association of this ERCC2SNP was only detected in the group of SCCHN patients treated with platinum. The Wilcoxon log rank test showed significance (p< 0.044, n=143). The cases with the homozygous common allele AA had a reduced survival compared to individuals with at least one variant C allele. The Cox proportional hazard ratio after adjusting for age, gender and stage was 2.4 (95% CI 1.2-4.6). This was not observed in cases that received surgery alone where the hazard ratio after adjusting for age, gender and stage was 0.92 (95% CI 0.5-1.6). These data suggest the ERCC2A35931C polymorphism is an independent predictive variable of treatment efficacy. The impact of the polymorphism was therefore not evident in a group where the treatment modality did not lead to major DNA damage. Our data are consistent with recent reports of increased survival in patients treated with platinum that have a reduced NER capacity. These results provide a strong rationale for a further comprehensive evaluation of the role of genetic variation in DNA repair pathways in a larger study population. Supported in part by NIH 1P50 CA097190.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4853.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO