Interleukin 8 Promoter Polymorphism Predicts the Initial Response to Bevacizumab Treatment for Exudative Age-Related Macular Degeneration

Hautamäki, Asta; Kivioja, Jarno; Vavuli, Satu; Kakko, Sakari; Savolainen, Eeva‐Riitta; Savolainen, Markku J.; Liinamaa, Johanna; Seitsonen, Sanna; Onkamo, Päivi; Järvelä, Irma; Immonen, Ilkka

doi:10.1097/iae.0b013e318285cf92

Cited by 31 publications

(31 citation statements)

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“…This apparent discrepancy is not surprising, since PFS is widely accepted as a surrogate endpoint in first-line treatment, due to dilution of effects on OS by post-progression treatments. Similar observations on this IL-8 SNP were recently shown in patients with breast cancer treated with bevacizumab-based chemotherapy [27, 28] and in exudative macular degeneration after bevacizumab treatment [29]. Since the “A” allele of the IL-8 SNP is associated with increased IL-8 production [11], a plausible biological explanation of our results is that patients carrying the A allele might benefit less from bevacizumab because of higher IL-8 serum levels.…”

Section: Discussionsupporting

confidence: 83%

IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients

et al. 2017

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BackgroundPredictive biomarkers of efficacy and toxicity of bevacizumab have not yet been validated. This study assessed the influence of IL-8, eNOS and VEGF-A polymorphisms in RAS mutated metastatic colorectal cancer patients receiving bevacizumab-based chemotherapy.Methods120 patients treated with first-line combination FOLFOX6 plus bevacizumab were included. A historical cohort of 112 RAS mutated colorectal cancer patients treated with FOLFOX6 alone served as control group. The following SNPs were analyzed: IL-8 c.-251T>A; eNOS c.-786T>C and c.-894G>T; VEGF-A c.936C>T, c.958T>C, c.1154A>G and c.2578C>A. Correlation of SNPs, baseline IL-8 serum levels and bevacizumab-efficacy was done.ResultsIn the bevacizumab group, carriers of the IL-8 alleles c.-251TA+AA showed a shorter PFS (P=0.002) and OS (P=0.03) compared to TT alleles. Patients with pre-treatment IL-8 < 18.25 pg/ml showed significantly longer median PFS and OS (PFS: 10.9 vs 7.6 months, P=0.005; OS: 30.7 vs 18.2 months, P<0.001) compared to patients with IL-8 higher levels (>18,25 pg/ml). IL-8 c.-251TA+AA carriers had significantly higher IL-8 levels (P<0.0001). Multivariate analysis confirmed association of IL-8 polymorphism with PFS, and of IL-8 baseline levels with both PFS and OS. IL-8 SNP did not affect the outcome in the control group. The eNOS polymorphism c.-894G>T was found associated with higher severe toxicity (P=0.0002) in patients carrying the c.-894TT genotype.ConclusionsAlthough our data need prospective validation, IL-8 and eNOS SNPs may be have a role as predictive biomarkers for bevacizumab efficacy and toxicity.

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Section: Discussionsupporting

confidence: 83%

IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients

et al. 2017

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“…In patients with renal cell carcinoma, the development of acquired resistance to sunitinib was associated with an increased secretion of IL-8 by the tumor cells and the subsequent co-administration of sunitinib and IL-8 neutralizing antibodies was able to restore sensitivity [27]. Gyanchandani [31].…”

Section: Discussionmentioning

confidence: 98%

Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis

et al. 2015

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“…30 Interleukin 8 is a proinflammatory cytokine related to ocular angiogenesis and to increased vascular permeability. 31 In an investigation of biomarkers related to cancer resistance to bevacizumab, Hayashi et al 32 detected higher serum concentrations of interleukin 8, angiopoietin 2, and VEGF-C in nonresponders compared with responders to bevacizumab.…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Cabral

Lima

Mello

et al. 2018

Ophthalmology Retina

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Purpose To evaluate the expression of 19 angiogenic biomarkers in the aqueous humor before and after intravitreal bevacizumab injection (IVB) in eyes with neovascular age-related macular degeneration (AMD). Design Prospective, noncomparative, interventional case series. Participants Twenty-three eyes of 23 treatment-naïve patients with choroidal neovascularization (CNV) secondary to neovascular AMD. Methods Eyes were diagnosed with CNV secondary to neovascular AMD and were treated with 3 monthly IVBs. Aqueous humor samples were obtained by anterior chamber paracentesis at baseline and immediately before each intravitreal bevacizumab injection. Main Outcome Measures Aqueous humor levels of 19 angiogenic biomarkers (angiopoietin 2, bone morphogenetic protein 9 [BMP-9], epidermal growth factor [EGF], endoglin, endothelin 1, fibroblast growth factor [FGF]-1 and FGF-2, follistatin, granulocyte colony-stimulating factor [GCSF], heparin-binding EGF-like growth factor [HB-EGF], hepatocyte growth factor [HGF], interleukin 8, leptin, placental growth factor [PLGF], vascular endothelial growth factor [VEGF]-A, VEGF-C, VEGF-D, and tissue inhibitor of metalloproteinases [TIMP]-1 and TIMP-2) were measured. Best-corrected visual acuity (BCVA), spectral-domain OCT parameters, and intraocular pressure also were evaluated. Results Baseline aqueous VEGF-A expression was elevated in all study eyes before treatment initiation. A statistically significant decrease of VEGF-A was observed at the 1- and 2-month follow-ups. A statistically significant increased concentration was observed in 7 biomarkers: VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8. The other 11 study biomarker levels (VEGF-D, BMP-9, EGF, endoglin, FGF-1, FGF-2, GCSF, leptin, PLGF, TIMP-1, and TIMP-2) did not show any significant difference during follow-up. The BCVA statistically improved significantly at 2 months. Spectral-domain OCT parameters improved significantly at all follow-ups. Mean intraocular pressure values were not statistically different during the study period. Conclusions Despite a decrease in VEGF-A, the aqueous levels of VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8 increased significantly after intravitreal injection of bevacizumab. These upregulated angiogenic biomarkers may represent new therapeutic targets in exudative AMD.

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Interleukin 8 Promoter Polymorphism Predicts the Initial Response to Bevacizumab Treatment for Exudative Age-Related Macular Degeneration

Abstract: The A allele and the homozygous AA genotype of interleukin 8 -251A/T were associated with anatomical nonresponse to bevacizumab treatment.

Cited by 31 publications

References 54 publications

IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients

IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients

Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis

Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

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