title: Significance of folate receptor alpha and thymidylate synthase protein expression in patients with non-small-cell lung cancer treated with pemetrexed.
abstract: BACKGROUND
  Folate receptor alpha (FRA) regulates cellular uptake of folates and antifolates. Information about FRA protein expression in metastatic non-small-cell lung cancer (NSCLC) is limited. We investigated FRA as a biomarker for pemetrexed-based chemotherapy and compared it with thymidylate synthase (TS), the main target of pemetrexed.
  
  
  METHODS
  Pretreatment tumor specimens from 207 patients with advanced NSCLC were assessed for FRA and TS protein expression by immunohistochemistry using the H-score (range, 0-300) and correlated to patients' clinicopathological data, radiographic response, progression-free survival (PFS), and overall survival (OS).
  
  
  RESULTS
  Low total (cytoplasmic and nuclear) TS protein expression (H-score < 210) was associated with improved PFS (median: 5.6 versus 3.5 months; hazard ratio [HR] = 0.6379, p = 0.0131) and prolonged OS (median: 22.5 versus 11.5 months; HR = 0.5680,p = 0.0107). An association between lower TS levels and response to pemetrexed-based therapy was found-mean H-score 187 ± 5, median 180 for responders versus mean H-score 201 ± 4, median 210, for non-responders, p = 0.0244. High intracellular FRA expression (H-score ≥110) was associated with prolonged OS (28.9 versus 11.7 months, HR = 0.5316, p = 0.0040) and a trend for association with PFS (5.6 versus 4.1 months, HR = 0.7395, p = 0.0801) was noted. Membranous FRA expression was seen in 83% of patients, moreover, high membranous expression (H-score ≥20) was associated with improved PFS (5.6 versus 3.7 months, HR = 0.6445, p = 0.0306) and OS (22.1 versus 11.5 months, HR = 0.5378, p = 0.0131).
  
  
  CONCLUSIONS
  A large number of NSCLC patients have high expression of FRA and/or a low level of TS expression. Expression levels of FRA and TS were associated with clinical benefit from pemetrexed therapy.
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Christoph
authors.forename: Bernadette Reyna
authors.initials: BR
authors.lastname: Asuncion
authors.forename: Biftu
authors.initials: B
authors.lastname: Hassan
authors.forename: Cindy
authors.initials: C
authors.lastname: Tran
authors.forename: Julia D
authors.initials: JD
authors.lastname: Maltzman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Shannessy
authors.forename: Murry W
authors.initials: MW
authors.lastname: Wynes
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Gauler
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.forename: Mathias
authors.initials: M
authors.lastname: Hoiczyk
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.forename: Wilfried E
authors.initials: WE
authors.lastname: Eberhardt
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D058975:Folate Receptor 1 / Q000378:metabolism*; D005971:Glutamates / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012372:ROC Curve; D018709:Statistics, Nonparametric; D013940:Thymidylate Synthase / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058975:Folate Receptor 1; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase