KEY TAKEAWAYS
- The present study conducted a prospective phase III clinical trial (CAIRO5) to assess whether ctDNA-based treatment response monitoring could be performed in a tumor tissue-independent manner.
- The use of ctDNA has the potential to guide therapy selection and monitor treatment response in patients with metastatic cancer.
- Longitudinal analyses of ctDNA were more predictive of overall survival than standard-of-care radiological response evaluation.
- Combining cfDNA and patient-matched WBC genomic DNA analysis provides a tissue biopsy-independent approach for accurately calling ctDNA mutations.
- The study identified ctDNA mutations related to primary or acquired resistance to panitumumab in 42% of patients.
The potential of circulating tumor DNA (ctDNA) to direct therapy selection and track treatment response in patients with metastatic cancer is being investigated. Tumor-specific mutations can be identified in cell-free DNA (cfDNA), typically complicated by germline and clonal hematopoiesis modifications. By integrating ultra-deep targeted sequencing studies of cfDNA with patient-matched white blood cell (WBC) generated DNA, the current work investigated the feasibility of tumor tissue-independent ctDNA-based treatment response monitoring.
Ultra-deep targeted sequencing liquid biopsy assay was used to evaluate 183 cfDNA samples, 49 WBC samples, and 28 tissue samples from 52 patients with metastatic colorectal cancer who were included in the prospective phase III CAIRO5 clinical trial.
False-positive results from germline or hematopoietic variations could have been missed in 40% of patients if cfDNA and WBC analysis had not been used. Sequencing of tumor tissue from the same yielded no new insights. Comparisons of ctDNA over time were more indicative of overall survival than the gold standard of radiological response assessment. In 42 percent of patients, researchers found ctDNA alterations associated with intrinsic or acquired resistance to panitumumab.
The combination of circulating free DNA (cfDNA) and patient-matched white blood cell (WBC) genomic DNA analysis enables accurate calling of ctDNA mutations for therapy response monitoring without requiring access to tumor tissue. This method streamlines sample collection by eliminating the need for a tissue biopsy. In addition, it makes it possible to use ctDNA testing in liquid biopsies to detect and assess the development of drug resistance more quickly, allowing for more timely adjustments to be made to treatment plans.
Source: https://pubmed.ncbi.nlm.nih.gov/36534496/
Clinical trial: https://clinicaltrials.gov/ct2/show/NCT02162563/
van ’t Erve, I., Medina, J.E., Leal, A., Papp, E., Phallen, J., Adleff, V., Chiao, E.Jiayuee., Arun, A.S., Bolhuis, K., Simmons, J.K., Karandikar, A., Valkenburg, K.C., Sausen, M., Angiuoli, S.V., Scharpf, R.B., Punt, C.J.A., Meijer, G.A., Velculescu, V.E. and Fijneman, R.J.A. (2022). Metastatic colorectal cancer treatment response evaluation by ultra-deep sequencing of cell-free DNA and matched white blood cells. Clinical Cancer Research. doi:https://doi.org/10.1158/1078-0432.ccr-22-2538.
