Article | Published:

Molecular Diagnostics

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

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

Abstract

Background

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.

Methods

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”.

Results

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).

Conclusion

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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Acknowledgements

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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Author notes

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

Affiliations

  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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The authors declare no competing interests.

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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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https://doi.org/10.1038/s41416-018-0360-y