Prospective molecular profiling of medulloblastoma in children on the Head Start 4 consortium trial
Elaine Mardis, PhD
BACKGROUND: Brain cancer represents the most prevalent childhood cancer second only to leukemia and, in North America, the most common cause of disease-related death in children and adolescents. Medulloblastoma is the most common childhood malignant brain tumor, with peak incidence around 4-6 years of age and survival rates substantially lower in younger children. Because of long-recognized permanent, irreversible side-effects of radiotherapy on the developing brain, treatments for young children with medulloblastoma have sought to avoid irradiation. Since 1990, the “Head Start” Consortium has conducted three sequential, prospective, multi-national clinical trials using irradiation-avoiding chemotherapy for young children with medulloblastoma; these have documented improved cure rates as well as preserved quality of survival and intellectual functioning in such children. GAP: Over the last decade, molecular analyses of these tumors have led to identification of at least four medulloblastoma sub-groups. While these sub-groups are predictive of favorable or unfavorable outcomes for older children receiving irradiation-containing treatments, it is not clear if these groupings are predictive of chemotherapy responsiveness, as molecular profiling data have yet to be evaluated prospectively in young children with medulloblastoma treated with uniform irradiation-avoiding strategies. HYPOTHESIS: Predictive biomarkers will enable identification of medulloblastoma patients most likely to benefit from irradiation-avoiding chemotherapy regimens. METHODS: To test the above hypothesis, we will collect and molecularly profile tumor tissue and blood samples on all young children with medulloblastoma prospectively enrolled on the “Head Start” 4 Consortium trial. RESULTS: Pending. IMPACT: The identification of more precise molecular biomarkers of medulloblastoma within the setting of a prospective, uniform, irradiation-avoiding multi-national clinical trial will permit a more personalized treatment assignment to appropriately more or less intensive and toxic chemotherapy regimens. Ultimately, identification of such biomarkers may lead to incorporation of highly specific therapies directed against such molecular tumor targets.