Inferior outcome and poor response to conventional therapies in pediatric low-grade gliomas harboring the BRAF V600E mutation
Refereed conference paper presented and published in conference proceedings

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AbstractBACKGROUND: Pediatric low-grade gliomas (PLGG) are histologically and clinically diverse and molecular stratification is desperately needed. The BRAF-V600E mutation is highly targetable for therapy but its biological relevance and impact on PLGG outcome is controversial. METHODS: We determined RAS pathway and other secondary mutations in all patients diagnosed with PLGG since 1985 (n = 854 patients biopsied), 506 had sufficient tissue. Tumors were tested for these alterations using the QX200™Droplet Digital™PCR, Nanostring and SNP array technologies. Long-term clinical data and imaging response were collected on all patients. These data were validated on a large international cohort of V600E mutant PLGG. RESULTS: BRAF-V600E mutation was observed in 19 % of PLGG. Mutations were observed across a broad spectrum of histologies including less frequently reported such as pilocytic, pilomyxoid, and diffuse astrocytomas. Importantly, BRAF-V600E positive PLGG were common in midline locations, which are often not biopsied. BRAF-V600E PLGG had inferior long-term outcome when compared with wild-type (WT) cases. Fifteen-year PFS was 7 ± 6% and 64 ± 12% for BRAF-V600E and WT-PLGG respectively (p < 0.05). This translated to OS of 57 ± 16% and 94 ± 6%, respectively (p < 0.05). Secondary molecular alterations stratified BRAF-V600E tumors into low and high-risk tumors (p < 0.05). Specific quantitative imaging analysis revealed response to non-targeted chemotherapy in only 10% BRAF-V600E PLGG, while BRAF-V600E inhibition resulted in a greater response. CONCLUSIONS: In the largest assembled cohort of molecularly characterized pediatric LGG to date, BRAF-V600E mutations identify a unique group of PLGG with distinct biology and survival. Early detection and targeted therapies may transform the management and outcome of these children.
All Author(s) ListLassaletta A, Mistry M, Arnaldo A, Ryall S, Guerreiro-stucklin A, Krishnatry R, Ling C, Honnorat M, Zhukova N, Zapotocky M, Mckeown T, Ramaswany V, Bartels U, Hang A, Jabado N, Cruz O, de Torres C, Ho C, Packer T, Tatevossian R, Ellison D, Harreld J, Dalton J, Mulcahy-Levy J, Foreman N, Karajannis M, Mueller S, Theodore N, Eisenstat D, Carret AS, Kieran M, Ligon K, Jouvet A, Perbert R, Vasiljevic A, Frappaz D, Odile MJ, Chambeless L, Thompson R, Nageswara AR, Chan AK, Ng HK, Garre ML, Nozza P, Massimino M,Leary S, Crane C, Bouffet E
Name of Conference17th International Symposium on Pediatric Neuro-Oncology
Start Date of Conference12/06/2016
End Date of Conference15/06/2016
Place of ConferenceLiverpool
Country/Region of ConferenceGreat Britain
Proceedings TitleNeuro Oncology
Volume Number18
Issue NumberSuppl. 3
PublisherOxford University Press
Pagesiii89 - iii89
LanguagesEnglish-United Kingdom

Last updated on 2021-25-09 at 00:06