Determining viability of using APNG status as a prognostic marker in patients with glioblastoma multiforme.

Authors

null

Rikke Hedegaard Dahlrot

Department of Oncology, Odense University Hospital, Odense, Denmark

Rikke Hedegaard Dahlrot , Sofie Hellwege , Sigurd Fosmark , Kristian Lindstroem Jensen , Jesper Lohse , Helene Derand , Jacob Hjelmborg , Steinbjorn Hansen , Bjarne Winther Kristensen

Organizations

Department of Oncology, Odense University Hospital, Odense, Denmark, Institute of Clinical Research, University of Southern Denmark, Odense C, Denmark, Department of Pathology, Odense University Hospital, Odense C, Denmark, Dako Denmark A/S, Glostrup, Denmark, The Department of Biostatistics, Institute of Public Health, University of Southern Denmark, Odense C, Denmark, Odense University Hospital, Odense, Denmark

Research Funding

No funding sources reported

Background: Expression of the enzyme alkylpurine-DNA-N-glycosylase (APNG) has been associated with poor outcome in patients with glioblastoma multiforme (GBM). APNG is part of the base excision repair system, and expression of APNG is related to resistance towards temozolomide (TMZ). This study evaluates the prognostic value of APNG in a population-based cohort of 185 Danish GBM patients diagnosed between 2005 and 2009. Due to GBM’s cellular heterogeneity, APNG contribution from non-tumor cells was excluded. Methods: APNG expression was evaluated using image analysis and a novel quantitative immunohistochemical (IHC) assay (qIHC, Dako), where APNG protein levels were represented through dots. Non-tumor cells, which were found to express APNG, were excluded using an IHC/qIHC double-staining. To verify the qIHC results, APNG was measured in 177 of the patients using a quantitative in-house developed APNG immunofluorescence (IF) assay. MGMT methylation status was obtained in 152 patients by pyrosequencing. Results: Using qIHC, median expression of APNG was 0.31 dots/cell (range 0.099-0.96). An optimal cut-point was identified dichotomizing the patients at an APNG value of 0.24 (25% vs. 75% of the patients). In Cox regression high expression of APNG was associated with better overall survival (OS) (HR 0.53, p = 0.001) adjusting for the effect of age, performance status, tumor crossing midline, treatment and gender. APNG was associated with better OS (HR 0.57, p = 0.012) when adjusting for MGMT status. Retesting the cohort using IF, demonstrated similar results (HR 0.81, p = 0.2). Patients with methylated MGMT promoters and high APNG expression demonstrated a better OS, than with non-methylated MGMT promoters and low APNG expression (HR 0.55, p = 0.04). Conclusions: APNG measured by qIHC was found to be an independent significant prognostic factor for OS in GBMs, This was supported by IF measurements. Removing bias associated with APNG expression in non-tumor cells in both assays has, in this study contributed substantially to analyze the prognostic value of APNG in GBM patients. We expect that APNG qIHC can potentially identify patients who will not benefit from treatment with TMZ.

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Abstract Details

Meeting

2015 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Central Nervous System Tumors

Track

Central Nervous System Tumors

Sub Track

Central Nervous System Tumors

Citation

J Clin Oncol 33, 2015 (suppl; abstr 2028)

DOI

10.1200/jco.2015.33.15_suppl.2028

Abstract #

2028

Poster Bd #

17

Abstract Disclosures

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