title: A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer.
abstract: OBJECTIVE
  Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity.
  
  
  METHODS
  Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m(2) (P600 arm) or 900 mg/m(2) (P900 arm) of pemetrexed on day 1 of a 21-day cycle. All patients received folic acid and vitamin B(12) supplementation.
  
  
  RESULTS
  The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with approximately 50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. gamma-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low gamma-glutamyl hydrolase (P = 0.024).
  
  
  CONCLUSIONS
  The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.
authors.affiliation: Hospital Universitario Arnau Vilanova, Lleida, Spain. allombart@arnau.scs.es
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart-Cussac
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Rodica M
authors.initials: RM
authors.lastname: Anghel
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Eniu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Verrill
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.forename: Jacques
authors.initials: J
authors.lastname: De Grève
authors.forename: Allen S
authors.initials: AS
authors.lastname: Melemed
authors.forename: Romnee
authors.initials: R
authors.lastname: Clark
authors.forename: Lorinda
authors.initials: L
authors.lastname: Simms
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kaiser
authors.forename: Doreen
authors.initials: D
authors.lastname: Ma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy*; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid; D015870:Gene Expression / Q000187:drug effects; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D008875:Middle Aged; D000068437:Pemetrexed; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014805:Vitamin B 12
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D005971:Glutamates; D012333:RNA, Messenger; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; D014805:Vitamin B 12