Molecular Evolution of <i>IDH</i> Wild-Type Glioblastomas Treated With Standard of Care Affects Survival and Design of Precision Medicine Trials: A Report From the EORTC 1542 Study.

Abstract

Precision medicine trials in glioblastoma (GBM) are often conducted at tumor recurrence. However, second surgeries for recurrent GBM are not routinely performed, and therefore, molecular data for trial inclusion are predominantly derived from the primary sample. This study aims to establish whether molecular targets change during tumor progression and, if so, whether this affects precision medicine trial design. We collected 186 pairs of primary-recurrent GBM samples from patients receiving chemoradiotherapy with temozolomide and sequenced approximately 300 cancer genes. <i>MGMT</i>, <i>TERT</i>, and <i>EGFRvIII</i> status was individually determined. The molecular profile of our cohort was identical to that of other GBM cohorts (<i>IDH</i> wild-type [WT], 95%; <i>EGFR</i> amplified, approximately 50%), indicating that patients amenable to second surgery do not represent a specific molecular subtype. Molecular events in <i>IDH</i> WT GBMs were stable in approximately 80% of events, but changes in mutation status were observed for all examined genes (range, approximately 90% and 60% for <i>TERT</i> and <i>EGFR</i> mutations, respectively), and such changes strongly affected targeted trial size and design. A similar pattern of GBM driver instability was observed within <i>MGMT</i> promoter-methylated tumors. <i>MGMT</i> promoter methylation status remained prognostic at tumor recurrence. The observation that hypermutation at GBM recurrence was rare (8%) and not correlated with outcome was relevant for immunotherapy-based treatments. This large cohort of matched primary and recurrent <i>IDH</i> WT tumors establishes the frequency of GBM driver instability after chemoradiotherapy with temozolomide. This allows per gene or pathway calculation of trial size at tumor recurrence, using molecular data of the primary tumor only. We also identify genes for which repeat surgery is necessary because of low mutation retention rate.