Epidermal Growth Factor Receptor Variant III Status Defines Clinically Distinct Subtypes of Glioblastoma

Pelloski, Christopher E.; Ballman, Karla V.; Furth, Alfred; Zhang, Li; Lin, E.; Sulman, Erik P.; Bhat, Krishna; McDonald, J. Matthew; Yung, W. K. Alfred; Colman, Howard; Woo, Shiao Y.; Heimberger, Amy B.; Suki, Dima; Prados, Michael D.; Chang, Susan M.; Barker, Fred G.; Buckner, Jan C.; James, C. David; Aldape, Kenneth

doi:10.1200/jco.2006.08.0705

Cited by 260 publications

(194 citation statements)

References 34 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…The speculation that these tumors carry alterations in other genes involved in the same pathway as IDH1/ 2 has not been substantiated so far and is unlikely, given their differential genomic and epigenomic profiles. We confirm a lower rate of EGFR amplification in the LTS-36 cohort (26), but this can now be linked to its virtual absence in patients with IDH1/2-mutant tumors. Interestingly, the EGFR amplification rate in IDH1/2 wild-type tumors was similar in LTS-36 patients (43.2%) and in the control cohort (45.5%).…”

Section: Discussionsupporting

confidence: 61%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

165

108

View full text Add to dashboard Cite

Purpose: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.Experimental Design: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

show abstract

Section: Discussionsupporting

confidence: 61%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

165

108

View full text Add to dashboard Cite

show abstract

“…However, we found an association of the expression of these proteins with the proliferation index, which in the novel grading scheme for GEP-NET is the central classifier for tumour grade. mTOR expression and activity have been evaluated in a broad variety of human tumours, including most of the major tumour types, namely endometrial (Darb-Esfahani et al 2009), esophageal (Boone et al 2008), renal (Campbell et al 2008), colorectal (Tampellini et al 2007), prostate (Kremer et al 2006), liver (Sahin et al 2004), breast (Zhou et al 2004, Rojo et al 2007, lung (Anagnostou et al 2009) and ovarian (Noske et al 2008) cancer as well as glioblastoma (Pelloski et al 2006). In all tumour entities, mTOR was either upregulated and/or activated in the tumour tissue when compared with the Figure 5 Correlation of mTOR, 4EBP1, p-4EBP1, p-S6K and p-eIF4E expression with survival in stage IV midgut NET.…”

Section: Discussionmentioning

confidence: 99%

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Kasajima¹,

Pavel²,

Darb‐Esfahani³

et al. 2010

Endocrine Related Cancer

View full text Add to dashboard Cite

Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (PZ0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (PZ0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.

show abstract

“…More than 40% of GBMs carry the unique deletion mutant variant of EGFR called EGFRvIII that is characterized by a deletion of 267 amino acids in the receptor extracellular domain (104,105). This mutation causes constitutive ligandindependent receptor activation and signal propagation leading to cancer cell proliferation.…”

Section: Immunotherapy Of Gbmmentioning

confidence: 99%

“…There has also been great progress in immunotherapy research in GBM over the past few years. There are many different approaches currently being evaluated in GBM clinical trials, including passive immunotherapy with antibodies, utilization of autologously stimulated lymphocytes and cytokines, oncolytic virotherapy, and active immunotherapy with vaccine strategies based on tumor cells, peptides, or dendritic cells (DCs) (20,102,103).More than 40% of GBMs carry the unique deletion mutant variant of EGFR called EGFRvIII that is characterized by a deletion of 267 amino acids in the receptor extracellular domain (104,105). This mutation causes constitutive ligandindependent receptor activation and signal propagation leading to cancer cell proliferation.…”

mentioning

confidence: 99%

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

et al. 2017

View full text Add to dashboard Cite

Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

show abstract

Epidermal Growth Factor Receptor Variant III Status Defines Clinically Distinct Subtypes of Glioblastoma

Abstract: Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.

Cited by 260 publications

References 34 publications

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Contact Info

Product

Resources

About