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Circulating Tumor DNA Measurement by Picoliter Droplet-Based Digital PCR and Vemurafenib Plasma Concentrations in Patients with Advanced BRAF-Mutated Melanoma

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Abstract

Background

Circulating tumor DNA (ctDNA) has been reported as a prognostic marker in melanoma. In BRAF V600-mutant melanoma, a plasma under-exposure to vemurafenib could favor emerging resistance but no biological data are available to support this hypothesis.

Objective

We aimed to investigate the relationship between vemurafenib plasma concentrations and the ctDNA plasma concentration during follow-up of BRAF-mutated melanoma patients.

Patients and Methods

Eleven patients treated with single-agent vemurafenib for advanced BRAF V600-mutant melanoma were analyzed in an exploratory monocentric study. The vemurafenib plasma concentration was measured by liquid chromatography. ctDNA was extracted from plasma samples and the ctDNA concentration was evaluated using picoliter droplet-based digital PCR with Taqman® detection probes targeting the BRAF p.V600E/K mutation and wild-type BRAF sequences.

Results

At baseline, plasma ctDNA was detectable in 72% (n = 8/11) of patients and the ctDNA concentration decreased in 88% of these patients (n = 7/8) from day (D) 0 to D15 after vemurafenib initiation. During follow-up, an increased ctDNA concentration was detected in nine patients: in five patients, the first increase in ctDNA concentrations followed a decrease in vemurafenib concentrations. More interestingly, an inverse correlation between vemurafenib concentration and ctDNA concentrations was demonstrated (p = 0.026). The ctDNA concentration at baseline was associated with overall survival (hazard ratio = 2.61, 95% CI 1.04–6.56; p = 0.04).

Conclusions

This study demonstrates the relevance of vemurafenib plasma monitoring during the follow-up of metastatic melanoma patients. Plasma drug monitoring and ctDNA concentrations could be combined to monitor tumor evolution in melanoma patients treated with anti-BRAF therapies.

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Authors and Affiliations

  1. INSERM UMR-S1147, CNRS SNC5014, Equipe Labélisée Ligue Contre le Cancer, Université Paris Descartes, Centre Université Paris Sorbonne Cité, Universitaire des Saints-Pères, Paris, France

    Fanny Garlan, Pierre Laurent-Puig & Valerie Taly

  2. Assistance Publique des Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Paris, France

    Benoit Blanchet, Alicja Puszkiel, Gaelle Noe, Michel Vidal & Audrey Thomas-Schoemann

  3. Groupe de Pharmacologie Clinique Oncologique, Paris, France

    Benoit Blanchet

  4. Assistance Publique des Hôpitaux de Paris, Département de Dermatologie, Hôpital Cochin, Paris, France

    Nora Kramkimel & Nicolas Dupin

  5. Assistance Publique des Hôpitaux de Paris, Département de Biostatistiques, Hôpital Pitié- Salpétrière, Paris, France

    Jean-Louis Golmard

  6. UMR8638 CNRS, UFR De Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France

    Michel Vidal & Audrey Thomas-Schoemann

Authors
  1. Fanny Garlan
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  2. Benoit Blanchet
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  3. Nora Kramkimel
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  4. Alicja Puszkiel
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  5. Jean-Louis Golmard
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  6. Gaelle Noe
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  7. Nicolas Dupin
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  8. Pierre Laurent-Puig
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  9. Michel Vidal
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  10. Valerie Taly
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  11. Audrey Thomas-Schoemann
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Corresponding author

Correspondence to Audrey Thomas-Schoemann.

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Funding

This work was supported by the Ministère de l’Enseignement Supérieur et de la Recherche, the Université Paris-Descartes, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale de la Recherche (ANR Nanobiotechnologies; no. ANR-10-NANO-0002-09), the SIRIC CARPEM and the ligue nationale contre le cancer (LNCC, Program “Equipe labellisée LIGUE”; no. EL2016.LNCC/VaT). FG thanks the Fondation Servier for a fellowship within the Frontiers in Life Science PhD program (FdV).

Conflict of Interest

Authors declare that they have no conflict of interest.

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Garlan, F., Blanchet, B., Kramkimel, N. et al. Circulating Tumor DNA Measurement by Picoliter Droplet-Based Digital PCR and Vemurafenib Plasma Concentrations in Patients with Advanced BRAF-Mutated Melanoma. Targ Oncol 12, 365–371 (2017). https://doi.org/10.1007/s11523-017-0491-8

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  • DOI: https://doi.org/10.1007/s11523-017-0491-8

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