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Ref Type Journal Article
PMID (38787533)
Authors Bobin C, Iddir Y, Butterworth C, Masliah-Planchon J, Saint-Charles A, Bellini A, Bhalshankar J, Pierron G, Combaret V, Attignon V, André N, Corradini N, Dumont B, Mansuy L, Khanfar C, Klein S, Briandet C, Plantaz D, Millot F, Thouvenin S, Aerts I, Ndounga-Diakou LA, Laghouati S, Abbou S, Jehanno N, Tissot H, Renault S, Baulande S, Raynal V, Bozec L, Bieche I, Delattre O, Berlanga P, Schleiermacher G
Title Sequential analysis of cfDNA reveals clonal evolution in neuroblastoma patients receiving ALK targeted therapy.
URL
Abstract Text The study of cell free DNA (cfDNA) enables sequential analysis of tumor cell-specific genetic alterations in neuroblastoma patients.Eighteen patients with relapsing neuroblastoma having received Lorlatinib, a 3rd generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for 9 patients, and sequentially for 5 patients (blood/bone marrow plasma) by performing WGS library construction followed by ALK-targeted ddPCR of the hotspot mutations (F1174L, R1275Q, I1170N) (variant allele fraction (VAF) detection limit 0.1%) and WES to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES.Overall response rate to Lorlatinib was 33% (CI 13-59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF<0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after Lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples.We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in neuroblastoma patients receiving ALK targeted therapy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK I1171N ALK Y1278S neuroblastoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a retrospective analysis, a neuroblastoma patient harboring ALK Y1278S progressed on treatment with Lorbrena (lorlatinib) and was found to have acquired ALK I1171N (PMID: 38787533; NCT04477681). 38787533
ALK F1174L neuroblastoma predicted - sensitive Lorlatinib Case Reports/Case Series Actionable In a retrospective analysis, Lorbrena (lorlatinib) treatment resulted in partial remission in a neuroblastoma patient harboring ALK F1174L (PMID: 38787533; NCT04477681). 38787533
ALK I1170N neuroblastoma predicted - sensitive Lorlatinib Case Reports/Case Series Actionable In a retrospective analysis, Lorbrena (lorlatinib) treatment resulted in complete remission in a neuroblastoma patient harboring ALK I1170N (PMID: 38787533; NCT04477681). 38787533
ALK Y1278S neuroblastoma predicted - sensitive Lorlatinib Case Reports/Case Series Actionable In a retrospective analysis, Lorbrena (lorlatinib) treatment resulted in a partial response in a neuroblastoma patient harboring ALK Y1278S (PMID: 38787533; NCT04477681). 38787533