Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer

Susanne Klein-Scory; Ingo Wahner; Marina Maslova; Yosef Al-Sewaidi; Michael Pohl; Thomas Mika; Swetlana Ladigan; Roland Schroers; Alexander Baraniskin

doi:10.3389/fonc.2020.01115

Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer

Front Oncol. 2020 Jul 16:10:1115. doi: 10.3389/fonc.2020.01115. eCollection 2020.

Authors

Susanne Klein-Scory¹, Ingo Wahner¹, Marina Maslova², Yosef Al-Sewaidi², Michael Pohl³, Thomas Mika³, Swetlana Ladigan³, Roland Schroers³, Alexander Baraniskin^{1

3}

Affiliations

¹ IMBL Medical Clinic, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany.
² Department of Radiology, University Hospital Knappschaftskrankenhaus Bochum GmbH, Ruhr University Bochum, Bochum, Germany.
³ Department of Medicine, University Hospital Knappschaftskrankenhaus Bochum GmbH, Ruhr University Bochum, Bochum, Germany.

Abstract

Treatment options for patients with metastatic colorectal cancer (mCRC) are limited. This particularly affects the largest group of patients with RAS mutations, who are considered ineligible for therapy with antiEGFR antibodies. In this liquid biopsy-based study, we performed the first in-depth analysis of the RAS mutational status in initially RAS-mutated patients during first-line therapy. RAS status of twelve patients with initially RAS-mutated mCRC was monitored longitudinally in 69 liquid biopsy samples. We focused on patients with stable disease (SD) or partial remission (PR) during first-line therapy (11 patients). Detection of fragmented RAS-mutated circulating cell-free tumor DNA (ctDNA) in plasma was performed by digital-droplet PCR (ddPCR) and BEAMing. Patients' total tumor masses were determined by measuring the tumor volumes using CT scan data. All patients with PR or SD at first follow-up showed a significant decrease of RAS mutational load. In ten patients (91%), the ctDNA-based RAS mutational status converted to wild-type in ddPCR and BEAMing. Remarkably, conversions were observed early after the first cycle of chemotherapy. Plasma concentration of ctDNA was controlled by determination of methylated WIF1-promotor ctDNA burden as a second tumor marker for mCRC. Persistent presence of methylated WIF1-promotor fragments confirmed the ongoing release of ctDNA during treatment. In patients with initially RAS-mutated mCRC, RAS mutations rapidly disappeared during first-line therapy in liquid biopsy, independent of type and intensity of chemotherapy and irrespective of anti-VEGF treatments. Following our results demonstrating conversion of RAS-mutational status, potential effectiveness of anti-EGFR antibodies in selected patients becomes an attractive hypothesis for future studies.

Keywords: BEAMing; circulating tumor DNA; clonal selection; colorectal cancer; digital droplet PCR; liquid biopsy; methylation WIF1 promotor; neoRAS wild-type.