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Genetics and Genomics

CEA, CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC)

Abstract

Background

We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics.

Methods

Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle.

Results

A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p < 0.0001). By dichotomising by the median value, cfDNA, ctDNA and CA19-9 were associated with PD, PFS and OS in multivariate analysis. A circulating scoring system (CSS) combining CEA kinetics and baseline CA19-9 and cfDNA values classified patients based on high (n = 58) and low risk (n = 113) of PD and was independently associated with PD (ORa = 4.6, p < 0.0001), PFS (HRa = 2.07, p < 0.0001) and OS (HRa = 2.55, p < 0.0001).

Conclusions

CEA kinetics alone or combined with baseline CA19-9 and cfDNA are clinically relevant for predicting outcomes in mCRC.

Trial registration number

NCT01212510.

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Fig. 1: Flow diagram illustrating all the biomarkers of the Coca Colon cohort study.
Fig. 2: Result of biomarkers for prediction of progression at 12-weeks evaluation.
Fig. 3: Survival according to the circulating markers.
Fig. 4: Forest plot of hazard ratios for patient’s survival.

References

  1. 1.

    Phelip, J. M., Tougeron, D., Léonard, D., Benhaim, L., Desolneux, G., Dupré, A. et al. Metastatic colorectal cancer (mCRC): French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR). Dig. Liver Dis. 51, 1357–1363 (2019).

    Article  Google Scholar 

  2. 2.

    Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 27, 1386–1422 (2016).

    Article  Google Scholar 

  3. 3.

    Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    CAS  Article  Google Scholar 

  4. 4.

    Hanash, S. M., Baik, C. S. & Kallioniemi, O. Emerging molecular biomarkers−blood-based strategies to detect and monitor cancer. Nat. Rev. Clin. Oncol. 8, 142–150 (2011).

    Article  Google Scholar 

  5. 5.

    Corcoran, R. B. & Chabner, B. A. Application of cell-free DNA analysis to cancer treatment. N. Engl. J. Med. 379, 1754–1765 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Heitzer, E., Haque, I. S., Roberts, C. E. S. & Speicher, M. R. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat. Rev. Genet. 20, 71–88 (2019).

    CAS  Article  Google Scholar 

  7. 7.

    Filella, X., Molina, R., Grau, J. J., Piqué, J. M., Garcia-Valdecasas, J. C., Astudillo, E. et al. Prognostic value of CA 19.9 levels in colorectal cancer. Ann. Surg. 216, 55–59 (1992).

    CAS  Article  Google Scholar 

  8. 8.

    Hanke, B., Riedel, C., Lampert, S., Happich, K., Martus, P., Parsch, H. et al. CEA and CA 19-9 measurement as a monitoring parameter in metastatic colorectal cancer (CRC) under palliative first-line chemotherapy with weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and folinic acid (FA). Ann. Oncol. 12, 221–226 (2001).

    CAS  Article  Google Scholar 

  9. 9.

    Duffy, M. J., van Dalen, A., Haglund, C., Hansson, L., Klapdor, R., Lamerz, R. et al. Clinical utility of biochemical markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines. Eur. J. Cancer 39, 718–727 (2003).

    CAS  Article  Google Scholar 

  10. 10.

    Iwanicki-Caron, I., Di Fiore, F., Roque, I., Astruc, E., Stetiu, M., Duclos, A. et al. Usefulness of the serum carcinoembryonic antigen kinetic for chemotherapy monitoring in patients with unresectable metastasis of colorectal cancer. J. Clin. Oncol. 26, 3681–3686 (2008).

    Article  Google Scholar 

  11. 11.

    Petrioli, R., Licchetta, A., Roviello, G., Pascucci, A., Francini, E., Bargagli, G. et al. CEA and CA19.9 as early predictors of progression in advanced/metastatic colorectal cancer patients receiving oxaliplatin-based chemotherapy and bevacizumab. Cancer Invest. 30, 65–71 (2012).

    CAS  Article  Google Scholar 

  12. 12.

    Michl, M., Stintzing, S., Fischer von Weikersthal, L., Decker, T., Kiani, A., Vehling-Kaiser, U. et al. CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial). Ann. Oncol. 27, 1565–1572 (2016).

