The mutational status of driver glioma genes remained mostly stable from samples taken at primary compared with recurrent disease, according to a recent study.

However, researchers did find that at the individual gene and pathway level, as many as one-third of samples showed a mutational change at tumor recurrence.

According to the researchers, “this change is significant because it directly affects clinical trial design for patients with recurrent glioblastomas.”

The study looked at paired primary-recurrent glioblastoma samples taken from 186 patients receiving chemoradiotherapy with temozolomide. The researchers sequenced these samples for 300 cancer genes, with MGMT, TERT, and EGFRvIII individually determined.


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Samples of this type were available because patients had disease amenable to second surgery at cancer recurrence. Molecular testing indicated that the molecular profile of the patients was identical to that of other glioblastoma groups, “indicating that patients amenable to second surgery do not represent a specific molecular subtype.”

As an example, the researchers found a stable EGFR amplification status in 87.5% of samples; however, at the individual gene level they found that 37% of samples had loss of EGFRvIII mutations at disease recurrence.

“A subgroup analysis of MGMT promotor–methylated and –unmethylated tumors showed that MSH6 and TERT promotor mutations were more likely to be gained in MGMT-methylated tumors,” the researchers wrote. “For most other molecular events, evolutional patterns were similar between MGMT-methylated and -unmethylated tumors.”

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In addition, MGMT promoter methylation was prognostic at tumor recurrence.

“The observed molecular changes at glioblastoma recurrence demonstrate the importance of monitoring genomic evolution when considering targeted therapy at tumor recurrence; a repeated biopsy should be considered before inclusion in targeted therapy trials,” the researchers concluded.

Reference

Draaisma K, Chatzipli A, Taphoom M, et al. 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 [published online November 19, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.00367