| Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy |
Seung-been Lee1
, Ji-Won Kim2
, Hong-Geun Kim1, Sung-Hyun Hwang3, Kui-Jin Kim3, Ju Hyun Lee2,4, Jeongmin Seo2, Minsu Kang2, Eun Hee Jung2, Koung Jin Suh2, Se Hyun Kim2, Jin Won Kim2, Yu Jung Kim2, Jee Hyun Kim2, Nak-Jung Kwon1
, Keun-Wook Lee2
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1Macrogen, Inc., Seoul, Korea
2Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
3Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea
4Department of Statistics, Hankuk University of Foreign Studies, Yongin, Korea
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Received: January 4, 2024; Accepted: April 26, 2024. Published online: April 29, 2024.
*Seung-been Lee and Ji-Won Kim contributed equally to this work. |
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| ABSTRACT |
Purpose
This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy.
Materials and Methods
We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data.
Results
Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival.
Conclusion
While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer’s clonal evolution. Additionally, baseline-ctDNA’s VAF values were prognostic after treatment. |
| Key words:
Circulating tumor DNA, Colorectal neoplasms, Anti-cancer therapy, Clonal evolution |
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