    CAS  Article  Google Scholar 

  13. 13.

    Jia, J., Zhang, P., Gou, M., Yang, F., Qian, N., Dai, G. The role of serum CEA and CA19-9 in efficacy evaluations and progression-free survival predictions for patients treated with cetuximab combined with FOLFOX4 or FOLFIRI as a first-line treatment for advanced colorectal cancer. Dis Markers 2019, 6812045 (2019).

  14. 14.

    Cohen, S. J., Punt, C. J. A., Iannotti, N., Saidman, B. H., Sabbath, K. D., Gabrail, N. Y. et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 3213–3221 (2008).

    Article  Google Scholar 

  15. 15.

    Tol, J., Koopman, M., Miller, M. C., Tibbe, A., Cats, A., Creemers, G. J. M. et al. Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents. Ann. Oncol. 21, 1006–1012 (2010).

    CAS  Article  Google Scholar 

  16. 16.

    Spindler, K. L. G., Pallisgaard, N., Vogelius, I. & Jakobsen, A. Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin. Cancer Res. 18, 1177–1185 (2012).

    CAS  Article  Google Scholar 

  17. 17.

    Spindler, K. L. G., Appelt, A. L., Pallisgaard, N., Andersen, R. F., Brandslund, I. & Jakobsen, A. Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer. Int. J. Cancer 135, 2984–2991 (2014).

    CAS  Article  Google Scholar 

  18. 18.

    Tabernero, J., Lenz, H. J., Siena, S., Sobrero, A., Falcone, A., Ychou, M. et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 16, 937–948 (2015).

    CAS  Article  Google Scholar 

  19. 19.

    El Messaoudi, S., Mouliere, F., Du Manoir, S., Bascoul-Mollevi, C., Gillet, B., Nouaille, M. et al. Circulating DNA as a strong multi-marker prognostic tool for metastatic colorectal cancer patient management care. Clin. Cancer Res. 22, 3067–3077 (2016).

    CAS  Article  Google Scholar 

  20. 20.

    Hamfjord, J., Guren, T. K., Dajani, O., Johansen, J. S., Glimelius, B., Sorbye, H. et al. Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy. Ann. Oncol. 30, 1088–1095 (2019).

    CAS  Article  Google Scholar 

  21. 21.

    Tie, J., Kinde, I., Wang, Y., Wong, H. L., Roebert, J., Christie, M. et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann. Oncol. 26, 1715–1722 (2015).

    CAS  Article  Google Scholar 

  22. 22.

    Garlan, F., Laurent-Puig, P., Sefrioui, D., Siauve, N., Didelot, A., Sarafan-Vasseur, N. et al. Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL Study). Clin. Cancer Res. 23, 5416–5425 (2017).

    CAS  Article  Google Scholar 

  23. 23.

    Parikh, A. R., Mojtahed, A., Schneider, J. L., Kanter, K., Van Seventer, E. E., Fetter, I. J. et al. Serial ctDNA monitoring to predict response to systemic therapy in metastatic gastrointestinal cancers. Clin. Cancer Res. 26, 1877–1885 (2020).

    CAS  Article  Google Scholar 

  24. 24.

    Souza, E., Silva, V., Chinen, L. T. D., Abdallah, E. A., Damascena, A., Paludo, J., Chojniak, R. et al. Early detection of poor outcome in patients with metastatic colorectal cancer: tumor kinetics evaluated by circulating tumor cells. Onco Targets Ther. 9, 7503–7513 (2016).

    Article  Google Scholar 

  25. 25.

    Ma, B., King, A. D., Leung, L., Wang, K., Poon, A., Ho, W. M. et al. Identifying an early indicator of drug efficacy in patients with metastatic colorectal cancer-a prospective evaluation of circulating tumor cells, 18F-fluorodeoxyglucose positron-emission tomography and the RECIST criteria. Ann. Oncol. 28, 1576–1581 (2017).

    CAS  Article  Google Scholar 

  26. 26.

    Seeberg, L. T., Brunborg, C., Waage, A., Hugenschmidt, H., Renolen, A., Stav, I. et al. Survival impact of primary tumor lymph node status and circulating tumor cells in patients with colorectal liver metastases. Ann. Surg. Oncol. 24, 2113–2121 (2017).

