Impact of Molecular Subgroups on Outcomes Following Radiation Treatment Randomizations for Average Risk Medulloblastoma: A Planned Analysis of Children’s Oncology Group (COG) ACNS0331

Abstract

The COG conducted a randomized trial for average-risk medulloblastoma (AR-MB). Patients age 3-21 years were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT) after receiving CSI. Patients age 3-7 years were also randomized to standard dose CSI (23.4Gy, SDCSI) or low dose CSI (18Gy, LDCSI). A total of 464 evaluable patients were available to compare PFRT vs. IFRT and 226 for SDCSI vs. LDCSI. 380 cases had sufficient tissue for DNA methylation-based molecular classification: 362 confirmed medulloblastoma; 6 non-medulloblastoma; and 12 inconclusive. Molecular subgrouping confirmed the following representation amongst the evaluable cohort: 156 Group 4 (43.1%), 76 Group 3 (21.0%), 66 SHH (18.2%), 64 WNT (17.7%). Five-year event-free survival (EFS) estimates were 82.5±2.7% and 80.5±2.7% for IFRT and PFRT, respectively (p = 0.44). Five-year overall survival (OS) estimates were 84.6±2.5% and 85.2±2.4% for the IFRT and PFRT regimen, respectively (p = 0.44). Five-year EFS estimates were 71.4±4.4% and 82.9±3.7% for LDCSI and SDCSI, respectively (p = 0.028). Five-year estimates of OS were 77.5±4.0% and 85.6±3.5% for the LDCSI and SDCSI regimens, respectively (p = 0.049). EFS distributions differed significantly by molecular subgroup (p<0.0001). Group 3 had the worst outcome, while WNT had the best outcome. There was a significant difference in EFS by RT group among SHH patients; SHH patients receiving IFRT arm had better EFS compared to PFRT (p = 0.018). There was a significant difference in EFS distributions by CSI group in Group 4 patients; young Group 4 patients treated with SDCSI had better EFS compared to LDCSI (p = 0.047). There were differences in EFS by the presence of specific mutations and/or copy number variations (CNVs). Among SHH patients, chromosome 14q loss (p<0.001) and chromosome 10q loss (p = 0.012) were associated with worse EFS. SHH patients with GLI2 amplification had inferior outcome, though not statistically significant (p = 0.056); there were only 3 SHH patients with amplified GLI2 however. Group 3 patients with MYC amplification and/or isochromosome 17 had inferior EFS. For group 4 patients none of the mutations or CNVs showed statistically significant differences in EFS at the nominal 0.05 level. These included presence of isochromosome 17 (p = 0.48), chromosome 11 loss (p = 0.056), chromosome 17 gain (p = 0.84), and chromosome 11 loss and/or chromosome 17 gain (p = 0.32). As previously reported, IFRT is noninferior to PFRT in all patients with AR-MB but LDCSI is worse than SDCSI in younger children. Significant differences in outcome by study randomization and molecular subgroup are observed.