title: Pemetrexed Plus Cisplatin Versus Gemcitabine Plus Cisplatin According to Thymidylate Synthase Expression in Nonsquamous Non-Small-Cell Lung Cancer: A Biomarker-Stratified Randomized Phase II Trial.
abstract: OBJECTIVE
  We investigated whether thymidylate synthase (TS) expression is a predictive marker for the clinical outcome of pemetrexed/cisplatin in patients with nonsquamous non-small-cell lung cancer.
  
  
  METHODS
  Eligible patients were tested for TS expression by immunohistochemistry and stratified into either a TS-negative or a TS-positive group. After stratification, patients in each group were randomly assigned (1:1 ratio) to receive either pemetrexed/cisplatin or gemcitabine/cisplatin for a maximum of six cycles until disease progression. The primary end point was evaluation of the interaction between TS groups and treatment allocation for objective response rate.
  
  
  RESULTS
  Of 321 enrolled patients with nonsquamous non-small-cell lung cancer, 315 received at least one dose of study chemotherapy and were analyzed. By investigator assessment, response rates were 47% for the pemetrexed/cisplatin arm and 21% for the gemcitabine/cisplatin arm in the TS-negative group and 40% and 39%, respectively, for the TS-positive group (interaction P = .0084). By independent reviewers, response rates of pemetrexed/cisplatin and gemcitabine/cisplatin were 39% and 21%, respectively, in the TS-negative group and 40% and 48% in the TS-positive group (interaction P = .0077). The median progression-free survival times for the pemetrexed/cisplatin and the gemcitabine/cisplatin arms were 6.4 and 5.5 months, respectively, in the TS-negative group and 5.9 and 5.3 months in the TS-positive group (interaction P = .07).
  
  
  CONCLUSIONS
  With regard to response rate and progression-free survival, pemetrexed/cisplatin was superior to gemcitabine/cisplatin in the TS-negative group but not in the TS-positive group, indicative of TS expression as a potential predictive marker. Additional prospective studies involving larger cohorts are warranted to confirm the predictive role of TS expression.
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC.
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC.
authors.forename: Sin-Ho
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC.
authors.forename: Jiyu
authors.initials: J
authors.lastname: Sun
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC.
authors.forename: Sang Yun
authors.initials: SY
authors.lastname: Ha
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC.
authors.forename: Joungho
authors.initials: J
authors.lastname: Han
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Jong-Mu Sun, Jin Seok Ahn, Sin-Ho Jung, Jiyu Sun, Sang Yun Ha, Joungho Han, Keunchil Park, and Myung-Ju Ahn, Sungkyunkwan University School of Medicine, Seoul, Korea; and Sin-Ho Jung, Duke University, Durham, NC. silkahn@skku.edu.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D000068437:Pemetrexed; D011237:Predictive Value of Tests; D013940:Thymidylate Synthase / Q000378:metabolism*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D013940:Thymidylate Synthase; D002945:Cisplatin; D000093542:Gemcitabine