418 Population pharmacokinetics of intravenous bolus 5-fluorouracil in a phase I trial for children and young adults with recurrent ependymoma

Abstract

(GA) in AYA CA have not been well characterized. To identify potential therapeutic targets, we profiled 669 AYA solid tumors, and describe 2 cases highlighting the efficacy of matching GA to targeted therapy. Methods: Tumor DNA extracted from FFPE tissue underwent library construction and hybrid capture for all exons of 236 CA-related genes and 47 introns of 19 genes frequently rearranged in CA and was sequenced to an average depth of >700× (Foundation Medicine, Cambridge, MA). Sequence data were assessed for base substitutions, insertions/deletions, copy number alterations, and rearrangements. We sought to characterize GAs in AYA and compare those with historical estimates for non-AYA CA patients. Results: 26 AYA tumor types were profiled; the most common sites of origin were breast (BC), (16%), brain (13%), sarcoma (9%), colon (9%), gynecologic (7%) and lung (LC) (7%). An average of 3.4 GAs/sample was found (range 0−22). Potentially actionable GAs were identified in 71% of cases. ALK fusions were found at 8× the frequency in AYA LC vs. LC patients >39; FISH concordance and outcomes data were obtained in half of the ALK positive AYA LC patients. AYA brain CA patients with a diagnosis of GBM had a >15 fold increase in ATRX and IDH1 mutations compared to GBM patients >39; As GBMs in young adults typically arise from astrocytomas (vs. de novo in older adults) and increased ATRX/IDH1 mutations are a known feature of astrocytomas, our findings are consistent with previous literature. AYA BC had high concordance in general with BC patients >39, with relative decreases in GA frequency in PIK3CA, MYST3, and CDH1 in the AYA population. Although not the primary focus of this study, 2 patient vignettes were notable. In one case, a 19 y/o F with LC was admitted to hospice having failed SOC chemotherapy. Prior testing was negative for EGFR, ALK and ROS1. Genomic profiling revealed a novel ALK rearrangement and she began crizotinib therapy. Within 5 days she was discharged to home and scans at 1 and 2 months showed PR by RECIST. A 39 y/o F with a rectal neuroendocrine tumor and BRAF V600E mutations experienced an 8 month response to vemurafenib with relief of tumor-related symptoms that is ongoing. Conclusion: Comprehensive genomic profiling can detect all classes of GAs across AYA tumor types. These data show significant differences with literature based reports of GA in adult CA and demonstrate the feasibility and relevance of identifying GAs that can potentially guide targeted treatment decisions in a high proportion of patients.