title: Genetic variation in platinating agent and taxane pathway genes as predictors of outcome and toxicity in advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide. Although clinical factors including age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of response and toxicity. The present study aimed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer (NSCLC) treated primarily with carboplatin and paclitaxel.
  
  
  METHODS
  Genomic DNA samples from 90 adult male patients diagnosed with stage IIIB/IV NSCLC were genotyped for SNPs in candidate genes of relevance to platinating agents and paclitaxel and analyzed for association with survival and toxicities in univariate and multivariate models.
  
  
  RESULTS
  After adjusting for performance status and stage, SNPs in the drug transporters ABCB1 and ABCC1, as well as within NQO1 were associated with progression-free survival. With respect to hematological and nonhematological toxicities, SNPs in drug transporters (ABCB1 and ABCG2) were associated with thrombocytopenia, nausea and neutropenia, whereas SNPs in the DNA repair pathway genes ERCC4 and XPC were significantly associated with neutropenia and sensory neuropathy, respectively.
  
  
  CONCLUSIONS
  Our study evaluated and identified SNPs in key candidate genes in platinating agent and taxane pathways associated with outcome and toxicity in advanced NSCLC. If validated in large prospective studies, these findings might provide opportunities to personalize therapeutic strategies.
authors.affiliation: Department of Experimental & Clinical Pharmacology, PUMA-Institute of Personalized Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jatinder Kaur
authors.initials: JK
authors.lastname: Lamba
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Taraswi M
authors.initials: TM
authors.lastname: Ghosh
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Gaurav
authors.initials: G
authors.lastname: Mehta
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001952:Bridged-Ring Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D009325:Nausea / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001952:Bridged-Ring Compounds; D016190:Carboplatin; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D017239:Paclitaxel; D043823:Taxoids; C513055:ABCB1 protein, human; C095888:xeroderma pigmentosum group F protein; C086984:XPC protein, human; C080625:taxane; C447479:NQO1 protein, human; C421109:multidrug resistance-associated protein 1
keywords: adverse effects; carboplatin; non-small cell lung cancer; pharmacogenetics; prognosis; single nucleotide polymorphisms; taxane