title: Clinical significance of ERCC2 haplotype-tagging single nucleotide polymorphisms in patients with unresectable non-small cell lung cancer treated with first-line platinum-based chemotherapy.
abstract: BACKGROUND
  First-line platinum-based chemotherapy is currently considered the standard treatment for unresectable non-small cell lung cancer (NSCLC). However, resistance to platinum-based chemotherapy results in poor prognoses. The DNA repair pathway is a crucial molecular mechanism potentially involved in resistance to platinum-based chemotherapy. ERCC2 plays an integral role in the nucleotide excision repair pathway. Furthermore, single nucleotide polymorphisms (SNPs) and haplotypes in the ERCC2 gene are thought to be associated with the risk of developing lung cancer and clinical outcomes. Therefore, we evaluated the impact of ERCC2 haplotype-tagging SNPs (htSNPs) on the clinical parameters of first-line platinum-based chemotherapy in unresectable NSCLC.
  
  
  METHODS
  We genotyped 8 ERCC2 htSNPs for 129 unresectable NSCLC (stage IIIA, 12; stage III, 36; stage IV, 82) cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, hematological and non-hematological toxicities, and predictive value of the htSNPs in patient response, survival, and adverse events related to platinum-based chemotherapy were analyzed according to each ERCC2 htSNP using the chi-square test, Kaplan-Meier method, and Cox proportional hazard model.
  
  
  RESULTS
  No differences were observed in patient or disease characteristics and response according to ERCC2 htSNPs. In a survival analysis, rs50872 was significantly related to overall survival (OS) (log-rank test, p=0.014). The median survival duration of rs50872 G/G, A/G, and A/A genotypes was 35.75 (95% confidence interval [CI] 21.05-50.45), 36.07 (hazard ratio [HR] 1.02, 95% CI 25.20-46.94), and 16.75 (HR 3.49, 95% CI 5.73-27.77) months, respectively. A significant association was observed between grades 3 and 4 infections and poor survival: OS in patients with a grade 0-2 infection: 35.75 months (95% CI 28.15-43.35); OS in patients with a grade 3-4 infection: 12.86 months (95% CI 8.99-16.72, HR 3.57) (log-rank test, p<0.001). In a subgroup analysis based on taxane-platinum vs. gemcitabine-platinum doublets, the rs238405 genotype was significantly related to OS in the taxane-platinum doublets group. However, the rs238416 genotype was significantly associated with OS in the gemcitabine-based group.
  
  
  CONCLUSIONS
  ERCC2 htSNPs rs50872 (overall), rs238405 (taxane-platinum doublets group), and rs238416 (gemcitabine-platinum doublets group) and infection related to first-line chemotherapy were associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. However, additional large prospective studies focusing on the role of ERCC2 htSNPs in unresectable NSCLC are needed.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea.
authors.forename: Seok-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Gyeong-Won
authors.initials: GW
authors.lastname: Lee
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Lee
authors.forename: Yu Ji
authors.initials: YJ
authors.lastname: Cho
authors.forename: Yi Yeong
authors.initials: YY
authors.lastname: Jeong
authors.forename: Ho-Cheol
authors.initials: HC
authors.lastname: Kim
authors.forename: Jong Duk
authors.initials: JD
authors.lastname: Lee
authors.forename: Young Sil
authors.initials: YS
authors.lastname: Hwang
authors.forename: In-Suk
authors.initials: IS
authors.lastname: Kim
authors.forename: Suee
authors.initials: S
authors.lastname: Lee
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Oh
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D002945:Cisplatin / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D002945:Cisplatin