OncoTargets and Therapy (Jun 2020)

Circulating Tumor DNA Correlates with Outcome in Metastatic Melanoma Treated by BRAF and MEK Inhibitors – Results of a Prospective Biomarker Study

  • Forschner A,
  • Weißgraeber S,
  • Hadaschik D,
  • Schulze M,
  • Kopp M,
  • Kelkenberg S,
  • Sinnberg T,
  • Garbe C,
  • Biskup S,
  • Battke F

Journal volume & issue
Vol. Volume 13
pp. 5017 – 5032

Abstract

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Andrea Forschner,1 Stephanie Weißgraeber,2 Dirk Hadaschik,2 Martin Schulze,3 Maria Kopp,2 Sabine Kelkenberg,2 Tobias Sinnberg,1 Claus Garbe,1 Saskia Biskup,2,3 Florian Battke2 1Center for Dermatooncology, Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany; 2Center for Genomics and Transcriptomics (CeGaT) GmbH, Tuebingen, Germany; 3Practice for Human Genetics, Tuebingen, GermanyCorrespondence: Andrea ForschnerCenter for Dermatooncology, Department of Dermatology, University Hospital Tuebingen, Tuebingen, GermanyEmail [email protected]: BRAF and MEK inhibitors significantly improved the prognosis of metastatic melanoma. Nevertheless, initial treatment response may be only temporary. Liquid biopsies (LB) offer a possibility to monitor patients by measuring circulating tumor DNA (ctDNA). We sought to find out whether ctDNA can be used to reliably determine progressive disease under targeted therapy. In addition, we wanted to check whether ctDNA may represent a possible prognostic marker for survival.Patients and Methods: We included 19 melanoma patients with BRAF and MEK inhibitor therapy. For each patient, a 710 gene panel was analyzed on the latest available tumor tissue before the start of therapy. Repetitive LB were collected in which BRAF V600E/K mutations were monitored using digital droplet PCR (ddPCR). We correlated radiological staging results and overall survival with ctDNA results.Results: In 13 patients, ctDNA was detectable when starting targeted therapy, whereas in six patients, ddPCR was always negative, which we confirmed with ultra-deep sequencing. All patients with initially detectable ctDNA had ctDNA values declining to zero during follow-up, increasing again at the time of extracerebral progression or even slightly before detection by imaging. Survival was significantly worse for patients with elevated LDH (p=0.034) or detectable ctDNA (p=0.008) at the start of targeted therapy.Conclusion: Therapy monitoring by ctDNA seems to be a reliable method for detecting extracranial progression, even more sensitive and specific than LDH or S100B. However, due to the small number of cases in our study, further studies are necessary.Keywords: metastatic melanoma, BRAF and MEK inhibition, circulating tumor DNA, ctDNA

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