Molecular evolution of IDH wild-type glioblastomas treated with standard of care affects survival and design of precision medicine trials: A report from the EORTC 1542 study

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisReviewForskningpeer review

DOI

  • Kaspar Draaisma, Erasmus University Rotterdam, University of Liege
  • ,
  • Aikaterini Chatzipli, Wellcome Sanger Institute
  • ,
  • Martin Taphoorn, Haaglanden Medisch Centrum
  • ,
  • Melissa Kerkhof, Haaglanden Medisch Centrum
  • ,
  • Astrid Weyerbrock, University of Freiburg
  • ,
  • Marc Sanson, Sorbonne Université
  • ,
  • Ann Hoeben, Maastricht University
  • ,
  • Slávka Lukacova
  • Giuseppe Lombardi, IRCCS Istituto Oncologico Veneto - Padova
  • ,
  • Sieger Leenstra, ETZ Elisabeth - Tweesteden Ziekenhuis
  • ,
  • Monique Hanse, ETZ Elisabeth - Tweesteden Ziekenhuis
  • ,
  • Ruth Fleischeuer, ETZ Elisabeth - Tweesteden Ziekenhuis
  • ,
  • Colin Watts, University of Birmingham
  • ,
  • Joseph McAbee, National Institutes of Health
  • ,
  • Nicos Angelopoulos, Wellcome Sanger Institute
  • ,
  • Thierry Gorlia, European Organisation for Research and Treatment of Cancer Data Center
  • ,
  • Vassilis Golfinopoulos, European Organisation for Research and Treatment of Cancer Data Center
  • ,
  • Johan M. Kros, Erasmus University Rotterdam
  • ,
  • Roel G.W. Verhaak, Jackson Laboratory
  • ,
  • Vincent Bours, University of Liege
  • ,
  • Martin J. van den Bent, Erasmus University Rotterdam
  • ,
  • Ultan McDermott, Wellcome Sanger Institute
  • ,
  • Pierre A. Robe, University of Liege, Utrecht University
  • ,
  • Pim J. French, Erasmus University Rotterdam

PURPOSE 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. MATERIALS AND METHODS We collected 186 pairs of primary-recurrent GBM samples from patients receiving chemoradiotherapy with temozolomide and sequenced approximately 300 cancer genes. MGMT, TERT, and EGFRvIII status was individually determined. RESULTS The molecular profile of our cohort was identical to that of other GBM cohorts (IDH wild-type [WT], 95%; EGFR amplified, approximately 50%), indicating that patients amenable to second surgery do not represent a specific molecular subtype. Molecular events in IDH 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 TERT and EGFR mutations, respectively), and such changes strongly affected targeted trial size and design. A similar pattern of GBM driver instability was observed within MGMT promoter–methylated tumors. MGMT 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 immunotherapybased treatments. CONCLUSION This large cohort of matched primary and recurrent IDH 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.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Oncology
Vol/bind38
Nummer1
Sider (fra-til)81-99
Antal sider19
ISSN0732-183X
DOI
StatusUdgivet - 2020

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