Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

Arlou Kristina Angeles; Petros Christopoulos; Zhao Yuan; Simone Bauer; Florian Janke; Simon John Ogrodnik; Martin Reck; Matthias Schlesner; Michael Meister; Marc A Schneider; Steffen Dietz; Albrecht Stenzinger; Michael Thomas; Holger Sültmann

doi:10.1038/s41698-021-00239-3

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

NPJ Precis Oncol. 2021 Dec 7;5(1):100. doi: 10.1038/s41698-021-00239-3.

Authors

Arlou Kristina Angeles^#^{1

2}, Petros Christopoulos^#^{2

3}, Zhao Yuan⁴, Simone Bauer^{1

2}, Florian Janke^{1

2

5}, Simon John Ogrodnik^{1

2}, Martin Reck⁶, Matthias Schlesner^{2

4

7}, Michael Meister^{2

8}, Marc A Schneider^{2

8}, Steffen Dietz^{1

2

9}, Albrecht Stenzinger^{10

11}, Michael Thomas^{2

3}, Holger Sültmann^{12

13}

Affiliations

¹ Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
² Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany.
³ Department of Oncology, Thoraxklinik and National Center for Tumor Disease (NCT) at Heidelberg University Hospital, Heidelberg, Germany.
⁴ Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Medical Faculty, Heidelberg University, Heidelberg, Germany.
⁶ Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
⁷ Biomedical Informatics, Data Mining and Data Analytics, Faculty for Applied Informatics, Augsburg University, Augsburg, Germany.
⁸ Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany.
⁹ AstraZeneca GmbH, Wedel, Germany.
¹⁰ Institute of Pathology, Heidelberg University, Heidelberg, Germany.
¹¹ German Cancer Consortium (DKTK), Heidelberg, Germany.
¹² Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany. h.sueltmann@dkfz.de.
¹³ Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany. h.sueltmann@dkfz.de.

^# Contributed equally.

Abstract

Targeted kinase inhibitors improve the prognosis of lung cancer patients with ALK alterations (ALK+). However, due to the emergence of acquired resistance and varied clinical trajectories, early detection of disease progression is warranted to guide patient management and therapy decisions. We utilized 343 longitudinal plasma DNA samples from 43 ALK+ NSCLC patients receiving ALK-directed therapies to determine molecular progression based on matched panel-based targeted next-generation sequencing (tNGS), and shallow whole-genome sequencing (sWGS). ALK-related alterations were detected in 22 out of 43 (51%) patients. Among 343 longitudinal plasma samples analyzed, 174 (51%) were ctDNA-positive. ALK variant and fusion kinetics generally reflected the disease course. Evidence for early molecular progression was observed in 19 patients (44%). Detection of ctDNA at therapy baseline indicated shorter times to progression compared to cases without mutations at baseline. In patients who succumbed to the disease, ctDNA levels were highly elevated towards the end of life. Our results demonstrate the potential utility of these NGS assays in the clinical management of ALK+ NSCLC.