Satoshi Matsusaka 1 , Diana L Hanna 1 , Shu Cao 1 , Wu Zhang 1 , Dongyun Yang 1 , Yan Ning 1 , Yu Sunakawa 1 , Satoshi Okazaki 1 , Martin D Berger 1 , Yuji Miyamato 1 , Anish Parekh 1 , Sebastian Stintzing 2 , Fotios Loupakis 3 , Heinz-Josef Lenz 4 Show Affiliations »
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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. CONCLUSIONS: 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. ©2016 American Association for Cancer Research.
RCT Entities: Population
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Outcomes
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 SN Ps in genes involved in IL6 /STAT3 signaling can predict efficacy of bevacizumab -based chemotherapy in metastatic colorectal cancer (mCRC) patients . EXPERIMEN TAL DESIGN: Associations between potentially functional IL6 (rs2069837 and rs1800795 ) and STAT3 (rs744166 and rs4796793 ) SN Ps 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 DN A 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 thos e 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. CONCLUSIONS: IL6 rs2069837 genotype is a clinically relevant prognos tic factor in mCRC patients treated with first-line bevacizumab -based chemotherapy. Clin Cancer Res; 22(13); 3218-26. ©2016 AACR. ©2016 American Association for Cancer Research.
Entities: CellLine
Chemical
Disease
Gene
Mutation
Species
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Year: 2016
PMID： 26839145 PMCID： PMC4930688 DOI： 10.1158/1078-0432.CCR-15-2422
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531