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Updated: Mar 10, 2026
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Transient appearance of circulating tumor DNA associated with de novo treatment
Kikuya Kato1, Junji Uchida2, Yoji Kukita1
1Department of Molecular and Medical Genetics, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Abstract:
The limitation of circulating tumor DNA (ctDNA) is its inability to detect cancer cell subpopulations with few or no dying cells. Lung cancer patients subjected to the EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment were prospectively collected, and ctDNA levels represented by the activating and T790M mutations were measured. The first data set (21 patients) consisting of samples collected in the period from before initiation of EGFR-TKI to at least 2 weeks after initiation: the ctDNA dynamics generally exhibited a rapid decrease and/or a transient increase. In 4 patients, we detected a transient increase of ctDNA bearing activating mutations not identified in biopsy samples. ctDNA with the same genotypical pattern was identified in 7 out of the 39 patients of the second data set intended to include samples until the onset of disease progression. In 6 of the 7 patients, this unique ctDNA appeared in the early period after treatment initiation, and did not reappear even after disease progression or chemotherapy. In another patient, similar ctDNA appeared upon radiation therapy. The identification of ctDNA with a unique genotype indicates the presence of cancer cell subpopulations that normally contain few or no dying cells, but generate dead cells because of the treatment.
Insights
Circulating tumor DNA (ctDNA) can miss cancer subpopulations. This study shows unique ctDNA genotypes emerging during EGFR-TKI treatment indicate treatment-resistant cells, improving cancer detection.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Circulating tumor DNA (ctDNA) analysis is a powerful tool for cancer monitoring.
- A key limitation of ctDNA is its inability to detect cancer cell subpopulations with minimal cell death.
Purpose of the Study:
- To investigate the dynamics of ctDNA during EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer patients.
- To identify if unique ctDNA genotypes can reveal the presence of treatment-resistant cancer cell subpopulations.
Main Methods:
- Prospective collection of samples from lung cancer patients undergoing EGFR-TKI treatment.
- Measurement of ctDNA levels, focusing on activating and T790M mutations.
- Analysis of ctDNA dynamics and genotypical patterns in relation to treatment phases.
Main Results:
- In a subset of patients, a transient increase in ctDNA with previously unidentified activating mutations was observed early in EGFR-TKI treatment.
- A unique ctDNA genotype, not present in initial biopsies, was detected in several patients during or after treatment.
- This unique ctDNA signature persisted even after disease progression or subsequent therapies, suggesting a distinct subpopulation.
Conclusions:
- The emergence of ctDNA with unique genotypes during EGFR-TKI therapy signifies the presence of cancer cell subpopulations.
- These subpopulations may not be readily detected by standard ctDNA analysis due to low cell turnover.
- Treatment can induce cell death in these previously undetected subpopulations, making their ctDNA detectable.
