Detection and Monitoring of Tumor-Derived Mutations in Circulating Tumor DNA Using the UltraSEEK Lung Panel on the MassARRAY System in Metastatic Non-Small Cell Lung Cancer Patients

Author:

Leest Paul van der1ORCID,Janning Melanie23456ORCID,Rifaela Naomi1,Azpurua Maria L. Aguirre1,Kropidlowski Jolanthe6,Loges Sonja345,Lozano Nicolas7ORCID,Sartori Alexander8,Irwin Darryl9ORCID,Lamy Pierre-Jean710ORCID,Hiltermann T. Jeroen N.11ORCID,Groen Harry J. M.11ORCID,Pantel Klaus6ORCID,Kempen Léon C. van1ORCID,Wikman Harriet6ORCID,Schuuring Ed1ORCID

Affiliation:

1. Department of Pathology (EA10), University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

2. German Cancer Research Center (DKFZ)-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany

3. Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

4. Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany

5. Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany

6. Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany

7. Institut d’Analyse Génomique Imagenome, Labosud, 34070 Montpellier, France

8. Agena Bioscience GmbH, 22761 Hamburg, Germany

9. Agena Bioscience, Brisbane 4006, Australia

10. Department of Clinical Research, Clinique BeauSoleil, 34070 Montpellier, France

11. Department of Pulmonary Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

Abstract

Analysis of circulating tumor DNA (ctDNA) is a potential minimally invasive molecular tool to guide treatment decision-making and disease monitoring. A suitable diagnostic-grade platform is required for the detection of tumor-specific mutations with high sensitivity in the circulating cell-free DNA (ccfDNA) of cancer patients. In this multicenter study, the ccfDNA of 72 patients treated for advanced-stage non-small cell lung cancer (NSCLC) was evaluated using the UltraSEEK® Lung Panel on the MassARRAY® System, covering 73 hotspot mutations in EGFR, KRAS, BRAF, ERBB2, and PIK3CA against mutation-specific droplet digital PCR (ddPCR) and routine tumor tissue NGS. Variant detection accuracy at primary diagnosis and during disease progression, and ctDNA dynamics as a marker of treatment efficacy, were analyzed. A multicenter evaluation using reference material demonstrated an overall detection rate of over 90% for variant allele frequencies (VAFs) > 0.5%, irrespective of ccfDNA input. A comparison of UltraSEEK® and ddPCR analyses revealed a 90% concordance. An 80% concordance between therapeutically targetable mutations detected in tumor tissue NGS and ccfDNA UltraSEEK® analysis at baseline was observed. Nine of 84 (11%) tumor tissue mutations were not covered by UltraSEEK®. A decrease in ctDNA levels at 4–6 weeks after treatment initiation detected with UltraSEEK® correlated with prolonged median PFS (46 vs. 6 weeks; p < 0.05) and OS (145 vs. 30 weeks; p < 0.01). Using plasma-derived ccfDNA, the UltraSEEK® Lung Panel with a mid-density set of the most common predictive markers for NSCLC is an alternative tool to detect mutations both at diagnosis and during disease progression and to monitor treatment response.

Funder

Agena Bioscience

Bio-Rad

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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