Prognostic relevance of clinical and biological risk factors in childhood medulloblastoma: Results of patients treated in the prospective multicenter trial HIT'91

Abstract

Purpose: To identify better risk stratification systems in childhood medulloblastoma based on clinical factors and analysis of routinely processed formalin-fixed tumor material. Experimental Design: Formalin-fixed paraffin-embedded tumor samples from well-documented patients treated within the prospective randomized multicenter trial HIT'91 were analyzed for DNA amplification of c-myc and N-myc (n = 133) and mRNA expression of c-myc and trkC (n = 104; compared with human cerebellum) using validated methods of quantitative PCR and reverse transcription-PCR. Results were related to clinical data and outcome. Results: TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified, (a) Favorable risk group: all 8 patients (2 metastatic) with high trkC (> 1 x human cerebellum) and low c-myc mRNA expression (≤1 x human cerebellum) remained relapse-free [7-year event-free survival (EFS), 100%]. (b) Poor risk group: 10 of 15 patients with metastatic disease and high c-myc and low trkC mRNA expression relapsed (7-year EFS, 33%). (c) Intermediate risk group: the 7-year EFS of the remaining 78 patients was 65%. Among 47 M 0 stage patients, all 10 patients with high trkC mRNA expression remained relapse-free compared with 15 events in 37 patients with low trkC mRNA expression levels (7-year EFS, 100% versus 62%; P = 0.056). Conclusions: Whereas the collection of fresh-frozen tumor samples remains a major challenge in large clinical trials, routinely processed paraffin-embedded tissue samples can be used to quantitate the prognostic biological markers trkC and c-myc. On prospective validation of cutoff levels, this may lead to improved stratification of treatment for children with medulloblastoma. © 2007 American Association for Cancer Research.