Clin Transl Oncol (2010) 12:310-314 DOI 10.1007/s12094-010-0510-z
C A S E R E P O RT S
Response to erlotinib in recurrent glioblastoma multiforme showing coexpression of EGFRvIII and PTEN Ana Custodio · Antonio Calles · Pedro Pérez-Segura
Received: 27 May 2009 / Accepted: 26 September 2009
Abstract Glioblastoma multiforme (GBM) is the most aggressive brain tumour in adults and remains incurable despite multimodal intensive treatment regimens. We present a patient with a recurrent glioblastoma who showed coexpression of the epidermal growth factor receptor mutant variant III (EGFRvIII) and the tumour-suppressor protein PTEN. She was treated with the tyrosine kinase inhibitor erlotinib for four months, achieving a partial response with improvement of neurologic symptoms. A review of the pertinent literature supporting the future use of therapies against epidermal growth factor receptor (EGFR) in highgrade gliomas is also provided.
cal progress, genetic analysis has improved our understanding of the molecular pathogenesis of these malignancies and provided enough information to stratify tumours into categories amenable to targeted treatment modalities. In this setting, the epidermal growth factor receptor (EGFR) pathway represents a particularly attractive therapeutic target in GBM because EGFR is dysregulated in the majority of human malignant gliomas through overexpression, amplification and activating mutations [1, 2].
Keywords Glioblastoma multiforme · Recurrent disease · Epidermal growth factor receptor · PTEN · Tyrosine kinase inhibitors
A 58-year-old woman with a diagnosis of a multinodular goitre treated with right hemithyroidectomy and substitutive therapy and no other relevant data in her past medical history was admitted to the Neurosurgery Department. A 10-day history of loss of left visual field, nausea, unilateral headache on the left and progressive memory deficit constituted the main symptomatology. The neurological examination revealed left homonym hemianopsy without other relevant findings and laboratory tests were within normal range. A brain computed tomography (CT) detected a 3035 mm hyperdense right parietal mass surrounded by vasogenic oedema, which suggested high-grade glioma, and magnetic resonance imaging (MRI) showed a ring-enhancing lesion, hyperintense in T2 sequences, with evidence of recent haemorrhage and necrosis areas. High-dose steroid treatment was started, with an improvement of neurologic symptoms, and a craniotomy was performed. The neurosurgeon described a hypervascular, infiltrating right parietal lesion, near sagittal sinus, and cerebri sickle. A complete macroscopic resection was performed and the examination of the surgical specimen revealed a GBM with extensive necrosis areas and high cellular density. Surgical margins were not affected and postsurgical MRI showed no evidence of disease. The patient was submitted to the Medical Oncology Department of our institution. She was treated with concomitant chemoradiotherapy followed by adjuvant chemotherapy according to the Stupp regimen. Radiotherapy consisted of fractionated focal irradiation at a dose of 2 Gy per fraction given once daily five days per week over a period of six weeks, for a total dose of 60 Gy. Concomitant chemotherapy consisted of temozolamide at a dose of 75 mg/m2 given 7 days per week from the first to the last day of radiotherapy. After a 4-week break, she received six cycles of adjuvant temozolamide according to the standard 5-day schedule every 28 days. The dose was
Introduction Glioblastoma multiforme (GBM) is the most common primary malignant neoplasm of the central nervous system in adults. Efforts to improve surgical, radiotherapy and chemotherapy approaches to high-grade glioma treatment have not substantially increased long-term survival. Although standard antineoplastic therapies have produced little clini-
A. Custodio (쾷) · A. Calles · P. Pérez-Segura Medical Oncology Department Hospital Universitario Clínico San Carlos C/ Profesor Martín Lagos, s/n ES-28040 Madrid, Spain e-mail:
[email protected]
Case report
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Fig. 1A,B Recurrent GBM: hyperenhanced gyriform areas in the right parasagittal cortex and a 1215 mm nodular lesion surrounded by vasogenic oedema in brain MRI
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Fig. 2A,B Partial response in a follow-up MRI after two months of erlotinib treatment
150 mg/m2 for the first cycle and was increased to 200 mg/m2 beginning with the second cycle. There were no significant toxic effects and the brain MRI performed after adjuvant chemotherapy showed no evidence of disease. Ten months after completion of the chemoradiation regimen a local recurrence of 1012 mm in the previous surgical area was demonstrated in a follow-up brain MRI. A second craniotomy with a complete macroscopic resection of the lesion was carried out with pathological report of GBM. She received a salvage temozolamide-based schedule at a dose of 150 mg/m2 7 days on/7 days off for 6 months. Nevertheless, seven months after the sixth cycle the patient’s neurological state worsened progressively. She described increased instability, headache and loss of the left visual field. Brain MRI revealed hyperenhanced gyriform areas in the right parasagittal cortex and a 1215 mm nodular lesion surrounded by vasogenic oedema (Fig. 1). At this time the expression of the epidermal growth factor receptor mutant variant type III (EGFRvIII) and the tumour-suppressor protein PTEN was determined. The immunohistochemical analysis revealed coexpression of both EGFRvIII and PTEN in the frozen specimen. So, continuous erlotinib at a dose of 150 mg daily was started. After two weeks of treatment the patient experienced an important clinical improvement and a radiologic partial response in a follow-up MRI (Fig. 2). Up to four months with erlotinib were applied. The side effects that the patient suffered were grade 2 acneiform rash and grade 1 diarrhoea. Finally neurologic and radiologic progression was documented in a re-evaluation study. The patient was offered palliative chemotherapy with bevacizumab at 10 mg/kg plus irinotecan every 2 weeks, but after the first cycle she suffered a progressive deterioration of her clinical and neurological status. It was decided to give supportive care and she died from her disease 38 months after her initial diagnosis.
