title: High levels of phosphorylated MAP kinase are associated with poor survival among patients with glioblastoma during the temozolomide era.
abstract: We investigated whether high levels of activated mitogen-activated protein kinase (p-MAPK) were associated with poor survival among patients with newly diagnosed glioblastoma during the temozolomide era. Nuclear p-MAPK expression of 108 patients with GBM was quantified and categorized in the following levels: low (0%-10%), medium (11%-40%), and high (41%-100%). Independent predictors of overall survival were determined using a multivariate Cox proportional hazards model. Our study included 108 patients with newly diagnosed GBM. Median age was 65 years, and 74% had high Karnofsky performance status (KPS ≥ 80). Median overall survival among all patients was 19.5 months. Activated MAPK expression levels of <10%, 11%-40%, and ≥ 41% were observed in 33 (30.6%), 37 (34.3%), and 38 (35.2%) patients, respectively. Median survival for low, medium, and high p-MAPK expression was 32.4, 18.2, and 12.5 months, respectively. Multivariate analysis showed 2.4-times hazard of death among patients with intermediate p-MAPK than low p-MAPK expression (hazard ratio [HR], 2.4; P = .02); high-expression patients were 3.9 times more likely to die, compared with patients with low p-MAPK (HR, 3.9; P = .007). Patients aged ≥ 65 years (HR, 2.8; P = .002) with KPS < 80 (HR, 3.1; P = .0003) and biopsy or partial resection (HR, 1.9; P = .02) had higher hazard of death. MGMT and PTEN expression were not associated with survival differences. This study provides quantitative means of evaluating p-MAPK in patients with GBM. It confirms the significant and independent prognostic relevance of p-MAPK in predicting survival of patients with GBM treated in the temozolomide era and highlights the need for therapies targeting the p-MAPK oncogenic pathway.
authors.affiliation: Center for Neurosurgical Outcomes Research, Department of Neurosurgery, Cedars-Sinai Medical Center, 8631 W Third St, Suite 800E, Los Angeles, CA 90048, USA. chiragpatil@gmail.com
authors.forename: Chirag G
authors.initials: CG
authors.lastname: Patil
authors.forename: Miriam
authors.initials: M
authors.lastname: Nuño
authors.forename: Adam
authors.initials: A
authors.lastname: Elramsisy
authors.forename: Debraj
authors.initials: D
authors.lastname: Mukherjee
authors.forename: Christine
authors.initials: C
authors.lastname: Carico
authors.forename: Jocelynn
authors.initials: J
authors.lastname: Dantis
authors.forename: Jethro
authors.initials: J
authors.lastname: Hu
authors.forename: John S
authors.initials: JS
authors.lastname: Yu
authors.forename: Xuemo
authors.initials: X
authors.lastname: Fan
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Serguei I
authors.initials: SI
authors.lastname: Bannykh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; C512478:EGFR protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077204:Temozolomide