Abstract 2293: Is a single driver gene mutation sufficient for monitoring early response in advanced colorectal cancer
Authors: Kehagias Pashalina , Vandeputte Caroline , Ameye Lieveke , Housni Hakim El , Deleporte Amélie , Geboes Karen , Delaunoit Thierry , Demolin Gauthier , Peeters Marc , D'Hondt Lionel , Janssens Jos , Carrasco Javier , Galdon Maria Gomez , Heimann Pierre , Paesmans Marianne , Flamen Patrick , Hendlisz Alain 
Published: August 2019

Abstract
Purpose: Circulating tumor DNA (ctDNA) monitoring based on an individual mutation profile during therapy is under intense investigation in modern oncology. We previously reported that the increase of ≥50% of at least one somatic mutation among multiple monitored mutations per patient is associated with a significantly worse outcome1. This study investigates whether the ctDNA monitoring of one driver gene mutation, provides enough information as compared to multiple mutations to assess response to regorafenib in advanced chemorefractory colorectal cancer (aCRC) at an early timepoint.
Experimental procedures: Archival tumor tissue and plasma samples (PL) at baseline (BL) and 14 days (D14) after treatment initiation in aCRC pts (n=141) were prospectively collected in the RegARd-C multicenter clinical trial (NCT01929616). Somatic mutations were identified based on a CRC-oriented targeted gene sequencing of tumor tissue. All available (median 2 (1-4)) driver gene mutations were monitored per patient in PL at BL and D14 via droplet digital PCR (Bio-Rad QX200 ddPCR system) to assess ctDNA dynamics.
Results: In 96 evaluable patients, the most frequently monitored mutated genes were APC (73%), TP53 (72%), KRAS (66%), and PI3KCA (23%). Among patients with ≥2 monitored mutations (73/96), one was selected at random and compared to previous methodology taking in account dynamics of all followed mutations. Optimal cutoff (CO) evaluation (Contal & O’Quigley method) separated patients (n=96) according to a ctDNA increase of ≥50% versus an increase of &lt;50% or a decrease. The concordance of ctDNA dynamics based on one randomly selected mutation and multiple monitored mutations was 91%. Our data demonstrated that a ctDNA increase based on one single mutation taken at random is significantly associated with a worse clinical outcome in terms of progression-free survival (HR 2.42, 95% CI (1.56-3.74), P&lt;0.001) and overall-survival (HR 2.17, 95% CI (1.41-3.34), P&lt;0.001). In addition, when combining patients’ ctDNA dynamics to BL ctDNA levels (≥ or &lt; 5 ng/mL optimal CO) or BL cell-free DNA (cfDNA) levels (≥ or &lt; 50 ng/mL optimal CO), we could distinguish 4 patients’ subgroups with different prognosis. However, when performing a multivariate analysis including clinical parameters, BL ctDNA and BL cfDNA levels, BL ctDNA was not relevant in the presence of BL cfDNA.
Conclusion: The monitoring of ctDNA dynamics based on only one randomly selected driver gene mutation versus multiple is equally informative to describe adequately aCRC patients’ outcome under regorafenib after 14 days of treatment onset. Especially, combined with pre-treatment ctDNA levels, this simplifies a personalized patient monitoring. 1 P. Kehagias, et al. Circulating tumor DNA detects early response to regorafenib in advanced colorectal cancer [abstract]. AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-221
Citation Format: Pashalina Kehagias, Caroline Vandeputte, Lieveke Ameye, Hakim El Housni, Amélie Deleporte, Karen Geboes, Thierry Delaunoit, Gauthier Demolin, Marc Peeters, Lionel D'Hondt, Jos Janssens, Javier Carrasco, Maria Gomez Galdon, Pierre Heimann, Marianne Paesmans, Patrick Flamen, Alain Hendlisz. Is a single driver gene mutation sufficient for monitoring early response in advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2293.