Discussion GBM is the most aggressive form of adult brain tumour, with a median survival time of 12–14 months with maximal therapy [3]. Recurrent GBM has a strikingly low rate of clinical response and frequent treatment failure. Current therapies target tumours in a nonspecific fashion, usually through DNA damage. Novel targeted therapies currently under development include small-molecule inhibitors of membrane receptor-associated tyrosine kinase activity to block pathways mediating critical tumour phenotypes. Membrane receptor-associated tyrosine kinases activities are key regulators of intracellular signalling [4]. Mutated intracellular domains with anchored tyrosine kinase activity that induces a constitutive phosphorylation in the absence of extracellular domain binding occur in many types of cancer and contribute to the development and progression of tumours [5]. The dependence of tumour cells on persistently activated tyrosine kinases may render tumours susceptible to inhibitors of these kinases. The EGFR, a single-pass type I membrane glycoprotein that belongs to the epidermal growth factor (EGF) receptor subfamily, is a target for such inhibitors because it is mutated, amplified or both in numerous malignancies [6]. Activity of the EGF pathway in a variety of cancer types has been linked to an increase in motility, adhesion, invasion and proliferation of
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tumour cells as well as an inhibition of apoptosis and induction of angiogenesis [7]. In non-small-cell lung cancers activity of the EGFR inhibitors is limited to the approximately 10% of patients with small activating mutations in the EGFR tyrosine kinase domain (exons 19–21) [8]. It is not known, however, whether such mutations affect the responsiveness of other types of cancer to these agents. Among patients with GBM, a small subgroup seems to benefit from the EGFR kinase inhibitors gefitinib and erlotinib [9]. However, the infrequency of mutations in the tyrosine kinase domain of the EGFR gene cannot account for responsiveness to EGFR kinase inhibitors [10]. An increased number of EGFR allele copies (amplification) are usually seen in GBM [11], but this abnormality also does not correlate with responsiveness to EGFR kinase inhibitors [9]. GBM often express EGFRvIII, also named de2-7 EGFR and deltaEGFR, which is reported in 67% of tumours with amplified EGFR and in 38% of all glioblastomas [12]. It is characterised by the deletion of exons 2–7 of the EGFR gene with loss of 267 amino acids from the extracellular domain, resulting in a sense mutation that has a truncated extracellular ligand-binding domain [13]. This truncated mutant receptor has been exclusively found in tumours, suggesting selection for EGFRvIII during the process of tumorigenesis and, according to some reports, imparts a worse prognosis and confers therapeutic resistance [14–16]. Although EGFRvIII is incapable of binding the EGF family of ligands, it has a constitutively phosphorylated tyrosine kinase domain and it has been shown to strongly and persistently activate antiapoptotic signals through the phosphatidylinositol 3’ kinase (PI3K)-Akt signalling pathway, which provides critical information for cell survival, proliferation and motility [17, 18]. Persistent PI3K signalling is believed to cause “pathway addiction”; addicted tumour cells die if the pathway is disrupted by tyrosine kinase inhibitors [19]. Inhibition of this antiapoptotic signal by gefitinib appears to be critical to the efficacy of the drug [9]. Like the EGFR kinase domain mutants in lung cancer, EGFRvIII may sensitise glioblastoma cells to EGFR kinase inhibitors by promoting chronic dependence on PI3K signalling. Whereas PI3K and Akt are positive regulators, PTEN (phosphatase and tensin homologue), a tumour-suppressor protein, acts as an inhibitor of the PI3K-Akt signalling pathway. So, PTEN deletions may leave Akt activity without negative control, an event frequently described in GBM cells [11, 20, 21]. Loss of PTEN may promote cellular resistance to EGFR kinase-inhibitor therapy by dissociating EGFR inhibition from downstream PI3K pathway inhibition [22]. Several studies have investigated the activity of erlotinib in recurrent GBM, showing different results [23–27]. In a phase I trial of erlotinib with or without temozolamide, in which 57 assessable patients experienced eight responses, six of the responding patients had only received erlotinib [23]. In that trial, six patients were free from progression at 6 months. Another study showed greater than
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20% 6-month progression-free survival in recurrent GBM after erlotinib treatment [24]. A third study noted erlotinib activity in particular in recurrent malignant gliomas with combined presence of the EGFRvIII mutant and PTEN expression [25]. Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors in that study, 9 had a partial response of at least 25%. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response. EGFRvIII was detected in 12 of 26 malignant gliomas (46%). Of the 12 patients whose tumours expressed EGFRvIII, 6 had a response to EGFR kinase inhibitors, whereas 1 of 14 patients whose tumours did not express EGFRvIII had a response to EGFR kinase inhibitors (p=0.03). None of 13 patients whose tumours lacked PTEN had a response to EGFR inhibitors, whereas 7 of 13 patients with PTEN-positive tumours had a response (p=0.005). The greatest likelihood of a clinical response to EGFR kinase inhibitors was associated with coexpression of EGFRvIII and PTEN (odds ratio, 51; 95% confidence interval, 4–669; p
