Fanny Garlan1, Benoit Blanchet2,3, Nora Kramkimel4, Alicja Puszkiel2, Jean-Louis Golmard5, Gaelle Noe2, Nicolas Dupin4, Pierre Laurent-Puig1, Michel Vidal2,6, Valerie Taly1, Audrey Thomas-Schoemann7,8. 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. 2. Assistance Publique des Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Paris, France. 3. Groupe de Pharmacologie Clinique Oncologique, Paris, France. 4. Assistance Publique des Hôpitaux de Paris, Département de Dermatologie, Hôpital Cochin, Paris, France. 5. Assistance Publique des Hôpitaux de Paris, Département de Biostatistiques, Hôpital Pitié- Salpétrière, Paris, France. 6. UMR8638 CNRS, UFR De Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France. 7. Assistance Publique des Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Paris, France. schoemann.audrey@gmail.com. 8. UMR8638 CNRS, UFR De Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France. schoemann.audrey@gmail.com.
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.
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 melanomapatients. 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 BRAFp.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 melanomapatients. Plasma drug monitoring and ctDNA concentrations could be combined to monitor tumor evolution in melanomapatients treated with anti-BRAF therapies.
Authors: E Funck-Brentano; J C Alvarez; C Longvert; E Abe; A Beauchet; C Funck-Brentano; P Saiag Journal: Ann Oncol Date: 2015-04-21 Impact factor: 32.976
Authors: Mark R Gray; Sara Martin del Campo; Xu Zhang; Haowei Zhang; Frederico F Souza; William E Carson; Andrew D Smith Journal: Radiology Date: 2013-10-28 Impact factor: 11.105
Authors: Jeffrey A Sosman; Kevin B Kim; Lynn Schuchter; Rene Gonzalez; Anna C Pavlick; Jeffrey S Weber; Grant A McArthur; Thomas E Hutson; Stergios J Moschos; Keith T Flaherty; Peter Hersey; Richard Kefford; Donald Lawrence; Igor Puzanov; Karl D Lewis; Ravi K Amaravadi; Bartosz Chmielowski; H Jeffrey Lawrence; Yu Shyr; Fei Ye; Jiang Li; Keith B Nolop; Richard J Lee; Andrew K Joe; Antoni Ribas Journal: N Engl J Med Date: 2012-02-23 Impact factor: 91.245
Authors: Helen Davies; Graham R Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J Riggins; Darell D Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W C Ho; Suet Y Leung; Siu T Yuen; Barbara L Weber; Hilliard F Seigler; Timothy L Darrow; Hugh Paterson; Richard Marais; Christopher J Marshall; Richard Wooster; Michael R Stratton; P Andrew Futreal Journal: Nature Date: 2002-06-09 Impact factor: 49.962
Authors: Benjamin J Hindson; Kevin D Ness; Donald A Masquelier; Phillip Belgrader; Nicholas J Heredia; Anthony J Makarewicz; Isaac J Bright; Michael Y Lucero; Amy L Hiddessen; Tina C Legler; Tyler K Kitano; Michael R Hodel; Jonathan F Petersen; Paul W Wyatt; Erin R Steenblock; Pallavi H Shah; Luc J Bousse; Camille B Troup; Jeffrey C Mellen; Dean K Wittmann; Nicholas G Erndt; Thomas H Cauley; Ryan T Koehler; Austin P So; Simant Dube; Klint A Rose; Luz Montesclaros; Shenglong Wang; David P Stumbo; Shawn P Hodges; Steven Romine; Fred P Milanovich; Helen E White; John F Regan; George A Karlin-Neumann; Christopher M Hindson; Serge Saxonov; Bill W Colston Journal: Anal Chem Date: 2011-10-28 Impact factor: 6.986
Authors: Vincent L Biron; Ashlee Matkin; Morris Kostiuk; Jordana Williams; David W Cote; Jeffrey Harris; Hadi Seikaly; Daniel A O'Connell Journal: J Otolaryngol Head Neck Surg Date: 2018-09-24