    Article  Google Scholar 

  27. 27.

    Aggarwal, C., Meropol, N. J., Punt, C. J., Iannotti, N., Saidman, B. H., Sabbath, K. D. et al. Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Ann. Oncol. 24, 420–428 (2013).

    CAS  Article  Google Scholar 

  28. 28.

    Sefrioui, D., Sarafan-Vasseur, N., Beaussire, L., Baretti, M., Gangloff, A., Blanchard, F. et al. Clinical value of chip-based digital-PCR platform for the detection of circulating DNA in metastatic colorectal cancer. Dig. Liver Dis. 47, 884–890 (2015).

    CAS  Article  Google Scholar 

  29. 29.

    Sefrioui, D., Mauger, F., Leclere, L., Beaussire, L., Di Fiore, F., Deleuze, J. F. et al. Comparison of the quantification of KRAS mutations by digital PCR and E-ice-COLD-PCR in circulating-cell-free DNA from metastatic colorectal cancer patients. Clin. Chim. Acta 465, 1–4 (2016).

    Article  Google Scholar 

  30. 30.

    Iwanicki-Caron, I., Basile, P., Toure, E., Antonietti, M., Lecleire, S., Di Fiore, A. et al. Usefulness of circulating tumor cell detection in pancreatic adenocarcinoma diagnosis. Am. J. Gastroenterol. 108, 152–155 (2013).

    Article  Google Scholar 

  31. 31.

    Hansen, B. B. The prognostic analogue of the propensity score. Biometrika 95, 481–488 (2008).

    Article  Google Scholar 

  32. 32.

    Thierry, A. R., El Messaoudi, S., Mollevi, C., Raoul, J. L., Guimbaud, R., Pezet, D. et al. Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment. Ann. Oncol. 28, 2149–2159 (2017).

    CAS  Article  Google Scholar 

  33. 33.

    Thierry, A. R., Pastor, B., Jiang, Z. Q., Katsiampoura, A. D., Parseghian, C., Loree, J. M. et al. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer. Clin. Cancer Res. 23, 4578–4591 (2017).

    CAS  Article  Google Scholar 

  34. 34.

    Farace, F., Massard, C., Vimond, N., Drusch, F., Jacques, N., Billiot, F. et al. A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas. Br. J. Cancer 105, 847–853 (2011).

    CAS  Article  Google Scholar 

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Acknowledgements

The authors thank the patients and their families, investigators and staff from all the participating sites. The authors also thank American Journal Expert (www.aje.com) for English language editing.

Author information

Affiliations

Authors

Contributions

Conception and design: P.M. and F.D.F. Administrative support: P.M. and F.D.F. Provision of study materials or patients: D.S., A.G., M.H., C.E., A.-L.B., A.P., P.G., K.B.-L., M.-P.G., P.M., and F.D.F. Collection and assembly of data: D.S., L.B., A.G., E.T., C.B., A.P., F.Z., F.B., C.T., F.C., J.-C.S., T.F., J.B., N.S.-V., P.M., and F.D.F. Data analysis and interpretation: D.S., L.B., A.G., E.T., C.B., A.P., F.Z., F.B., C.T., J.B., N.S.-V., P.M., and F.D.F. Manuscript writing, final approval of manuscript and accountable for all aspects of the work: all authors.

Corresponding author

Correspondence to David Sefrioui.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the institutional review board (Northwest I), and all patients provided written informed consent (NCT01212510). The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

N/A.

Data availability

Raw data are available from the corresponding author upon request.

Competing interests

The authors declare no competing interests.

Funding

This study was supported in part by the Grant “Pierre DURAND & Marie-Thérèse CHEVALIER (2013)” and the pharmaceutical industrial partners Roche, Merck and Amgen France. A grant was also provided by the Charles Nicolle Foundation and the association “des tulipes contre le cancer-Lions Club de France” for financing and acquisition of the digital PCR system used for the detection of circulating tumour DNA. The Northwest Data Center (CTD-CNO) that managed the data was supported by grants from the French National League Against Cancer (LNC) and the French National Cancer Institute (INCa).

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Sefrioui, D., Beaussire, L., Gillibert, A. et al. CEA, CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC). Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01431-9

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