Abstract 540: Molecular response evaluation of patients with metastatic colorectal cancer using circulating tumor DNA
Authors: van 't Erve Iris , Medina Jamie E. , Leal Alessandro , Papp Eniko , Bolhuis Karen , Simmons John K. , Angiuoli Samuel , Punt Cornelis J. , Meijer Gerrit A. , Velculescu Victor E. , Fijneman Remond J. 
Published: July 2021

Abstract
Introduction: Patients with colorectal cancer with unresectable and isolated liver metastases (CRLM) are mostly treated with chemotherapy and targeted treatments like anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. Clinical response evaluation of systemic treatment is performed by radiological CT imaging, which can detect disease progression. However, CT imaging does not always give information about the viability of the tumor tissue nor does it constitute the genomic changes of the tumor, i.e. development of sub-clones following the pressure of treatment. Cell-free circulating tumor DNA (ctDNA) derived from liquid biopsies is a minimally invasive biomarker that has great potential for tumor detection and is present in relatively high levels in the plasma of patients with CRLM. Liquid biopsy ctDNA allows for longitudinal follow-up and gives the possibility to track intratumor heterogeneity caused by different sub-clones without a repeated tumor biopsy. Here, we aim to assess the use of molecular profiling using serial liquid biopsies as a biomarker for treatment response evaluation.
Methods: Tumor tissue obtained prior to treatment as well as longitudinal liquid biopsies were collected from patients with CRLM who participated in a prospective clinical trial with CRC and were treated with panitumumab and doublet chemotherapy. Liquid biopsy ctDNA was isolated and analyzed by targeted sequencing using a panel of 33-genes, allowing to map dynamic molecular changes during treatment. ctDNA sequencing results were corrected for germline variants and clonal hematopoiesis variants by using targeted sequencing data of patient-matched tumor tissue DNA and white blood cell (WBC) genomic DNA, respectively. ‘Molecular response' was defined as the elimination of more than 95% of ctDNA after treatment compared to the measurement before treatment initiation. Detection of disease progression by ctDNA was compared to CT imaging.
Results: At present, 110 longitudinal plasma samples as well as WBC genomic DNA and tumor tissue DNA are analyzed from a cohort of 33 patients. Currently, we are expanding the number of patients and samples. Molecular responders to treatment showed a significantly longer overall survival than non-responders (median 51 vs 25 months; p=0.033; HR=3.7). In addition, significantly earlier detection of disease progression was observed using ctDNA compared to radiological imaging (median difference of 4.8 months; p=0.006).
Conclusion: Serial plasma ctDNA analyses in patients with mCRC provide a minimally-invasive tool for longitudinal treatment response evaluation of dynamic genomic alterations and creates an opportunity for patient subset selection for possible adaptation of the treatment regimen.
Citation Format: Iris van 't Erve, Jamie E. Medina, Alessandro Leal, Eniko Papp, Karen Bolhuis, John K. Simmons, Samuel Angiuoli, Cornelis J. Punt, Gerrit A. Meijer, Victor E. Velculescu, Remond J. Fijneman. Molecular response evaluation of patients with metastatic colorectal cancer using circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 540.