title: Prognostic Impact of IL6 Genetic Variants in Patients with Metastatic Colorectal Cancer Treated with Bevacizumab-Based Chemotherapy.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  IL6 rs2069837 genotype is a clinically relevant prognostic factor in mCRC patients treated with first-line bevacizumab-based chemotherapy. Clin Cancer Res; 22(13); 3218-26. ©2016 AACR.
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Hanna
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Shu
authors.initials: S
authors.lastname: Cao
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Berger
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyamato
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Anish
authors.initials: A
authors.lastname: Parekh
authors.affiliation: Department of Hematology and Oncology, University of Munich, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. lenz@med.usc.edu.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D000074322:Antineoplastic Agents, Immunological; C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000068258:Bevacizumab; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
references.citation: Eur Heart J. 2001 Dec;22(24):2243-52
references.pmid: 11728144
references.citation: Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18321-6
references.pmid: 25489084
references.citation: Cancer Res. 2015 Jan 15;75(2):306-15
references.pmid: 25492861
references.citation: Mol Cancer Res. 2015 Nov;13(11):1502-8
references.pmid: 26184038
references.citation: Hum Genet. 2013 Mar;132(3):301-12
references.pmid: 23180271
references.citation: Oncogene. 2002 Mar 27;21(13):2000-8
references.pmid: 11960372
references.citation: Oncogene. 2003 Mar 13;22(10):1517-27
references.pmid: 12629515
references.citation: Exp Ther Med. 2012 Oct;4(4):633-639
references.pmid: 23170117
references.citation: Clin Exp Immunol. 2014 Jul;177(1):253-60
references.pmid: 24580121
references.citation: BMC Cancer. 2014 May 10;14:330
references.pmid: 24885636
references.citation: Br J Haematol. 2001 Oct;115(1):3-12
references.pmid: 11722403
references.citation: Carcinogenesis. 2015 Apr;36(4):459-68
references.pmid: 25750173
references.citation: Mutat Res. 2009 Jan 15;660(1-2):12-21
references.pmid: 18992263
references.citation: Lancet Oncol. 2014 Sep;15(10):1065-75
references.pmid: 25088940
references.citation: Int J Clin Exp Med. 2015 Apr 15;8(4):6252-6
references.pmid: 26131234
references.citation: Mol Biol Rep. 2012 Aug;39(8):8457-63
references.pmid: 22714907
references.citation: Anticancer Res. 2014 Jul;34(7):3481-7
references.pmid: 24982357
references.citation: J Biol Chem. 2015 Sep 4;290(36):22212-24
references.pmid: 26209639
references.citation: Gastroenterology. 2015 Mar;148(3):579-89
references.pmid: 25461668
references.citation: Proc Natl Acad Sci U S A. 1990 Apr;87(8):3092-6
references.pmid: 1691500
references.citation: J Clin Pathol. 2010 Oct;63(10):873-8
references.pmid: 20876317
references.citation: Mol Neurobiol. 1997 Dec;15(3):307-39
references.pmid: 9457704
references.citation: Br J Cancer. 2013 Jul 9;109(1):138-46
references.pmid: 23756862
references.citation: Cytokine. 2013 Apr;62(1):64-9
references.pmid: 23490413
references.citation: Cancer Causes Control. 2007 Dec;18(10):1095-105
references.pmid: 17694420
references.citation: BMC Cancer. 2011 Aug 05;11:339
references.pmid: 21819567
references.citation: Carcinogenesis. 2008 Jun;29(6):1202-6
references.pmid: 18448485
references.citation: Blood. 2001 Nov 1;98(9):2720-5
references.pmid: 11675343
references.citation: World J Gastroenterol. 2006 Aug 21;12(31):5037-43
references.pmid: 16937502
references.citation: Oncogene. 2005 Aug 25;24(36):5552-60
references.pmid: 16007214
references.citation: Pharmacogenomics J. 2015 Feb;15(1):69-76
references.pmid: 25069475
references.citation: J Immunol. 2010 Jun 15;184(12):7219-28
references.pmid: 20483735
references.citation: Hypertension. 2012 Jan;59(1):136-44
references.pmid: 22068875
references.citation: Crit Rev Oncol Hematol. 2014 Jan;89(1):129-39
references.pmid: 24029605
references.citation: Cancer Res. 2015 Aug 1;75(15):3098-107
references.pmid: 26081809
references.citation: Cancer Res. 2011 Dec 1;71(23 ):7226-37
references.pmid: 21900397
references.citation: Br J Cancer. 2014 Jan 21;110(2):469-78
references.pmid: 24346288
references.citation: Nat Rev Immunol. 2014 May;14(5):329-42
references.pmid: 24751956
references.citation: Mol Genet Genomics. 2015 Dec;290(6):2261-70
references.pmid: 26063618
references.citation: Nat Immunol. 2015 May;16(5):448-57
references.pmid: 25898198
references.citation: Cancer Res. 2003 Jul 1;63(13):3560-6
references.pmid: 12839942
references.citation: Ann Surg Oncol. 2015 Dec;22 Suppl 3:S1548-55
references.pmid: 25773877
references.citation: J Clin Oncol. 2009 Jun 20;27(18):3020-6
references.pmid: 19470921
references.citation: Int J Mol Med. 2014 Sep;34(3):651-60
references.pmid: 24993179
references.citation: N Engl J Med. 2014 Oct 23;371(17):1609-18
references.pmid: 25337750
references.citation: Oncogene. 2014 Feb 13;33(7):851-61
references.pmid: 23416975
references.citation: Int J Biol Sci. 2012;8(9):1248-53
references.pmid: 23136553
references.citation: Clin Cancer Res. 2003 Jun;9(6):2173-6
references.pmid: 12796383
references.citation: Cancer Biomark. 2008;4(2):83-91
references.pmid: 18503159