Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2024 May 24		Clin Cancer Res

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 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
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