Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy
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Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy. / Haselmann, Verena; Gebhardt, Christoffer; Brechtel, Ingrid; Duda, Angelika; Czerwinski, Claudia; Sucker, Antje; Holland-Letz, Tim; Utikal, Jochen; Schadendorf, Dirk; Neumaier, Michael.
In: CLIN CHEM, Vol. 64, No. 5, 05.2018, p. 830-842.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy
AU - Haselmann, Verena
AU - Gebhardt, Christoffer
AU - Brechtel, Ingrid
AU - Duda, Angelika
AU - Czerwinski, Claudia
AU - Sucker, Antje
AU - Holland-Letz, Tim
AU - Utikal, Jochen
AU - Schadendorf, Dirk
AU - Neumaier, Michael
N1 - © 2018 American Association for Clinical Chemistry.
PY - 2018/5
Y1 - 2018/5
N2 - BACKGROUND: The current standard for determining eligibility of patients with metastatic melanoma forBRAF-targeted therapy is tissue-based testing ofBRAFmutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoringBRAFtherapy.METHODS: In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance toBRAFinhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy.RESULTS: Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary BRAF-mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection ofBRAFmutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase.CONCLUSIONS: Blood-based testing compares favorably with standard-of-care tissue-basedBRAFmutation testing. Importantly, blood-basedBRAFtesting correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment.
AB - BACKGROUND: The current standard for determining eligibility of patients with metastatic melanoma forBRAF-targeted therapy is tissue-based testing ofBRAFmutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoringBRAFtherapy.METHODS: In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance toBRAFinhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy.RESULTS: Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary BRAF-mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection ofBRAFmutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase.CONCLUSIONS: Blood-based testing compares favorably with standard-of-care tissue-basedBRAFmutation testing. Importantly, blood-basedBRAFtesting correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment.
KW - Journal Article
U2 - 10.1373/clinchem.2017.281543
DO - 10.1373/clinchem.2017.281543
M3 - SCORING: Journal article
C2 - 29483107
VL - 64
SP - 830
EP - 842
JO - CLIN CHEM
JF - CLIN CHEM
SN - 0009-9147
IS - 5
ER -