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 immunotherapy-based 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.
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 immunotherapy-based 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.
Authors: Patrick Y Wen; Michael Weller; Eudocia Quant Lee; Brian M Alexander; Jill S Barnholtz-Sloan; Floris P Barthel; Tracy T Batchelor; Ranjit S Bindra; Susan M Chang; E Antonio Chiocca; Timothy F Cloughesy; John F DeGroot; Evanthia Galanis; Mark R Gilbert; Monika E Hegi; Craig Horbinski; Raymond Y Huang; Andrew B Lassman; Emilie Le Rhun; Michael Lim; Minesh P Mehta; Ingo K Mellinghoff; Giuseppe Minniti; David Nathanson; Michael Platten; Matthias Preusser; Patrick Roth; Marc Sanson; David Schiff; Susan C Short; Martin J B Taphoorn; Joerg-Christian Tonn; Jonathan Tsang; Roel G W Verhaak; Andreas von Deimling; Wolfgang Wick; Gelareh Zadeh; David A Reardon; Kenneth D Aldape; Martin J van den Bent Journal: Neuro Oncol Date: 2020-08-17 Impact factor: 12.300
Authors: Dorothee Gramatzki; Jörg Felsberg; Patrick Roth; Kerstin Kaulich; Andreas von Deimling; Elisabeth Jane Rushing; Guido Reifenberger; Michael Weller Journal: Neuro Oncol Date: 2021-02-25 Impact factor: 12.300
Authors: Daniel J Brat; Kenneth Aldape; Julia A Bridge; Peter Canoll; Howard Colman; Meera R Hameed; Brent T Harris; Eyas M Hattab; Jason T Huse; Robert B Jenkins; Dolores H Lopez-Terrada; William C McDonald; Fausto J Rodriguez; Lesley H Souter; Carol Colasacco; Nicole E Thomas; Michelle Hawks Yount; Martin J van den Bent; Arie Perry Journal: Arch Pathol Lab Med Date: 2022-05-01 Impact factor: 5.686
Authors: Andrew S Chi; Daniel P Cahill; David A Reardon; Patrick Y Wen; Tom Mikkelsen; David M Peereboom; Eric T Wong; Elizabeth R Gerstner; Jorg Dietrich; Scott R Plotkin; Andrew D Norden; Eudocia Q Lee; Lakshmi Nayak; Shota Tanaka; Hiroaki Wakimoto; Nina Lelic; Mara V Koerner; Lindsay K Klofas; Mia S Bertalan; Isabel C Arrillaga-Romany; Rebecca A Betensky; William T Curry; Darrel R Borger; Leonora Balaj; Robert R Kitchen; Sudipto K Chakrabortty; Michael D Valentino; Johan Skog; Xandra O Breakefield; A John Iafrate; Tracy T Batchelor Journal: JCO Precis Oncol Date: 2020-06-08
Authors: Eudocia Q Lee; Michael Weller; Joohee Sul; Stephen J Bagley; Solmaz Sahebjam; Martin van den Bent; Manmeet Ahluwalia; Jian L Campian; Evanthia Galanis; Mark R Gilbert; Matthias Holdhoff; Glenn J Lesser; Frank S Lieberman; Minesh P Mehta; Marta Penas-Prado; Karisa C Schreck; Roy E Strowd; Michael A Vogelbaum; Tobias Walbert; Susan M Chang; L Burt Nabors; Stuart Grossman; David A Reardon; Patrick Y Wen Journal: Neuro Oncol Date: 2020-05-15 Impact factor: 12.300
Authors: Radia M Johnson; Heidi S Phillips; Carlos Bais; Cameron W Brennan; Timothy F Cloughesy; Anneleen Daemen; Ulrich Herrlinger; Robert B Jenkins; Albert Lai; Christoph Mancao; Michael Weller; Wolfgang Wick; Richard Bourgon; Josep Garcia Journal: Neuro Oncol Date: 2020-12-18 Impact factor: 12.300
Authors: C Mircea S Tesileanu; Marc Sanson; Wolfgang Wick; Alba A Brandes; Paul M Clement; Sara C Erridge; Michael A Vogelbaum; Anna K Nowak; Jean-Francois Baurain; Warren P Mason; Helen Wheeler; Olivier L Chinot; Sanjeev Gill; Matthew Griffin; Leland Rogers; Walter Taal; Roberta Rudà; Michael Weller; Catherine McBain; Myra E van Linde; Kenneth Aldape; Robert B Jenkins; Johan M Kros; Pieter Wesseling; Andreas von Deimling; Youri Hoogstrate; Iris de Heer; Peggy N Atmodimedjo; Hendrikus J Dubbink; Rutger W W Brouwer; Wilfred F J van IJcken; Kin Jip Cheung; Vassilis Golfinopoulos; Brigitta G Baumert; Thierry Gorlia; Pim J French; Martin J van den Bent Journal: Clin Cancer Res Date: 2022-06-13 Impact factor: 13.801