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Circulating cell-free BRAF V600E as a biomarker in children with Langerhans cell histiocytosis

Sébastien Héritier 1, 2, 3, * Zofia Hélias-Rodzewicz 2, 4 Hélène Lapillonne 3 Nathalie Terrones 2, 4 Sonia Garrigou 5 Corinne Normand 5 Mohamed-Aziz Barkaoui 1 Jean Miron 1 Genevieve Plat 6 Nathalie Aladjidi 7 Anne Pagnier 8 Anne Deville 9 Marion Gillibert-Yvert 10 Despina Moshous 11 Alain Lefèvre-Utile 11 Anne Lutun 12 Catherine Paillard 13 Caroline Thomas 14 Eric Jeziorski 15 Philippe Nizard 5 Valérie Taly 5, * Jean-François Emile 2, 4 Jean Donadieu 1, 2, 3 
Abstract : The BRAFV600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAFV600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E -mutated LCH were investigated to detect ccf BRAFV600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO- patients (mean, 0·16%; range, 0·01-0·39) (P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.
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Submitted on : Friday, September 27, 2019 - 6:03:00 PM
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Sébastien Héritier, Zofia Hélias-Rodzewicz, Hélène Lapillonne, Nathalie Terrones, Sonia Garrigou, et al.. Circulating cell-free BRAF V600E as a biomarker in children with Langerhans cell histiocytosis. British Journal of Haematology, Wiley, 2017, 178 (3), pp.457-467. ⟨10.1111/bjh.14695⟩. ⟨inserm-02299526⟩



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