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Originally published as JCO Early Release 10.1200/JCO.2008.18.1776 on September 8 2008 © 2008 American Society of Clinical Oncology.
DNA Repair Enzyme Expression and Differential Response to Temozolomide in a Patient With Both Glioblastoma and Metastatic Pancreatic Neuroendocrine Tumor
Center for Neuro-Oncology, Boston, MA; Dana-Farber/Brigham and Women's Cancer Center, Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA; Universitätsklinikum, Medizinische Fakultät, Georg-August-Universität, Robert-Koch-Strasse, Göttingen, Germany
Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center; Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA
Department of Pathology, Brigham and Women's Hospital, Boston, MA
Department of Pathology, Brigham and Women's Hospital, Boston, MA; AmeriPath Inc, Palm Beach Gardens, FL
Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA
Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA
Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center; Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA
Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center; Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA A 55-year old man presented to the emergency department in November 2005 with a 2-week history of headaches, aphasia, and memory loss. He had no significant past medical history. A gadolinium-enhanced brain magnetic resonance imaging (MRI) scan revealed a large cystic partially enhancing left temporal lobe tumor (Fig 1A), as well as two pancreatic and multiple liver masses (Fig 2A and B, arrows). A left temporal craniotomy with partial tumor resection was performed. Pathology demonstrated a cellular specimen composed of tumor cells showing astrocytic differentiation, as highlighted with glial fibrillary acidic protein, and readily identified mitoses, as well as foci of tumor necrosis and endothelial proliferation consistent with glioblastoma (WHO grade 4/4). Ultrasound-guided fine-needle aspiration of his liver mass showed a relatively monotonous cell population with small- to intermediate-sized round nuclei, variably prominent nucleoli, and ample granular cytoplasm. Immunostains were strongly positive for chromogranin and synaptophysin, consistent with metastatic neuroendocrine tumor (NET) from the pancreas. Considering the nature of pancreatic NETs, which are slow growing but usually not curable, priority was given to treatment of the glioblastoma. The patient underwent concurrent involved-field chemoradiotherapy consisting of 6000 cGy in 30 fractions over 6 weeks together with temozolomide (75 mg/m2/d). Treatment was completed in February 2006. His postradiation brain MRI in early March 2006 showed reduction of enhancement consistent with response to treatment. Temozolomide was continued in the adjuvant setting at an initial dose of 150 mg/m2/d for 5 days every 28 days. Due to treatment-related appetite and weight loss during the first cycle, chemotherapy was increased only to 175 mg/m2/d for the second cycle instead of the usual 200 mg/m2/d. In May 2006, brain MRI scan revealed tumor progression. The concurrent diagnosis of pancreatic NET excluded him from clinical trials for glioblastoma. The patient was treated with a dose-dense regimen of temozolomide at 137.5 mg/m2 for 1 week on, then one week off. This regimen had shown some activity in malignant glioma patients with relapsed disease following treatment with standard dose temozolomide.1 Surprisingly, an abdominal computed tomography scan performed in May 2006 showed reduction of all sites of metastatic lesions in the liver and pancreas consistent with treatment response to temozolomide. Figures 2A and 2B demonstrate segment 6 and 7 liver lesions in November 2005 before temozolomide. Figures 2C and 2D demonstrate marked interval improvement in these two lesions (arrows) in May 2006. Unfortunately, a follow-up brain MRI scan in June 2006 indicated further progression of the enhancing tumor in the left temporoparietal region (Fig 1B) compared with his postradiation MRI scan from March 2006 (Fig 1A). Due to progressive neurologic decline, treatment was discontinued, and the patient died in October 2006. O6-methylguanine–DNA-methyltransferase (MGMT) expression in paraffin-embedded tumor tissue of the brain and pancreatic liver lesions was determined by immunohistochemistry using a mouse monoclonal antibody to MGMT. Although MGMT was expressed in glioblastoma cells, it was absent in pancreatic tumor cells. Figure 3A demonstrates glioblastoma showing a high mitotic rate and prominent vascular proliferation (hematoxylin and eosin stain, x400). Immunohistochemistry for MGMT shows intact nuclear staining in tumor cells (x400; Fig 3B). Figure 3C demonstrates the liver fine needle aspiration smear of metastatic NET showing uniform nuclei and abundant cytoplasm (Wright-Giemsa, x600). Immunohistochemistry for MGMT performed on cell block sections shows absence of staining in tumor cells (x600; Fig 3D). This is consistent with the differential responses seen with the two tumors in this patient.
The DNA repair enzyme MGMT is believed to confer cancer cell resistance to O6-alkylating agents, such as temozolomide, through its ability to remove methyl/alkyl groups from the O6-position of guanine, thus preventing temozolomide-induced DNA damage.2,3 In 45% of glioblastomas, the MGMT promoter is hypermethylated, resulting in inactivation of the gene and reduced cellular expression of MGMT. These glioblastomas with decreased MGMT expression have compromised DNA repair, increased sensitivity to temozolomide, and prolonged survival.2,4,5 There is mounting evidence suggesting MGMT inactivation as a valuable prognostic marker and predictor of chemosensitivity in glioblastomas.5 The addition of temozolomide to radiotherapy produces little or no benefit in glioblastoma patients with unmethylated MGMT promoters.6 The lack of response in our patient is consistent with this. In contrast, the MGMT-deficient metastatic pancreatic neuroendocrine tumor responded to temozolomide with significant reduction in tumor mass. Temozolomide has recently been reported to be effective in a subset of patients with NETs, particularly those with pancreatic primary tumors. The most significant treatment benefit was found among patients whose tumors lacked MGMT expression.7 This case of differential response to temozolomide based on tumor MGMT expression highlights the potential utility of evaluating tumor MGMT status in guiding therapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print at www.jco.org on September 8, 2008 REFERENCES
1. Wick W, Steinbach JP, Kuker WM, et al: One week on/one week off: A novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62:2113-2115, 2004 2. Ekeblad S, Sundin A, Janson ET, et al: Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 13:2986-2991, 2007 3. Kaina B, Christmann M, Naumann S, et al: MGMT: Key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst) 6:1079-1099, 2007[CrossRef][Medline] 4. Hau P, Stupp R: MGMT methylation status: The advent of stratified therapy in glioblastoma? Dis Markers 23:97-104, 2007[Medline] 5. Idbaih A, Omuro A, Ducray F, et al: Molecular genetic markers as predictors of response to chemotherapy in gliomas. Curr Opin Oncol 19:606-611, 2007[Medline] 6. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005 7. Kulke MH, Frauenhoffer CS, Hooshmand SM, et al: Prediction of response to temozolomide (TMZ)–based therapy by loss of MGMT expression in patients with advanced neuroendocrine tumors (NET). J Clin Oncol 25:18s, 2007 (abstr 4505)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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