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Serum IL-8 level as a candidate prognostic marker of response to anti-angiogenic therapy for metastatic colorectal cancer

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Abstract

Purpose

Liver metastasis (LM) is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC). Here, we investigated the prognostic utility of several serum factors in mCRC patients with or without LM who were treated with anti-angiogenic agents in first-line (FL) or salvage-line (SL) settings.

Methods

A combined cohort of 125 patients was analyzed in this single institute pooled analysis: FL cohort receiving bevacizumab (n = 71) and SL cohort receiving regorafenib (n = 54). Blood samples were obtained at baseline (BL) and during treatment, and serum factors were measured by ELISA. Overall survival (OS) was analyzed using Kaplan–Meier curves, the log-rank test, and Cox proportional hazard regression methods.

Results

In univariate analysis of the combined cohort, right-sided CRC, primary unresected tumor, wild-type KRAS, LM, ≥ 2 metastatic sites, and SL were associated with shorter OS; in multivariable analysis, LM and SL remained significant. Serum angiopoietin-2 (Ang-2) levels ≥ 2190.3 pg/ml and interleukin (IL)-8 levels ≥ 15.1 pg/ml at BL were significantly associated with LM. Using these cut-off values, patients with higher Ang-2 or IL-8 levels at BL had shorter OS than those with lower BL levels (Ang-2: hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.47–4.51, P = 0.001; IL-8: HR 4.31, 95%CI 2.11–8.79, P < 0.001). High serum IL-8 level remained a significant predictor of shorter OS in multivariable analysis (HR 3.24, 95%CI 1.47–7.16, P = 0.004).

Conclusion

Circulating IL-8 and Ang-2 levels are associated with LM in mCRC patients. IL-8 may be a prognostic marker of response to anti-angiogenic therapy, regardless of the treatment timing.

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References

  1. Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, el-Khoueiry AB, Watson P, Benson AB III, Mulkerin DL, Mayer RJ, Blanke C (2017) Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 317:2392–2401

    Article  CAS  Google Scholar 

  2. Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Giessen-Jung C, Moehler M, Jagenburg A, Kirchner T, Jung A, Heinemann V, FIRE-3 investigators (2016) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomized open-label phase 3 trial. Lancet Oncol 17:1426–1434

    Article  CAS  Google Scholar 

  3. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD (2013) Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023–1034

    Article  CAS  Google Scholar 

  4. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303–312

    Article  CAS  Google Scholar 

  5. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372:1909–1919

    Article  Google Scholar 

  6. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11:753–762

    Article  Google Scholar 

  7. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520

    Article  CAS  Google Scholar 

  8. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18:1182–1191

    Article  CAS  Google Scholar 

  9. Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, Lieu C, Yan S, Tran HT, Ellis LM, Abbruzzese JL, Heymach JV (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453–459

    Article  CAS  Google Scholar 

  10. Hegde PS, Jubb AM, Chen D, Li NF, Meng YG, Bernaards C, Elliott R, Scherer SJ, Chen DS (2013) Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin Cancer Res 19:929–937

    Article  CAS  Google Scholar 

  11. Matsusaka S, Suenaga M, Mishima Y, Takagi K, Terui Y, Mizunuma N, Hatake K (2011) Circulating endothelial cells predict for response to bevacizumab-based chemotherapy in metastatic colorectal cancer. Cancer Chemother Pharmacol 68:763–768

    Article  CAS  Google Scholar 

  12. NCCN. Clinical practice guideline: Colon cancer. Ver. 1. 2020. Available from: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 24 Feb 2020.

