R Váraljai1, S Elouali1, S S Lueong2,3, K Wistuba-Hamprecht4, T Seremet5, J T Siveke2,3, J C Becker6, A Sucker1, A Paschen1, P A Horn7, B Neyns5, B Weide4, D Schadendorf1, A Roesch1. 1. Department of Dermatology, University Hospital of Essen, University Duisburg-Essen and German Cancer Consortium (DKTK) partner site Essen/Düsseldorf, Essen, Germany. 2. Institute for Developmental Cancer Therapeutics & Division of Solid Tumor Translational Oncology (DKTK/DKFZ partner site Essen), West German Cancer Center University Hospital of Essen, Essen, Germany. 3. German Cancer Consortium and German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany. 5. Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium. 6. Department of Translational Skin Cancer Research (TSCR), University Hospital of Essen, University of Duisburg-Essen and German Cancer Consortium (DKTK) partner site Essen/Düsseldorf, Essen, Germany. 7. Institute for Transfusion Medicine, University Hospital of Essen, Essen, Germany.
Abstract
BACKGROUND: Melanoma is the leading cause of skin cancer-related deaths worldwide. While there have been significant improvements in the treatment of advanced melanoma in the past decade, biomarker development lagged behind. OBJECTIVES: The majority of liquid biopsy biomarkers rely on the analyses of oncogenic mutations; however, about 20% of melanoma patients are wild type. Therefore, validation of universal predictive and prognostic biomarkers is urgently needed. METHODS: We analysed plasma samples in a discovery cohort (n = 20) and expansion cohort (n = 166) of metastatic melanoma patients and healthy donors (n = 116). Total plasma circulating cell-free DNA (cfDNA) concentrations were measured on the Qubit® platform using assays for single-(ss) and double (ds)-stranded DNA, DNA spectrophotometry and RNase P qPCR. We explored the diagnostic, predictive and prognostic potential of cfDNA concentration by bio-statistical methods and established a cfDNA threshold for risk stratification. RESULTS: Our selected best method was Qubit® dsDNA assay which quantified higher plasma cfDNA concentrations in melanoma patients than in healthy controls (AUC 72%). Measurement of baseline cfDNA concentration revealed that high cfDNA was associated with presence of metastases and higher AJCC stage (P < 0.05). Furthermore, high baseline cfDNA was an indicator of shorter overall survival in patients with oncogenic mutations (HR 2.12, P = 0.0008), and in wild-type patients (HR 5.55, P < 0.0001). CONCLUSIONS: We provide evidence that total cfDNA can be used as a biomarker for melanoma irrespective of the tumour genotype and can provide information on tumour load, risk of progression and risk of death.
BACKGROUND:Melanoma is the leading cause of skin cancer-related deaths worldwide. While there have been significant improvements in the treatment of advanced melanoma in the past decade, biomarker development lagged behind. OBJECTIVES: The majority of liquid biopsy biomarkers rely on the analyses of oncogenic mutations; however, about 20% of melanomapatients are wild type. Therefore, validation of universal predictive and prognostic biomarkers is urgently needed. METHODS: We analysed plasma samples in a discovery cohort (n = 20) and expansion cohort (n = 166) of metastatic melanomapatients and healthy donors (n = 116). Total plasma circulating cell-free DNA (cfDNA) concentrations were measured on the Qubit® platform using assays for single-(ss) and double (ds)-stranded DNA, DNA spectrophotometry and RNase P qPCR. We explored the diagnostic, predictive and prognostic potential of cfDNA concentration by bio-statistical methods and established a cfDNA threshold for risk stratification. RESULTS: Our selected best method was Qubit® dsDNA assay which quantified higher plasma cfDNA concentrations in melanomapatients than in healthy controls (AUC 72%). Measurement of baseline cfDNA concentration revealed that high cfDNA was associated with presence of metastases and higher AJCC stage (P < 0.05). Furthermore, high baseline cfDNA was an indicator of shorter overall survival in patients with oncogenic mutations (HR 2.12, P = 0.0008), and in wild-type patients (HR 5.55, P < 0.0001). CONCLUSIONS: We provide evidence that total cfDNA can be used as a biomarker for melanoma irrespective of the tumour genotype and can provide information on tumour load, risk of progression and risk of death.
Authors: Wael Al Zoughbi; Jesse Fox; Shaham Beg; Eniko Papp; Erika Hissong; Kentaro Ohara; Laurel Keefer; Michael Sigouros; Troy Kane; Daniel Bockelman; Donna Nichol; Emily Patchell; Rohan Bareja; Aanavi Karandikar; Hussein Alnajar; Gustavo Cerqueira; Violeta Beleva Guthrie; Ellen Verner; Jyothi Manohar; Noah Greco; David Wilkes; Scott Tagawa; Murtaza S Malbari; Kevin Holcomb; Kenneth Wha Eng; Manish Shah; Nasser K Altorki; Andrea Sboner; David Nanus; Bishoy Faltas; Cora N Sternberg; John Simmons; Yariv Houvras; Ana M Molina; Samuel Angiuoli; Olivier Elemento; Juan Miguel Mosquera Journal: Oncologist Date: 2021-08-04