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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

Subjects

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.

Data availability

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

References

  1. Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019;20:71–88.

    Article  CAS  Google Scholar 

  2. Alix-Panabieres C, Pantel K. Liquid biopsy: from discovery to clinical application. Cancer Discov. 2021;11:858–73.

    Article  CAS  Google Scholar 

  3. Corcoran RB, Chabner BA. Application of cell-free DNA analysis to cancer treatment. N. Engl J Med. 2018;379:1754–65.

    Article  CAS  Google Scholar 

  4. Cescon DW, Bratman SV, Chan SM, Siu LL. Circulating tumor DNA and liquid biopsy in oncology. Nat Cancer. 2020;1:276–90.

    Article  CAS  Google Scholar 

  5. Cheng ML, Pectasides E, Hanna GJ, Parsons HA, Choudhury AD, Oxnard GR. Circulating tumor DNA in advanced solid tumors: Clinical relevance and future directions. CA Cancer J Clin. 2021;71:176–90.

    Article  Google Scholar 

  6. Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol. 2018;36:1631–41.

    Article  CAS  Google Scholar 

  7. Scholer LV, Reinert T, Orntoft MW, Kassentoft CG, Arnadottir SS, Vang S, et al. Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer. Clin Cancer Res. 2017;23:5437–45.

    Article  CAS  Google Scholar 

  8. Tie J, Cohen JD, Wang Y, Li L, Christie M, Simons K, et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. Gut. 2019;68:663–71.

    Article  CAS  Google Scholar 

  9. Coombes RC, Page K, Salari R, Hastings RK, Armstrong A, Ahmed S, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res. 2019;25:4255–63.

    Article  CAS  Google Scholar 

  10. Strickler JH, Loree JM, Ahronian LG, Parikh AR, Niedzwiecki D, Pereira AAL, et al. Genomic landscape of cell-free DNA in patients with colorectal cancer. Cancer Discov. 2018;8:164–73.

    Article  CAS  Google Scholar 

  11. Cao H, Liu X, Chen Y, Yang P, Huang T, Song L, et al. Circulating tumor DNA is capable of monitoring the therapeutic response and resistance in advanced colorectal cancer patients undergoing combined target and chemotherapy. Front Oncol. 2020;10:466.

    Article  Google Scholar 

  12. Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21:827.

    Article  CAS  Google Scholar 

  13. Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20:430–5.

    Article  CAS  Google Scholar 

  14. Vidal J, Muinelo L, Dalmases A, Jones F, Edelstein D, Iglesias M, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol. 2017;28:1325–32.

    Article  CAS  Google Scholar 

  15. Grasselli J, Elez E, Caratu G, Matito J, Santos C, Macarulla T, et al. Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol. 2017;28:1294–301.

    Article  CAS  Google Scholar 

  16. Thierry AR, Pastor B, Jiang ZQ, Katsiampoura AD, Parseghian C, Loree JM, et al. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer. Clin Cancer Res. 2017;23:4578–91.

    Article  CAS  Google Scholar 

  17. Hsu HC, Lapke N, Wang CW, Lin PY, You JF, Yeh CY, et al. Targeted sequencing of circulating tumor DNA to monitor genetic variants and therapeutic response in metastatic colorectal cancer. Mol Cancer Ther. 2018;17:2238–47.

    Article  CAS  Google Scholar 

  18. Leighl NB, Page RD, Raymond VM, Daniel DB, Divers SG, Reckamp KL, et al. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer. Clin Cancer Res. 2019;25:4691–4700.

    Article  CAS  Google Scholar 

  19. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  Google Scholar 

  20. Meddeb R, Pisareva E, Thierry AR. Guidelines for the preanalytical conditions for analyzing circulating cell-free DNA. Clin Chem. 2019;65:623–33.

    Article  CAS  Google Scholar 

  21. Salvianti F, Gelmini S, Costanza F, Mancini I, Sonnati G, Simi L, et al. The pre-analytical phase of the liquid biopsy. N. Biotechnol. 2020;55:19–29.

    Article  CAS  Google Scholar 

  22. Volckmar AL, Sultmann H, Riediger A, Fioretos T, Schirmacher P, Endris V, et al. A field guide for cancer diagnostics using cell-free DNA: from principles to practice and clinical applications. Genes Chromosomes Cancer. 2018;57:123–39.

    Article  CAS  Google Scholar 

  23. Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv arXiv. 2013;1303:3997v2.

    Google Scholar 

  24. Pereira B, Chen CT, Goyal L, Walmsley C, Pinto CJ, Baiev I, et al. Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer. Nat Commun. 2021;12:3199.

    Article  CAS  Google Scholar 

  25. Parikh AR, Mojtahed A, Schneider JL, Kanter K, Van Seventer EE, Fetter IJ, et al. Serial ctDNA monitoring to predict response to systemic therapy in metastatic gastrointestinal cancers. Clin Cancer Res. 2020;26:1877–85.

    Article  CAS  Google Scholar 

  26. Oikkonen J, Zhang K, Salminen L, Schulman I, Lavikka K, Andersson N, et al. Prospective longitudinal ctDNA workflow reveals clinically actionable alterations in ovarian cancer. JCO Precis Oncol. 2019;3:1–12.

  27. Jacob S, Davis AA, Gerratana L, Velimirovic M, Shah AN, Wehbe F, et al. The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer. Clin Cancer Res. 2021;27:1361–70.

    Article  CAS  Google Scholar 

  28. Lim Y, Kim S, Kang JK, Kim HP, Jang H, Han H, et al. Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR. Sci Rep. 2021;11:16333.

    Article  CAS  Google Scholar 

  29. Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010;16:790–9.

    Article  CAS  Google Scholar 

  30. Mao C, Wu XY, Yang ZY, Threapleton DE, Yuan JQ, Yu YY, et al. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep. 2015;5:8065.

    Article  CAS  Google Scholar 

  31. Scherer F. Capturing tumor heterogeneity and clonal evolution by circulating tumor DNA profiling. In: Schaffner F, Merlin F, & von Bubnoff N, editors. Tumor liquid biopsies. Cham: Springer International Publishing; 2020. 213-30.

  32. Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov. 2016;6:147–53.

    Article  CAS  Google Scholar 

  33. Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol. 2015;26:1715–22.

    Article  CAS  Google Scholar 

  34. Jones RP, Pugh SA, Graham J, Primrose JN, Barriuso J. Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis. Eur J Cancer. 2021;144:368–81.

    Article  CAS  Google Scholar 

  35. Kang JK, Heo S, Kim HP, Song SH, Yun H, Han SW, et al. Liquid biopsy-based tumor profiling for metastatic colorectal cancer patients with ultra-deep targeted sequencing. PLoS ONE. 2020;15:e0232754.

    Article  CAS  Google Scholar 

  36. Kato S, Schwaederle MC, Fanta PT, Okamura R, Leichman L, Lippman SM, et al. Genomic assessment of blood-derived circulating tumor DNA in patients with colorectal cancers: correlation with tissue sequencing, therapeutic response, and survival. JCO Precis Oncol. 2019;3:1–16.

  37. Bando H, Nakamura Y, Taniguchi H, Shiozawa M, Yasui H, Esaki T, et al. Impact of a metastatic site on circulating tumor DNA (ctDNA) analysis in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2021;39:3554.

    Article  Google Scholar 

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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.

Ethics declarations

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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