Molecular Genetics in Brain Tumors – Case Report of a 7-year-old Girl with Recurrent Glioblastoma

Background: The median overall survival for children with glioblastoma is in spite of better diagnostics and therapies still 1.2 +/-0.08 years [1]. Molecular diagnostic studies like INFORM, MNP 2.0, PTT 2.0 (KiTZ Heidelberg) improve diagnostics and in some cases lead to an individualised therapy. One example is Larotrectinib, a selective tropomyosin receptor kinase inhibitors (TRKI). TRKs are involved in growth, differentiation and angiogenesis. NTRK-gene fusions lead to inappropriate cell proliferation. Larotrectinib was reported to have a response rate of 75% shown in three early-phase clinical trials (LOXO-TRK-14001, NAVIGATE und SCOUT) with 55 patients with NTRK-positive solid Tumors. [2]

Case Report: We report on a seven-year-old girl with glioblastoma multiforme (GBM). As specified by the HIT-HGG-2007 protocol, the girl received the initiation with radiotherapy (54 gray) combined with temozolomide and valproate. After 6 cycles of the maintenance therapy with temozolomide the girl presented with a new hemiparesis. Cranial MRI revealed a big tumor progression. The girl was operated upon promptly and tumor material was sent to the INFORM study for molecular diagnostic. 4 weeks after surgery a cranial MRI was done to plan the radiotherapy. The MRI showed another relapse with intracranial metastasis. Because of the poor prognosis and in consideration for the girl`s quality of life treatment was ceased in agreement with the parents. Only one week later exome sequencing analyses revealed a fusion in NTRK2-gene (SPECC1L:NTRK2 fusion) in the girl`s brain tumor. The girl was included in the phase I/II trial with Larotrectinib (LOXO-TRK-15003) in the study center Charité Berlin. 11 months after tumor manifestation and 7 weeks after the second surgery the therapy with Larotrectinib 100 mg/m² started. Since then, 6 month after starting Larotrectinib, the girl exhibits a stable neurological clinical status with good life quality and the MRI present a partial response.

Conclusion: Larotrectinib is a potent target therapy for patients with a tumor relapse and a NTKR-mutation in the tumor material. Larotrectinib may enable a temporary stable disease and a partial response in the MRI - irrespective of the tumors localization and histology. Although molecular diagnostics rarely lead to therapeutic consequences so far, the exceptional activity of Larotrectinib makes NTRK alterations an important predictive biomarker to screen for in any cancer. Molecular diagnostics emend the knowledge of the tumor`s biology, the identification of tumor sub groups and may estimate the individual prognosis and enable the development of new therapy targets and strategies.

References

1. Überlebensdaten für referenzhistologisch bestätigte pädGBM, Patientenkollektiv HIT-HGG 2007 (n = 429)

2. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378(8):731–739