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

    Article  Google Scholar 

  14. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH (1999) Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230:309–318

    Article  CAS  Google Scholar 

  15. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  CAS  Google Scholar 

  16. Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177

    Article  CAS  Google Scholar 

  17. Biel NM, Siemann DW (2016) Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference. Cancer Lett 380:525–533

    Article  CAS  Google Scholar 

  18. Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC, Weihrauch MR, Cremer B, Kashkar H, Odenthal M, Augustin HG, Schmiegel W, Hallek M, Hacker UT (2010) Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer 103:1407–1414

    Article  CAS  Google Scholar 

  19. Rossi D, Zlotnik A (2000) The biology of chemokines and their receptors. Annu Rev Immunol 18:217–242

    Article  CAS  Google Scholar 

  20. Brat DJ, Bellail AC, Van Meir EG (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-Oncology 7:12233

    Article  Google Scholar 

  21. Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI (1991) Structure and functional expression of a human interleukin-8 receptor. Science 253:1278–1280

    Article  CAS  Google Scholar 

  22. Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741

    Article  CAS  Google Scholar 

  23. Liu Y, Starr MD, Bulusu A, Pang H, Wong NS, Honeycutt W, Amara A, Hurwitz HI, Nixon AB (2013) Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab. Cancer Med 2:234–242

    Article  CAS  Google Scholar 

  24. Tiainen L, Hämäläinen M, Luukkaala T, Tanner M, Lahdenperä O, Vihinen P, Jukkola A, Karihtala P, Moilanen E, Kellokumpu-Lehtinen PL (2019) Low plasma IL-8 levels during chemotherapy are predictive of excellent long-term survival in metastatic breast cancer. Clin Breast Cancer 19:e522–e533

    Article  CAS  Google Scholar 

  25. Sanmamed MF, Carranza-Rua O, Alfaro C, Oñate C, Martín-Algarra S, Perez G, Landazuri SF, Gonzalez A, Gross S, Rodriguez I, Muñoz-Calleja C, Rodríguez-Ruiz M, Sangro B, López-Picazo JM, Rizzo M, Mazzolini G, Pascual JI, Andueza MP, Perez-Gracia JL, Melero I (2014) Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin Cancer Res 20:5697–5707

    Article  CAS  Google Scholar 

  26. Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, Oñate C, Perez G, Alfaro C, Martín-Algarra S, Andueza MP, Gurpide A, Morgado M, Wang J, Bacchiocchi A, Halaban R, Kluger H, Chen L, Sznol M, Melero I (2017) Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol 28:1988–1995

    Article  CAS  Google Scholar 

  27. Bilusic M, Heery CR, Collins JM, Donahue RN, Palena C, Madan RA, Karzai F, Marté JL, Strauss J, Gatti-Mays ME, Schlom J, Gulley JL (2019) Phase I trial of HuMax-IL8 (BMS-986253), an anti-IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer 7:240

    Article  Google Scholar 

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Acknowledgments

We thank Anne M. O’Rourke, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This work was partly supported by the JSPS KAKENHI grant numbers 15 K06860 to MS.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Mitsukuni Suenaga, Naomi Kawata, Takeru Wakatsuki & Kensei Yamaguchi

  2. Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Mitsukuni Suenaga

  3. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Tetsuo Mashima, Naomi Kawata & Hiroyuki Seimiya

  4. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135–8550, Japan

    Shingo Dan

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  1. Mitsukuni Suenaga
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Contributions

Conceptualization: MS, TM, SD, and HS. Data curation: MS, TM, and TW. Formal analysis: MS and NK. Funding acquisition: MS. Investigation: MS, TM, and NK. Methodology: MS, TM, and HS. Project administration: MS, TM, and HS. Resources: MS and TM. Software: NK and SD. Supervision: HS and KY. Writing–original draft: MS. Writing–review and editing: all authors.

Corresponding author

Correspondence to Mitsukuni Suenaga.

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The study was approved by the Institutional Review Board at the Cancer Institute Hospital. Informed consent was obtained from all participants in the study.

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Suenaga, M., Mashima, T., Kawata, N. et al. Serum IL-8 level as a candidate prognostic marker of response to anti-angiogenic therapy for metastatic colorectal cancer. Int J Colorectal Dis 36, 131–139 (2021). https://doi.org/10.1007/s00384-020-03748-y

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