ID #692 The clinicopathologic characteristics and outcomes of KRAS-altered low-grade glioma

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Abstract Background KRAS alterations are known genetic drivers across different types of cancer. Low-grade gliomas (LGG) are rarely reported to harbor this alteration with limited study of this cohort. Methods An international retrospective cohort of KRAS-altered LGG was identified from pathology databases. Clinical data was collected with molecular analysis including targeted RNA sequencing and pathway analysis using Nanostring nCounter system. Results Thirty-two pediatric, adolescent and adult patients were identified to have KRAS-altered LGG. Median age of diagnosis was 12.7 years (range 0.4-69.8). Most patients (n = 31) had localized disease with tumors predominantly found in cerebral hemispheres (56%) and diencephalon (38%). Tectal tumors were rare (n = 1). Thirty-one patients had single nucleotide variants (18 at KRAS p.Q61 and 8 at KRAS p.G12 locus) with one deletion. Seven patients had co-occurring RAS/MAPK alterations (including FGFR1, NF1 and BRAF alterations) and one patient had co-occurring MYBL1 fusion. Outcome was excellent with 5-year overall survival and progression-free survival (PFS) of 100% and 69%, respectively. One patient with gross total resection (n = 11) had subsequent recurrence. For those with subtotal resection (n = 21), 9 had further post-operative therapy. Outcomes were comparable to that of BRAF-fused LGG (5 year PFS 65% vs 69% for KRAS-altered, p = 0.9), with a comparable number of patients with KRAS-altered LGG requiring therapy beyond surgery (31% vs 30%). There was no difference in PFS based on age, tumor location or KRAS genotype. Upregulation of the PI3K and NFκB pathway were seen compared to normal brain (p < 0.05), and upregulation of the PI3K pathway when compared to BRAF-mutant LGG (p = 0.03), suggesting these tumors may have different therapeutic vulnerability compared to other RAS/MAPK-driven LGG. Conclusions This suggests that conservative management to avoid long-term toxicity is imperative in KRAS-altered LGG and further data on response to targeted therapy is important to collect.

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