Abstract 444: Dynamics of tumor mutations in paired samples from glioblastoma patients during treatment
Authors: Noeroexe Dorte Schou , Oestrup Olga , Yde Christina Westmose , Nielsen Finn Cilius , Skjøth-Rasmussen Jane , Hamerlik Petra , Poulsen Hans Skovgaard , Lassen Ulrik 
Published: July 2021

Introduction: Glioblastoma (GBM) is a heterogenous cancer with a high degree of intratumoral subclonality. We foresee that future treatment will be a combination of non-targeted and targeted therapies against molecular features of each patient. In order to accommodate the personalized treatment strategy, it is therefore pivotal to know the dynamics of tumor alterations during treatment. Today, this is only possible by consecutive intracranial tissue samples for each patient and hence is a difficult discipline.

Materials and methods: We included 30 patients from the Copenhagen Glioblastoma Cohort who had undergone relapse surgery. Each sample had a tumor cell content &gt; 10%. The majority of patients 24/30 (80%) were treated with concurrent Temozolomide (TMZ)/radiation and adjuvant TMZ. Whole exome sequencing was performed in primary and corresponding relapse tumors focusing on GBM-related mutations.

Results: It was possible to identify the same specific mutation in 16/30 (53%) patients before and after treatment, with a total of 22 shared mutations identified. In 7 (23%) relapse samples, mutations were called but none were shared, suggesting temporal tumorogenesis and in the remaining 7 (23%) relapse samples, no mutations were identified. Progression-free survival (PFS) in the three groups was 6.6, 7.8 and 10.1 months, respectively. Corresponding overall survival (OS) was 15.0, 18.0 and 17.8 months, respectively. The results indicate a better PFS, but not OS, in the group with no mutations in the relapse sample. Six patients had three surgeries performed; one diagnostic surgery followed by two relapse surgeries. In one patient, a BRAF mutation (c.1786G&gt;C, p.G596R) was identified at diagnosis, not present at the first relapse but reappeared in the second relapse, most probably as the sign for development of resistance. This was also the case in two other patients with a BRCA- and a PTEN mutation, respectively. In two other patients, the same TP53 (c.814G&gt;A, p.R175H) and EGFR (c.866C&gt;T, p.A289V) mutations, respectively, were identified in all three samples. In the last patient, no mutations were identified in the diagnostic and first relapse sample, but two mutations were identified in the second relapse sample, demonstrating tumor evolution.

Conclusion: We show that mutation dynamics in GBM differ between patients, and frequencies of driver mutations vary during the tumor progression. It was possibly to identify the same mutation during treatment in the same patient. These observations can be used to design future targeted trials and potentially be used for evaluation of treatment response in the individual patient. The presence of mutations in the diagnostic and relapse samples, and specifically shared mutations, indicate potential treatment failure and/or presence of specifically malignant mutations.

Citation Format: Dorte Schou Noeroexe, Olga Oestrup, Christina Westmose Yde, Finn Cilius Nielsen, Jane Skjøth-Rasmussen, Petra Hamerlik, Hans Skovgaard Poulsen, Ulrik Lassen. Dynamics of tumor mutations in paired samples from glioblastoma patients during treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 444.