Genetischer Einfluss, individuelles genetisches Profil und zielgerichtete Behandlung bei Patienten mit NF2-assoziierten Vestibularisschwannomen

To investigate the relationship between genetic alterations (NF2 mutation type, VEGF expression, etc.) and clinical parameters (growth rate, hearing status, tumor load) in primary operated vestibular schwannomas (VS) in patients with neurofibromatosis Type 2 (NF2) related schwannomatosis. The response of the therapy (surgery, bevacizumab) as well as possible novel genes and pathways that can be individually targeted will also be investigated.

16 operated tumors in 8 NF2 patients with detailed long-term follow-up data (3D-volumes, pure-tone, and speech audiometry, auditory evoked potentials) and clinical parameters (e. g. tumor load) as well as their NF2 mutation type were included. 3D volumetric data sets were used, and the growth rate was calculated by a linear regression model. After DNA isolation of paraffin-embedded samples, whole-exome sequencing (WES) was performed for all tumors. Signaling pathway analysis was completed to assess response to treatment and to identify potential targeted genes and/or pathways.

The mean age at the time of diagnosis was 11± 5 (range 1-16) years and at the time of first surgery was 17± 4 (range 11-23) years. All tumors received (externally) off-label bevacizumab treatment before or after surgery with an initial dose of 5 mg/kg body weight every 2 weeks and adaptive dose reduction if radiological and clinical response was positive. Three tumors were operated on multiple times at different treatment intervals (with and without bevacizumab). A total of approximately 400 datasets of 3D volumetry and hearing parameters were collected and included. Patients with concomitant spinal ependymomas showed faster VS growth rates compared to patients with associated peripheral nerve schwannomas with lower VS growth rates. Six patients had truncating mutations (frameshift or nonsense) and two patients exhibited deletions of the NF2 gene.

The response of neoadjuvant or adjuvant bevacizumab treatment for the treatment of NF2-associated VS is heterogeneous, worse in surgically reduced (small) tumors, and in young patients. Spinal tumor load appears to have a stronger negative influence on VS growth rate than the protective positive influence of peripheral tumor load. WES analysis in primary operated tumors seems to be an opportunity for individualized targeted treatment, which can be validated and simulated in vitro models.