Prognostic Impact of IL6 Genetic Variants in Patients with Metastatic Colorectal Cancer Treated with Bevacizumab-Based Chemotherapy

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2016 Feb 4

PMID 26839145

Citations 17

Authors

Satoshi Matsusaka

Diana L Hanna

Shu Cao

Wu Zhang

Dongyun Yang

Yan Ning

Yu Sunakawa

Satoshi Okazaki

Martin D Berger

Yuji Miyamato

Anish Parekh

Sebastian Stintzing

Fotios Loupakis

Heinz-Josef Lenz

Affiliations

Soon will be listed here.

Abstract

Purpose: The IL6/STAT3 axis promotes inflammation, angiogenesis, and cancer. The effect of genetic variants within this pathway on benefit from antiangiogenic cancer therapy is unknown. We tested whether SNPs in genes involved in IL6/STAT3 signaling can predict efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer (mCRC) patients.

Experimental Design: Associations between potentially functional IL6 (rs2069837 and rs1800795) and STAT3 (rs744166 and rs4796793) SNPs and clinical outcomes [progression-free survival (PFS), overall survival, and tumor response rate] were evaluated in mCRC patients receiving first-line FOLFIRI plus bevacizumab in two randomized phase III trials: TRIBE (n = 223, training cohort) and FIRE-3 (n = 288, validation cohort). Patients receiving FOLFIRI plus cetuximab in FIRE-3 (n = 264) served as a control cohort. The interaction between genotype and primary tumor location with clinical outcomes was examined. Genomic DNA isolated from whole blood or tumor tissue was analyzed by PCR-based direct sequencing.

Results: Patients with an IL6 rs2069837 G allele treated with FOLFIRI plus bevacizumab had an inferior PFS than those with the A/A genotype in TRIBE [9.4 vs. 11.1 months; HR = 1.53; 95% confidence interval (CI), 1.12-2.10; P = 0.004] and FIRE-3 (8.8 vs. 10.9 months; HR = 1.40; 95% CI, 1.06-1.85; P = 0.015). These associations were confirmed in multivariable analyses and were not seen in the control cohort. In subgroup analysis, the effect of IL6 rs2069837 on PFS was present only in patients with left-sided cancers, but the test for interaction was not significant.

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References

Humphries S, Luong L, Ogg M, Hawe E, Miller G . The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J. 2001; 22(24):2243-52. DOI: 10.1053/euhj.2001.2678. View

Dejea C, Wick E, Hechenbleikner E, White J, Welch J, Rossetti B . Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A. 2014; 111(51):18321-6. PMC: 4280621. DOI: 10.1073/pnas.1406199111. View

Wang J, Cao Z, Zhang X, Nakamura M, Sun M, Hartman J . Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development. Cancer Res. 2014; 75(2):306-15. DOI: 10.1158/0008-5472.CAN-14-2819. View

Patel S, Gooderham N . IL6 Mediates Immune and Colorectal Cancer Cell Cross-talk via miR-21 and miR-29b. Mol Cancer Res. 2015; 13(11):1502-8. DOI: 10.1158/1541-7786.MCR-15-0147. View

Shi T, Zhu M, He J, Wang M, Li Q, Zhou X . Polymorphisms of the Interleukin 6 gene contribute to cervical cancer susceptibility in Eastern Chinese women. Hum Genet. 2012; 132(3):301-12. DOI: 10.1007/s00439-012-1245-4. View

Niu G, Wright K, Huang M, Song L, Haura E, Turkson J . Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002; 21(13):2000-8. DOI: 10.1038/sj.onc.1205260. View

Wei L, Kuo M, Chen C, Chou C, Lai K, Lee C . Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene. 2003; 22(10):1517-27. DOI: 10.1038/sj.onc.1206226. View

Jin C, Wang A, Chen J, Liu X, Wang G . Relationship between expression and prognostic ability of PTEN, STAT3 and VEGF-C in colorectal cancer. Exp Ther Med. 2012; 4(4):633-639. PMC: 3501400. DOI: 10.3892/etm.2012.651. View

Reitter E, Ay C, Kaider A, Pirker R, Zielinski C, Zlabinger G . Interleukin levels and their potential association with venous thromboembolism and survival in cancer patients. Clin Exp Immunol. 2014; 177(1):253-60. PMC: 4089174. DOI: 10.1111/cei.12308. View

10.

Xu H, Lai W, Zhang Y, Liu L, Luo X, Zeng Y . Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner. BMC Cancer. 2014; 14:330. PMC: 4024187. DOI: 10.1186/1471-2407-14-330. View

11.

Kerr R, Stirling D, Ludlam C . Interleukin 6 and haemostasis. Br J Haematol. 2001; 115(1):3-12. DOI: 10.1046/j.1365-2141.2001.03061.x. View

12.

Liu H, Ren G, Wang T, Chen Y, Gong C, Bai Y . Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition. Carcinogenesis. 2015; 36(4):459-68. PMC: 4392608. DOI: 10.1093/carcin/bgv017. View

13.

Slattery M, Wolff R, Curtin K, Fitzpatrick F, Herrick J, Potter J . Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res. 2008; 660(1-2):12-21. PMC: 2907671. DOI: 10.1016/j.mrfmmm.2008.10.001. View

14.

Heinemann V, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran S . FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15(10):1065-75. DOI: 10.1016/S1470-2045(14)70330-4. View

15.

Zheng X, Han C, Shan R, Zhang H, Zheng Z, Liu Y . Association of interleukin-6 polymorphisms with susceptibility to hepatocellular carcinoma. Int J Clin Exp Med. 2015; 8(4):6252-6. PMC: 4483998. View

16.

Yu Y, Wang W, Zhai S, Dang S, Sun M . IL6 gene polymorphisms and susceptibility to colorectal cancer: a meta-analysis and review. Mol Biol Rep. 2012; 39(8):8457-63. DOI: 10.1007/s11033-012-1699-4. View

17.

Kim Y, Kim S, Kim C, Kim I, Cho M, Kim N . Association of serum and intratumoral cytokine profiles with tumor stage and neutrophil lymphocyte ratio in colorectal cancer. Anticancer Res. 2014; 34(7):3481-7. View

18.

Mar A, Chu C, Lee H, Chien C, Cheng J, Yang S . Interleukin-1 Receptor Type 2 Acts with c-Fos to Enhance the Expression of Interleukin-6 and Vascular Endothelial Growth Factor A in Colon Cancer Cells and Induce Angiogenesis. J Biol Chem. 2015; 290(36):22212-24. PMC: 4571972. DOI: 10.1074/jbc.M115.644823. View

19.

Tseng-Rogenski S, Hamaya Y, Choi D, Carethers J . Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells. Gastroenterology. 2014; 148(3):579-89. PMC: 4339542. DOI: 10.1053/j.gastro.2014.11.027. View

20.

Motro B, Itin A, Sachs L, Keshet E . Pattern of interleukin 6 gene expression in vivo suggests a role for this cytokine in angiogenesis. Proc Natl Acad Sci U S A. 1990; 87(8):3092-6. PMC: 53840. DOI: 10.1073/pnas.87.8.3092. View