Clinical impact of panel-based next-generation sequencing in a real-world cohort of neuroblastoma patients.

Abstract

10028 Background: Neuroblastoma is a malignant childhood tumor with a low somatic mutation rate, making targeted therapy challenging. Using a targeted NGS panel in a large real-world cohort, we identified recurrent variants and assessed the clinical impact of NGS for this disease. Methods: A real-world cohort of 185 peripheral neuroblastic tumor samples from 181 patients were sequenced with a targeted NGS assay (OncoPanel). Samples were either obtained at baseline (“diagnostic”) or at relapse/progression (“relapse”). Variants include SNVs, CNAs, and SVs and were manually curated for pathogenicity. Recurrently altered genes were those curated as Pathogenic/Likely Pathogenic and occurring in more than 4% of samples. Clinically impactful findings were those with therapeutic implications (e.g., targetable ALK aberration) and those with prognostic implications at diagnosis (e.g. MYCN amplifications or segmental chromosomal aberrations (SCAs) included in the Children’s Oncology Group (COG) risk stratification system). SCAs were defined as regions of loss or gain of at least 3Mb. Mutual exclusivity analyses utilized false-discovery rate corrected Fisher exact tests. Results: All COG risk groups were represented. At time of last follow-up (median 65.9 months), 103 (59%) were alive with no disease, 31 (18%) were alive with disease or unknown disease status, and 41 (23%) were deceased. Of the diagnostic cohort (n=144), 78 (54%) had at least one clinically impactful alteration (n=42 prognostic only, n=13 therapeutic only, n=23 both). Of the relapse cohort (n=41), 14 (34%) had a therapeutically impactful variant. Recurrently altered genes in the diagnostic samples included MYCN , ALK, ATRX and MYCN , ALK, ATRX, BRAF, CREBBP, MLH3, PHOX2B and TERT in the relapse samples . The most commonly observed SCA was 17q gain. Among the 144 diagnostic samples, no patients were observed to have both MYCN amplification and an ATRX variant nor MYCN amplification and 11q loss; this mutual exclusivity was statistically significant for MYCN amplification and 11q loss (adjusted p <0.001). Conclusions: Targeted NGS panels provided clinically impactful results in a majority of cases in a real-world cohort of children with neuroblastoma. Future analyses will include survival analysis by genomic features and comparison of NGS to standard clinical testing. Key genomic findings across clinical cohorts. Diagnosis (n=144) Relapse (n=41) High-risk (HR)(n=53) Non-HR(n=62) ALK variant 29 (20.1%) 8 (19.5%) 14 (26.4%) 9 (14.5%) ATRX variant 7 (4.9%) 3 (7.3%) 5 (9.4%) 1 (1.6%) BRAF variant 1 (0.7%) 3 (7.3%) 0 (0%) 1 (1.6%) PHOX2B variant 5 (3.5%) 2 (4.9%) 4 (7.5%) 1 (1.6%) MYCN amplification 27 (18.8%) 10 (24.4%) 16 (30.2%) 3 (4.8%) 17q gain 87 (60.4%) 27 (65.9%) 33 (62.3%) 39 (62.9%) 1p loss 17 (11.8%) 11 (26.8%) 12 (22.6%) 3 (4.8%) 11q loss 35 (24.3%) 12 (29.3%) 14 (26.4%) 17 (27.4%)