TY - JOUR
T1 - Prognostic Significance of DNA Methylation Profiles at MRI Enhancing Tumor Recurrence
T2 - a Report from the EORTC 26091 TAVAREC Trial
AU - Draaisma, Kaspar
AU - S. Tesileanu, C. Mircea
AU - de Heer, Iris
AU - Klein, Martin
AU - Smits, Marion
AU - Reijneveld, Jaap C.
AU - Clement, Paul M.
AU - de Vos, Filip Y.F.
AU - Wick, Antje
AU - Mulholland, Paul J.
AU - Taphoorn, Martin J.B.
AU - Weller, Michael
AU - Chinot, Olivier L.
AU - Kros, Johan M.
AU - Verschuere, Tina
AU - Coens, Corneel
AU - Golfinopoulos, Vassilis
AU - Gorlia, Thierry
AU - Idbaih, Ahmed
AU - Robe, Pierre A.
AU - van den Bent, Martin J.
AU - French, Pim J.
N1 - Funding Information: M. Smits reports personal fees from GE Healthcare outside the submitted work. P.M. Clement reports nonfinancial support from Merck Sharp & Dohme during the conduct of the study; personal fees and nonfinancial support from AbbVie, Bayer, Bristol-Myers Squibb, Merck, LEO Pharma, Vifor Pharma, Merck Sharp & Dohme; grants and nonfinancial support from AstraZeneca; personal fees from Daiichii Sankyo, Rakuten; and nonfinancial support from Teva, Novartis, Amgen, and Roche outside the submitted work. F.Y.F. de Vos reports other support from EORTC during the conduct of the study and grants from AbbVie, Bristol-Myers Squibb, Novartis, Vaximm, BioClin Therapeutics, and Foundation STOPbraintumors outside the submitted work. M. Weller reports grants and personal fees from Apogenix, Merck Sharp & Dohme, Merck (EMD), Philogen, Bayer, and Novocure; and grants from Quercis Pharma; personal fees from Adastra, Medac, Nerviano, and Orbus Therapeutics outside the submitted work. O.L. Chinot reports grants and personal fees from Roche during the conduct of the study; personal fees from Servier; and nonfinancial support from Bristol-Myers Squibb and Novartis outside the submitted work; in addition, O.L. Chinot has a patent for 12305565.9 issued. T. Verschuere reports grants from Roche during the conduct of the study. C. Coens reports grants from F. Hoffmann-La Roche during the conduct of the study. A. Idbaih reports personal fees and other support from LEO Pharma, Novocure; personal fees from Boehringer Ingelheim Oncology; other support from Carthera; and grants from Sanofi, Nutritheragene, Servier, Transgene, and Air Liquide outside the submitted work. P.A. Robe reports grants from FNRS of Belgium during the conduct of the study. M.J. van den Bent reports personal fees and other support from Roche during the conduct of the study. P.J. French reports personal fees from AURIKAMED outside the submitted work. No disclosures were reported by the other authors. Funding Information: The TAVAREC trial is registered at EudraCT (2009–017422–39) and ClinicalTrials. gov (NCT01164189). We are grateful to F. Hoffmann-La Roche Ltd for supporting this independent EORTC study. The trial was supported by an unrestricted educational grant and free bevacizumab supply by F. Hoffmann-La Roche Ltd. Publisher Copyright: © 2022 American Association for Cancer Research
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Purpose: Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second-line treatments. The TAVAREC trial was a randomized, open-label phase II trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of World Health Organization grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome-wide DNA methylation profiles and copy-number variations on the TAVAREC trial samples. Experimental Design: Isocitrate dehydrogenase (IDH) mutation status was determined via Sanger sequencing and IHC. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27), and homozygous deletion of CDKN2A/B were determined. DNA methylation classes were determined according to classifiers developed in Heidelberg and The Cancer Genome Atlas (TCGA; “Heidelberg” and “TCGA” classifier respectively). Results: DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10 of 87 IDH-mutated samples and were prognostically unfavorable at recurrence. Conclusions: DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors.
AB - Purpose: Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second-line treatments. The TAVAREC trial was a randomized, open-label phase II trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of World Health Organization grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome-wide DNA methylation profiles and copy-number variations on the TAVAREC trial samples. Experimental Design: Isocitrate dehydrogenase (IDH) mutation status was determined via Sanger sequencing and IHC. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27), and homozygous deletion of CDKN2A/B were determined. DNA methylation classes were determined according to classifiers developed in Heidelberg and The Cancer Genome Atlas (TCGA; “Heidelberg” and “TCGA” classifier respectively). Results: DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10 of 87 IDH-mutated samples and were prognostically unfavorable at recurrence. Conclusions: DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors.
UR - http://www.scopus.com/inward/record.url?scp=85131225558&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1078-0432.CCR-21-3725
DO - https://doi.org/10.1158/1078-0432.CCR-21-3725
M3 - Article
C2 - 35294545
SN - 1078-0432
VL - 28
SP - 2440
EP - 2448
JO - Clinical cancer research : an official journal of the American Association for Cancer Research
JF - Clinical cancer research : an official journal of the American Association for Cancer Research
IS - 11
ER -