title: Expression of EGFRvIII in glioblastoma: prognostic significance revisited.
abstract: The epidermal growth factor receptor variant III (EGFRvIII) is associated with increased proliferation of glioma cells. However, the impact of EGFRvIII on survival of patients with glioblastoma (GBM) has not been definitively established. In the present study, we prospectively evaluated 73 patients with primary GBM treated with surgical resection and standard radio/chemotherapy. The EGFRvIII was assessed by reverse transcription-polymerase chain reaction (PCR), O(6)-methylguanine methyltransferase (MGMT) promoter methylation was assessed by methylation-specific PCR, and phosphatase and tension homolog (PTEN) expression was assessed by immunohistochemistry. In 14 patients of this series, who presented with tumor recurrence, EGFRvIII was determined by real-time PCR. Sensitivity to temozolomide (TMZ) was assessed in vitro on GBM neurosphere cell cultures with different patterns of EGFRvIII expression. Age 60 years or younger, preoperative Karnofsky Performance Status score of 70 or higher, recursive partitioning analysis score III and IV, methylated MGMT, and Ki67 index of 20% or less were significantly associated with longer overall survival (OS; P = .0069, P = .0035, P = .0007, P = .0437, and P = .0286, respectively). EGFRvIII identified patients with significantly longer OS (P = .0023) and the association of EGFRvIII/Ki67 of 20% or less, EGFRvIII/normal PTEN, EGFRvIII/methylated MGMT, and EGFRvIII/normal PTEN/methylated MGMT identified subgroups of GBM patients with better prognosis. In recurred GBMs, EGFRvIII expression was approximately two-fold lower than in primary tumors. In vitro, the EGFRvIII-negative GBM neurosphere cells were more resistant to TMZ than the positive ones. In conclusion, in contrast with previous studies, we found that EGFRvIII is associated with prolonged survival of GBM patients treated with surgery and radio/chemotherapy. Depletion of EGFRvIII in recurrent GBMs as well as differential sensitivity to TMZ in vitro indicates that the EGFRvIII-negative cell fraction is involved in resistance to radio/chemotherapy and tumor repopulation.
authors.affiliation: Istituti di Neurochirurgia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Montano
authors.forename: Tonia
authors.initials: T
authors.lastname: Cenci
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.forename: Quintino Giorgio
authors.initials: QG
authors.lastname: D'Alessandris
authors.forename: Federica
authors.initials: F
authors.lastname: Pelacchi
authors.forename: Lucia
authors.initials: L
authors.lastname: Ricci-Vitiani
authors.forename: Giulio
authors.initials: G
authors.lastname: Maira
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D018874:Spheroids, Cellular / Q000187:drug effects; D016019:Survival Analysis; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; C410723:epidermal growth factor receptor VIII; D003606:Dacarbazine; D066246:ErbB Receptors; D000077204:Temozolomide