Abstract
Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
Highlights
Genomically-driven therapy is increasingly being incorporated into the treatment of pediatric low- grade gliomas (LGGs), the most common type of brain tumor in children [1, 31, 44]
Two tumor specimens were available for 41 patients, and three tumor specimens were available for four patients who underwent more than two surgeries
Clinicians should feel confident that pediatric LGGs with BRAF fusions detected at diagnosis will retain this genetic alteration, such that targeted therapy with MEK inhibitors can be implemented at relapse without requiring genetic confirmation with repeat biopsy, in agreement with most providers’ current practice as well as previous clinical trials of these agents in the recurrent, refractory setting not mandating repeat molecular testing [5, 8, 50]
Summary
Genomically-driven therapy is increasingly being incorporated into the treatment of pediatric low- grade gliomas (LGGs), the most common type of brain tumor in children [1, 31, 44]. Recent discoveries have provided valuable insight into the genomic landscape of pediatric LGGs at diagnosis, facilitating a shift in treatment strategy toward a molecularly targeted approach [31, 44]. Expanded knowledge of the genetic landscape of LGGs has supported the growing investigation and utilization of molecularly targeted agents, such as MEK or BRAF inhibitors, for tumors with MAPK pathway alterations, especially at relapse or progression [5, 8, 23, 50]
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