Sequential Analysis of cfDNA Reveals Clonal Evolution in Patients with Neuroblastoma Receiving ALK-Targeted Therapy.
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Bobin Charles, Iddir Yasmine, Butterworth Charlotte, Masliah-Planchon Julien, Saint-Charles Alexandra, Bellini Angela, Bhalshankar Jaydutt, Pierron Gaelle, Combaret Valérie, Attignon Valéry, André Nicolas, Corradini Nadège, Dumont Benoit, Mansuy Ludovic, Khanfar Camille, Klein Sebastien, Briandet Claire, Plantaz Dominique, Millot Frederic, Thouvenin Sandrine, Aerts Isabelle, Ndounga-Diakou Lee Aymar, Laghouati Salim, Abbou Samuel, Jehanno Nina, Tissot Hubert, Renault Shufang, Baulande Sylvain, Raynal Virginie, Bozec Laurence, Bieche Ivan, Delattre Olivier, Berlanga Pablo, Schleiermacher Gudrun
Аннотация
EXPERIMENTAL DESIGN: Eighteen patients with relapsing neuroblastoma having received lorlatinib, a third-generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for nine patients and sequentially for five patients (blood/bone marrow plasma) by performing whole-genome sequencing library construction followed by ALK-targeted ddPCR of the hotspot mutations [F1174L, R1275Q, and I1170N; variant allele fraction (VAF) detection limit 0.1%] and whole-exome sequencing (WES) to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES.
RESULTS: 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.
CONCLUSIONS: 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 patients with neuroblastoma receiving ALK-targeted therapy.