Response prediction by mutation- or methylation-specific detection of ctDNA dynamics in pretreated metastatic colorectal cancer

Bernhard Doleschal; Patrick Kirchweger; Simon Schwendinger; Alexander Kupferthaler; Jonathan Burghofer; Gerald Webersinke; Emina Jukic; Helwig Wundsam; Matthias Biebl; Andreas Petzer; Holger Rumpold

doi:10.1177/17588359231200462

Response prediction by mutation- or methylation-specific detection of ctDNA dynamics in pretreated metastatic colorectal cancer

Ther Adv Med Oncol. 2023 Sep 29:15:17588359231200462. doi: 10.1177/17588359231200462. eCollection 2023.

Authors

Bernhard Doleschal¹, Patrick Kirchweger^{2

3}, Simon Schwendinger⁴, Alexander Kupferthaler^{3

5}, Jonathan Burghofer⁶, Gerald Webersinke⁶, Emina Jukic⁴, Helwig Wundsam⁷, Matthias Biebl⁷, Andreas Petzer¹, Holger Rumpold^{3

8}

Affiliations

¹ Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Oberösterreich, Austria.
² Department of Surgery, Ordensklinikum Linz, Linz, Oberösterreich, Austria.
³ Medical Faculty, Johannes Kepler University Linz, Linz, Austria.
⁴ Institute of Human Genetics, Medical University of Innsbruck, Austria.
⁵ Department of Diagnostic and Interventional Radiology, Ordensklinikum Linz, Linz, Austria.
⁶ Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, Linz, Austria.
⁷ Department of Surgery, Ordensklinikum Linz, Linz, Austria.
⁸ Gastrointestinal Cancer Center, Ordensklinikum Linz, Seilerstaette 4, Linz 4010, Austria.

Abstract

Background: Serial analysis of circulating tumor DNA (ctDNA) levels is a promising tool for both relapse prediction in the curative setting, as well as predicting clinical benefit from systemic treatment in metastasic colorectal cancer (mCRC). Most data in this context are derived from treatment naive patients.

Objective: To predict progressive disease (PD) as early as possible through monitoring of changes in ctDNA levels during systemic treatment in pretreated patients with mCRC.

Design: A prospective, single-center, observational study.

Methods: Patients treated beyond first-line were prospectively included between February 2020 and September 2021. Blood for ctDNA detection was taken before every treatment cycle from start of treatment until first restaging by CT-scan. ctDNA was detected by mutation- (mut-ctDNA) and methylation-specific ddPCR. Receiver Operating Characteristic (ROC)-analysis was used to describe sensitivity and specificity for prediction of PD at restaging for all time points.

Results: A total of 42 patients were included who all carried a mutation in tumor tissue. Detection rate of mut-ctDNA was 88.1% and 74.4% for meth-ctDNA. Absolute ctDNA levels before treatment were prognostic in terms of overall survival. Levels of ctDNA were significantly higher in patients with PD at restaging. Median time from start of treatment to restaging was 93 days (95% CI 88.8-96). After a median of 19 days of treatment (95% CI 16.1-20.2), a decline of either mutation- or methylation-specific ctDNA levels of ⩽58% predicted PD at restaging with a sensitivity/specificity of 92.9/85.7% and 85.7/100%, respectively. Median time to restaging was 66 days (95% CI 56.8-75.2). There was no significant increase of sensitivity/specificity at later time points of ctDNA measurements.

Conclusion: Monitoring early changes of ctDNA levels either by mut- or meth-ctDNA allows for early prediction of PD in pretreated patients with mCRC. This has the potential to complement RECIST-based treatment assessment with the aim to switch potentially insufficient treatments as early as possible, which is of particular interest in higher treatment lines.

Keywords: blood-based biomarker; colorectal cancer; liquid biopsy; palliative treatment; prognostic biomarker.