Integrated response analysis of pediatric low-grade gliomas during and after targeted therapy treatment

Abstract

Background Pediatric low grade gliomas (pLGGs) are the most common central nervous system tumor in children, characterized by RAS/MAPK pathway driver alterations. Genomic advances have facilitated use of molecular targeted therapies, however their long-term impact on tumor behavior remains critically unanswered. Methods We performed an IRB-approved, retrospective chart and imaging review of pLGGs treated with off-label targeted therapy at Dana-Farber/Boston Children’s from 2010 to 2020. Response analysis was performed for BRAFV600E and BRAF fusion/duplication driven pLGG subsets. Results Fifty-five patients were identified (dabrafenib n = 15, everolimus n = 26, trametinib n = 11, vemurafenib n = 3). Median duration of targeted therapy was 9.48 months (0.12 – 58.44). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation were 62.1%, 38.2%, and 31.8%, respectively. Mean volumetric change for BRAFV600E mutated pLGG on BRAF inhibitors was -54.11%; median time to best volumetric response was 8.28 months with 9 of 12 (75%) objective RAPNO response . Median time to largest volume post-treatment was 2.86 months (+13.49%); mean volume by last follow-up was -14.02%. Mean volumetric change for BRAF fusion/duplication pLGG on trametinib was +7.34%; median time to best volumetric response was 6.71 months with 3 of 7 (43%) objective RAPNO response . Median time to largest volume post-treatment was 2.38 months (+71.86%); mean volume by last follow up was +39.41%. Conclusions Our integrated analysis suggests variability in response by pLGG molecular subgroup and targeted therapy, as well as the transience of some tumor growth following targeted therapy cessation.

Unlocking the power of precision medicine for pediatric low-grade gliomas: molecular characterization for targeted therapies with enhanced safety and efficacy

“…It has been proven efficacious in the management of metastatic melanoma, a malignancy frequently mutated for BRAF. This drug's function has more recently been shown to be successful in BRAF p.V600E mutated pediatric malignant astrocytomas, while less data is currently available on its use in LGG patients, of which there are more studies on the combination of dabrafenib and trametinib (Table 3) (88,106,(198)(199)(200)205). The efficacy of the vemurafenib treatment in our small cohort of patients affected by pLGG is promising, with a rate of response of about 60% (88).…”

Basics for Pediatric Brain Tumor Imaging: Techniques and Protocol Recommendations

“…The current standard clinical practice for assessing tumor response involves using 2D or 3D measurements on the single cross section that best shows tumor extent. However, these measurements are prone to interrater variability, especially for tumors that are diffuse or irregular in shape [ 20 ]. In a recent study comparing volumetric and 2D tumor assessments, inconsistent responses were noted in 20% of 70 pediatric low-grade gliomas [ 21 ].…”

Optic Pathway Gliomas in Pediatric Population—Current Approach in Diagnosis and Management: Literature Review

“…NF1 is a tumor suppressor gene that controls cell proliferation, survival and differentiation, and it is inactivated in Recklinghausen disease. The mechanism works through the mitogen-activated kinase (MEK) and mTOR pathways [41,58]. The product of the NF1 gene (neurofibromin 1) normally binds to RAS, thereby inactivating it and controlling cell division.…”

“…Mutation in the MAPK pathway makes it possible for MAPK inhibitor therapy to be used in the course of pilocytic astrocytoma. This allows for targeted therapy, which is very promising, but further research and analysis of the impact of this treatment on glioma is still ongoing [31,35,58]. Tovorafenib, a highly selective type II pan-RAF kinase inhibitor, was approved in the US this year [106,107].…”