Integrated response analysis of pediatric low-grade gliomas during and after targeted therapy treatment
Jessica W Tsai1, Jungwhan John Choi2, Hakim Ouaalam2
1Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
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 the 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, and 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 responses. Median time to largest volume post-treatment was 2.86 months (+13.49%); mean volume by the 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 responses. Median time to largest volume post-treatment was 2.38 months (+71.86%); mean volume by the 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.
Insights
Targeted therapies show varied effectiveness for pediatric low-grade gliomas (pLGGs), with some tumor growth resuming after treatment cessation. BRAFV600E mutations responded better than BRAF fusions/duplications.
Area of Science:
- Pediatric neuro-oncology
- Molecular oncology
- Cancer therapeutics
Background:
- Pediatric low-grade gliomas (pLGGs) are the most common pediatric CNS tumors.
- RAS/MAPK pathway alterations drive pLGG development.
- Genomic advances enable targeted therapies, but long-term outcomes are unclear.
Purpose of the Study:
- To evaluate the efficacy and long-term impact of targeted therapies in pediatric low-grade gliomas.
- To analyze treatment response based on specific molecular subgroups (BRAFV600E vs. BRAF fusion/duplication).
Main Methods:
- Retrospective review of 55 pediatric low-grade glioma patients treated with targeted therapy (dabrafenib, everolimus, trametinib, vemurafenib) from 2010-2020.
- Analysis of volumetric changes and event-free survival (EFS).
- Subgroup analysis for BRAFV600E and BRAF fusion/duplication driven pLGGs.
Main Results:
- Overall 1, 3, and 5-year EFS were 62.1%, 38.2%, and 31.8%.
- BRAFV600E pLGGs on BRAF inhibitors showed significant mean volumetric decrease (-54.11%) with 75% objective response.
- BRAF fusion/duplication pLGGs on trametinib showed initial increase (+7.34%) with 43% objective response and later significant volume increase (+39.41% by last follow-up).
Conclusions:
- Targeted therapy response in pLGGs varies by molecular subgroup and drug.
- Tumor growth can resume after targeted therapy cessation, indicating potential transience of response.
- Further research is needed to optimize long-term management strategies for pediatric low-grade gliomas.
