Metastatic Colorectal Cancer Treatment Response Evaluation by Ultra-Deep Sequencing of Cell-Free DNA and Matched White Blood Cells

Iris van 't Erve, Jamie E. Medina, Alessandro Leal, Eniko Papp, Jillian Phallen, Vilmos Adleff, Elaine Jiayuee Chiao, Adith S. Arun, Karen Bolhuis, John K. Simmons, Aanavi Karandikar, Kenneth C. Valkenburg, Mark Sausen, Samuel V. Angiuoli, Robert B. Scharpf, Cornelis J.A. Punt, Gerrit A. Meijer, Victor E. Velculescu, Remond J.A. Fijneman

Research output: Contribution to journalArticlepeer-review


Purpose: Circulating tumor DNA (ctDNA) has the potential to guide therapy selection and monitor treatment response in patients with metastatic cancer. However, germline and clonal hematopoiesis- associated alterations can confound identification of tumorspecific mutations in cell-free DNA (cfDNA), often requiring additional sequencing of tumor tissue. The current study assessed whether ctDNA-based treatment response monitoring could be performed in a tumor tissue-independent manner by combining ultra-deep targeted sequencing analyses of cfDNA with patientmatched white blood cell (WBC)-derived DNA. Experimental Design: In total, 183 cfDNA and 49WBCsamples, along with 28 tissue samples, from 52 patients with metastatic colorectal cancer participating in the prospective phase III CAIRO5 clinical trial were analyzed using an ultra-deep targeted sequencing liquid biopsy assay. Results: The combined cfDNA and WBC analysis prevented false-positives due to germline or hematopoietic variants in 40% of patients. Patient-matched tumor tissue sequencing did not provide additional information. Longitudinal analyses of ctDNA were more predictive of overall survival than standard-of-care radiological response evaluation. ctDNA mutations related to primary or acquired resistance to panitumumab were identified in 42% of patients. Conclusions: Accurate calling of ctDNA mutations for treatment response monitoring is feasible in a tumor tissue-independent manner by combined cfDNA and patient-matched WBC genomic DNA analysis. This tissue biopsy-independent approach simplifies sample logistics and facilitates the application of liquid biopsy ctDNA testing for evaluation of emerging therapy resistance, opening new avenues for early adaptation of treatment regimens.

Original languageEnglish (US)
Pages (from-to)899-909
Number of pages11
JournalClinical Cancer Research
Issue number5
StatePublished - Mar 1 2023

ASJC Scopus subject areas

  • Medicine(all)


Dive into the research topics of 'Metastatic Colorectal Cancer Treatment Response Evaluation by Ultra-Deep Sequencing of Cell-Free DNA and Matched White Blood Cells'. Together they form a unique fingerprint.

Cite this