Data from Sequential Analysis of cfDNA Reveals Clonal Evolution in Patients with Neuroblastoma Receiving <i>ALK</i>-Targeted Therapy

• DOI: 10.1158/1078-0432.c.7380143
• Publication Date: 2024-08-01T13:26:52Z
• Authors: Charles Bobin; Yasmine Iddir; Charlotte Butterw...; Julien Masliah-Pl...; Alexandra Saint-C...; Angela Bellini; Jaydutt Bhalshankar; Gaelle Pierron; Valérie Combaret; Valéry Attignon; Nicolas André; Nadège Corradini; Benoit Dumont; Ludovic Mansuy; Camille Khanfar; Sebastien Klein; Claire Briandet; Dominique Plantaz; Frederic Millot; Sandrine Thouvenin; Isabelle Aerts; Lee Aymar Ndounga...; Salim Laghouati; Samuel Abbou; Nina Jehanno; Hubert Tissot; Shufang Renault; Sylvain Baulande; Virginie Raynal; Laurence Bozec; Ivan Bieche; Olivier Delattre; Pablo Berlanga; Gudrun Schleierma...

&lt;div&gt;AbstractPurpose:&lt;p&gt;The study of cell-free DNA (cfDNA) enables sequential analysis tumor cell–specific genetic alterations in patients with neuroblastoma.&lt;/p&gt;Experimental Design:&lt;p&gt;Eighteen relapsing neuroblastoma having received lorlatinib, a third-generation &lt;i&gt;ALK&lt;/i&gt; inhibitor, were identified (SACHA national registry and/or the institution). cfDNA was analyzed at relapse for nine and sequentially five (blood/bone marrow plasma) by performing whole-genome sequencing library construction followed &lt;i&gt;ALK&lt;/i&gt;-targeted ddPCR hotspot mutations [F1174L, R1275Q, I1170N; variant allele fraction (VAF) detection limit 0.1%] whole-exome (WES) to evaluate disease burden clonal evolution, following comparison tumor/germline WES.&lt;/p&gt;Results:&lt;p&gt;Overall response rate lorlatinib 33% (CI, 13%–59%), observed 6/10 cases without versus 0/8 &lt;i&gt;MYCN&lt;/i&gt; amplification (MNA). VAFs correlated overall clinical status, VAF &lt; 0.1% remission, higher (&gt;30%) progression. Importantly, detected earlier than imaging. WES revealed new SNVs, not seen primary tumor, all instances progression after treatment, indicating including genes linked aggressivity (&lt;i&gt;TP53&lt;/i&gt;) or novel targets (&lt;i&gt;EGFR&lt;/i&gt;). Gene pathway an enrichment targeting cell differentiation emerging clones, adhesion persistent clones. Evidence hematopoiesis could be follow-up samples.&lt;/p&gt;Conclusions:&lt;p&gt;We demonstrate utility combining monitoring evolution resistance mechanisms receiving therapy.&lt;/p&gt;&lt;/div&gt;