title: Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non-Small-cell Lung Cancer.
abstract: Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Previous studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic, marker of cellular folate status was associated with the response to pemetrexed-based chemotherapy in advanced nonsquamous non-small-cell lung cancer (NSCLC).
  
  
  
  We conducted a prospective cohort study of patients with stage IV nonsquamous NSCLC receiving first-line chemotherapy containing pemetrexed. The pretreatment RBC total folate level was quantified using liquid chromatography mass spectrometry. We then compared the objective response rate (ORR) between patients with RBC total folate concentrations greater than and less than an optimal cutoff value determined from the receiver operating characteristic curve. A logistic regression model was used to adjust for age, sex, and the use of bevacizumab.
  
  
  
  The ORR was 62% (32 of 52 patients). Receiver operating characteristic analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and nonresponders. Patients with RBC total folate < 364.5 nM had an ORR of 27% compared with 71% for patients with RBC total folate > 364.5 nM (P = .01). This difference persisted after adjusting for age, sex, and the use of bevacizumab (odds ratio, 0.07; 95% confidence interval, 0.01-0.57; P = .01).
  
  
  
  A low pretreatment RBC total folate was associated with an inferior response to pemetrexed-based chemotherapy in stage IV nonsquamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address: stephen.bagley@uphs.upenn.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Bagley
authors.affiliation: Penn Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA.
authors.forename: Steven
authors.initials: S
authors.lastname: Vitale
authors.affiliation: Center of Excellence in Environmental Toxicology and Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Suhong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Charu
authors.initials: C
authors.lastname: Aggarwal
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Evans
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Evan W
authors.initials: EW
authors.lastname: Alley
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.affiliation: Center of Excellence in Environmental Toxicology and Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Thoracic Oncology Group, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Anil
authors.initials: A
authors.lastname: Vachani
authors.affiliation: Center of Excellence in Environmental Toxicology and Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Whitehead
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D000068437:Pemetrexed; D014803:Vitamin B Complex; D005492:Folic Acid; D016190:Carboplatin
keywords: Biomarker; Chemotherapy; Folic acid; MTHFR; Polymorphism