Abstract 5748: Longitudinal evaluation of ctDNA molecular response for monitoring clinical benefit and investigating treatment related impacts in metastatic colorectal cancer patients treated with different drug regimens
Authors: Smith Neil R. , Pignon Jean-Christophe , Shell Scott A. , Yablonovitch Arialle , Scheuenpflug Juergen , Feng Zheng 
Published: June 2022

Abstract
Introduction: The patient-centric liquid biopsy approach to detect changes in ctDNA provides an early indication of treatment response to therapies and is an emerging tool to aid clinicians in treatment decision making. We investigated this approach in the mCRC palliative treatment setting by exploring the potential clinical utility of the validated Guardant Health Molecular Response (MR) algorithm.
Methods: Longitudinal plasma samples (70) were collected from 14 patients with mCRC and treated using chemotherapy alone or combined with one or more targeting agents. All patients were clinically stable or had clinical benefit over the course of plasma collection. 6 patients had radiological response by RECISTv1.1 and 10 had tumor RAS/RAF mutation status. Baseline and longitudinal plasma samples (27-276 days post treatment) were tested by GuardantOMNI® 500-gene liquid biopsy assay. Selection of qualifying alterations and generation of MR scores were pursued using the Guardant Health MR algorithm.
Results: Thirteen patients were evaluable for MR by having somatic alterations at each timepoint that exceeded the molecule threshold required for reliable MR score calculation. Mean variant allele fraction (mVAF) of all plasma samples outside the 4-10 week on-treatment window trended in the same direction as the early on-treatment plasma samples when compared to baseline. Eleven patients experienced a consistent reduction in mVAF compared to baseline. One outlier showed a mVAF increase at the earliest on-treatment timepoint, followed by molecular clearance at all subsequent timepoints. GuardantOMNI® detected a frameshift APC alteration at the baseline of this patient, which may have limited the tumor response to the chemotherapy. The second outlier patient was originally diagnosed as RAS/RAF wild-type and treated with anti-EGFR and anti-PD-L1. MR scores for this patient across all timepoints reflected an increase in mVAF compared to baseline. Notably, GuardantOMNI® detected a low level KRAS alteration in the baseline plasma sample of this patient, indicating this patient’s disease had elements of KRAS alteration that were not detected by tissue-based testing. All 6 patients with RECIST 1.1 information had partial responses (PR) and 5 showed a decrease in the MR score. The one patient whose MR score did not align with radiographic assessment was the mis-genotyped KRAS mutation-positive patient, who is under further investigation.
Conclusions: We demonstrate that ctDNA analysis of plasma samples taken at early timepoints (4-10 weeks) after treatment initiation are sufficient to support MR assessments and highlight the advantage of the patient-centric liquid biopsy approach over genetic testing of diagnostic tumor samples in detecting potential resistance mutations prior to therapy.
Citation Format: Neil R. Smith, Jean-Christophe Pignon, Scott A. Shell, Arialle Yablonovitch, Juergen Scheuenpflug, Zheng Feng. Longitudinal evaluation of ctDNA molecular response for monitoring clinical benefit and investigating treatment related impacts in metastatic colorectal cancer patients treated with different drug regimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5748.