title: Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer.
abstract: OBJECTIVE
  Standard treatment for advanced non-small-cell lung cancer (NSCLC) includes the use of a platinum-based chemotherapy regimen. However, response rates are highly variable. Newer agents, such as pemetrexed, have shown significant activity as second-line therapy and are currently being evaluated in the front-line setting. We utilized a genomic strategy to develop signatures predictive of chemotherapeutic response to both cisplatin and pemetrexed to provide a rational approach to effective individualized medicine.
  
  
  METHODS
  Using in vitro drug sensitivity data, coupled with microarray data, we developed gene expression signatures predicting sensitivity to cisplatin and pemetrexed. Signatures were validated with response data from 32 independent ovarian and lung cancer cell lines as well as 59 samples from patients previously treated with cisplatin.
  
  
  RESULTS
  Genomic-derived signatures of cisplatin and pemetrexed sensitivity were shown to accurately predict sensitivity in vitro and, in the case of cisplatin, to predict treatment response in patients treated with cisplatin. The accuracy of the cisplatin predictor, based on available clinical data, was 83.1% (sensitivity, 100%; specificity 57%; positive predictive value, 78%; negative predictive value, 100%). Interestingly, an inverse correlation was seen between in vitro cisplatin and pemetrexed sensitivity, and importantly, between the likelihood of cisplatin and pemetrexed response in patients.
  
  
  CONCLUSIONS
  The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors.
authors: Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC 27710, USA.
authors: David S
authors: DS
authors: Hsu
authors: Bala S
authors: BS
authors: Balakumaran
authors: Chaitanya R
authors: CR
authors: Acharya
authors: Vanja
authors: V
authors: Vlahovic
authors: Kelli S
authors: KS
authors: Walters
authors: Katherine
authors: K
authors: Garman
authors: Carey
authors: C
authors: Anders
authors: Richard F
authors: RF
authors: Riedel
authors: Johnathan
authors: J
authors: Lancaster
authors: David
authors: D
authors: Harpole
authors: Holly K
authors: HK
authors: Dressman
authors: Joseph R
authors: JR
authors: Nevins
authors: Phillip G
authors: PG
authors: Febbo
authors: Anil
authors: A
authors: Potti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D005971:Glutamates / Q000494:pharmacology* / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D018579:Patient Selection; D000068437:Pemetrexed; D011237:Predictive Value of Tests; D012044:Regression Analysis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D002945:Cisplatin