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Genetics and Genomics

Dynamic changes in longitudinal circulating tumour DNA profile during metastatic colorectal cancer treatment

British Journal of Cancer volume 127, pages 898–907 (2022)Cite this article

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Abstract

Background

Circulating tumour DNA (ctDNA) has been spotlighted as an attractive biomarker because of its easy accessibility and real-time representation of tumour genetic profile. However, the clinical utility of longitudinal ctDNA monitoring has not been clearly defined.

Methods

Serial blood samples were obtained from metastatic colorectal cancer patients undergoing first-line chemotherapy. ctDNA was sequenced using a targeted next-generation sequencing platform which included 106 genes. Changes in ctDNA profile and treatment outcome were comprehensively analysed.

Results

A total of 272 samples from 62 patients were analysed. In all, 90.3% of patients had detectable ctDNA mutation before treatment. ctDNA clearance after chemotherapy was associated with longer progression-free survival which was independent of radiological response (adjusted hazard ratio 0.22, 95% confidence interval 0.10–0.46). Longitudinal monitoring was able to detect ctDNA progression which preceded radiological progressive disease (PD) in 58.1% (median 3.3 months). Diverse resistant mutations (34.9%) and gene amplification (7.0%) at the time of PD were discovered. For 16.3% of the PD patients, the newly identified mutations could be potential candidates of targeted therapy or clinical trial.

Conclusion

ctDNA profile provided a more accurate landscape of tumour and dynamic changes compared to radiological evaluation. Longitudinal ctDNA monitoring may improve personalised treatment decision-making.

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Fig. 1: Pre-treatment genomic alterations from all 62 patients.
Fig. 2: Treatment response evaluation by ctDNA mutations.
Fig. 3: Treatment course of the 51 patients who were followed up till the end of the study.
Fig. 4: Dynamic changes of tumour burden represented by ctDNA variants.

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Data availability

All data generated or analysed during this study are included in this article and the supplementary information files.

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Acknowledgements

We thank all the patients and their caregivers for participating in this study.

Funding

This study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI18C2282).

Author information

Author notes

  1. These authors contributed equally: Sheehyun Kim, Yoojoo Lim.

Authors and Affiliations

  1. Department of Genomic Medicine, Seoul National University Hospital, Seoul, Korea

    Sheehyun Kim

  2. IMBdx, Inc., Seoul, Korea

    Yoojoo Lim, Jun-Kyu Kang, Hwang-Phill Kim, Hanseong Roh, Su Yeon Kim & Tae-You Kim

  3. Department of Chemistry, Yonsei University, Seoul, Korea

    Dongin Lee & Duhee Bang

  4. Department of Surgery, Seoul National University Hospital, Seoul, Korea

    Seung-Yong Jeong & Kyu Joo Park

  5. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

    Sae-Won Han & Tae-You Kim

  6. Cancer Research Institute, Seoul National University, Seoul, Korea

    Sae-Won Han & Tae-You Kim

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Contributions

S-WH and T-YK conceived the study and have oversight as principal investigators and designed the protocol. SK conducted the data management, clinical analysis and wrote the first draft of the manuscript. YL interpreted the work and wrote the first draft of the manuscript. J-KK, H-PK, HR and SK conducted the bioinformatic analysis. S-YJ and KJP contributed to data acquisition. All authors critically reviewed the drafts and approved the final manuscript.

Corresponding authors

Correspondence to Sae-Won Han or Tae-You Kim.

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Competing interests

YL, J-KK, H-PK, HR and SYK are employees of IMBdx. DB has owned stock of IMBdx and Celemics. DB and S-WH have received research fund from IMBdx. T-YK is the founder of IMBdx. The remaining authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted under the approval of the Institutional Review Board (IRB) of SNUH (IRB number: 1805-049-944) and in accordance with the Declaration of Helsinki in biomedical research involving human subjects. All participants provided written informed consent prior to any study procedures.

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Kim, S., Lim, Y., Kang, JK. et al. Dynamic changes in longitudinal circulating tumour DNA profile during metastatic colorectal cancer treatment. Br J Cancer 127, 898–907 (2022). https://doi.org/10.1038/s41416-022-01837-z

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