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Molecular Diagnostics

Circulating inflammation signature predicts overall survival and relapse-free survival in metastatic colorectal cancer

British Journal of Cancervolume 120pages340345 (2019) | Download Citation



Metastatic colorectal cancer (mCRC) is a highly heterogeneous disease from a clinical, molecular, and immunological perspective. Current predictive models rely primarily in tissue based genetic analysis, which not always correlate with inflammatory response. Here we evaluated the role of a circulating inflammatory signature as a prognostic marker in mCRC.


Two hundred eleven newly diagnosed patients with mCRC were enrolled in the study. One hundred twenty-one patients had unresectable metastases, whereas ninety patients had potentially resectable liver metastases at presentation. Analysis of miR-21, IL-6, and IL-8 in the plasma of peripheral blood was performed at baseline. Patients with high circulating levels of ≥2 of the three inflammation markers (miR-21, IL-6, and IL-8) were considered to have the “Inflammation phenotype-positive CISIG”.


Positive CISIG was found in 39/90 (43%) and 50/121 (45%) patients in the resectable and unresectable cohort, respectively. In the resectable population the median relapse-free survival was 18.4 compared to 31.4 months (p = 0.001 HR 2.09, 95% CI 1.2–3.67) for positive vs. negative CISIG. In contrast, the individual components were not significant. In the same population the median overall survival was 46.2 compared to 66.0 months (p = 0.0003, HR 2.57, 95% CI 1.26–5.27) for positive vs. negative CISIG, but not significant for the individual components. In the unresectable population, the median overall survival was 13.5 compared to 25.0 months (p = 0.0008, HR 2.49, 95% CI 1.46–4.22) for positive vs. negative CISIG. IL-6 was independently prognostic with overall survival of 16.2 compared to 27.0 months (p = 0.004, HR 1.96, 95% CI 1.24–3.11) for high vs. low IL-6, but not the other components. Using a Cox regression model, we demonstrated that CISIG is an independent predictive marker of survival in patients with unresectable disease (HR 1.8, 95% CI 1.2, 2.8, p < 0.01).


In two different cohorts, we demonstrated that CISIG is a strong prognostic factor of relapse-free and overall survival of patients with mCRC. Based on these data, analysis of circulating inflammatory signaling can be complimentary to traditional molecular testing.

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Work in Dr. Calin’s laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NIH/NCI grant 1 R01 CA182905-01, a U54 grant—UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Ladies Leukemia League grant, a CLL Moonshot Flagship project, a SINF 2017 grant, and the Estate of C. G. Johnson, Jr. Work in Dr. Kopetz’s laboratory is supported by NIH grants R01 CA184843, R01 CA172670, R01 CA187238, and a CRC Moonshot project.

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  1. These authors contributed equally: Andreas Varkaris, Anastasia Katsiampoura


  1. Department of Hematology Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    • Andreas Varkaris
  2. Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Anastasia Katsiampoura
    • , Neeraj Shah
    • , Michael Lam
    • , Rosa Lizeth Frias
    • , David Menter
    • , Michael Overman
    •  & Scott Kopetz
  3. St. Elizabeth’s Medical Center, Boston, MA, USA

    • Anastasia Katsiampoura
  4. Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Jennifer S. Davis
  5. Department of Experimental Therapeutics, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Cristina Ivan
    • , Masayoshi Shimizu
    •  & George Calin
  6. Department of Biostatistics, Division of Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Jeffrey Morris
  7. Department of Thoracic/Head and Neck Medical Oncology - Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Hai Tran
  8. Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • John Heymach
  9. Hepato-Pancreato-Biliary Section, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Yun Shin Chun
    •  & Jean-Nicolas Vauthey


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Competing interests

The authors declare no competing interests.


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

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Correspondence to Scott Kopetz.

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