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

Abstract

Background The IL-6/STAT3 axis promotes inflammation, angiogenesis, and cancer. The effect of genetic variants within this pathway on benefit from anti-angiogenic cancer therapy is unknown. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in IL-6/STAT3 signaling can predict efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer (mCRC) patients Methods Associations between potentially functional IL-6 (rs2069837, rs1800795) and STAT3 (rs744166, rs4796793) SNPs and clinical outcomes (progression-free survival, 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 IL-6 rs2069837 G allele treated with FOLFIRI plus bevacizumab had an inferior PFS than those with the A/A genotype in TRIBE (9.4 v. 11.1 months, HR=1.53, 95% CI 1.12, 2.10, P=0.004) and FIRE-3 (8.8 v. 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 IL-6 rs2069837 on PFS was present only in patients with left-sided cancers, but the test for interaction was not significant. Conclusion IL-6 rs2069837 genotype is a clinically relevant prognostic factor in mCRC patients treated with first-line bevacizumab-based chemotherapy.

Interleukin-6-174G>C gene promoter polymorphism and prognosis in patients with cancer

“…Table 1 shows the general characteristics of eligible studies. Fifteen studies were conducted on Caucasian [ 15 , 16 , 18 , 19 , 21 – 31 ], 1 were on American [ 32 ], and 1 was on Asian [ 33 ]. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), PCR-Sequencing, single-strand conformation polymorphism (SSCP), polymerase chain reaction-sequencing (PCR- sequencing), TaqMan and Sequenom were used.…”

Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes

“…In a multivariant analysis of two randomised phase III studies (CRYSTAL and FIRE-3), LCC and RCC were highly prognostic for PFS and OS even when patients with BRAF mutation were excluded [16]. In subgroup analysis from two randomised phase III studies (FIRE-3 and TRIBE), IL-6 genetic variants were identified as a prognostic factor for patients with mCRC treated with first-line bevacizumab-based chemotherapy, depending on primary tumour location [43].…”

Multi-disease associated risk locus inIL6represses the anti-inflammatory geneGPNMBthrough chromatin looping and recruiting MEF2-HDAC complex

“…Previous genetic association studies have reported a protective effect of the A allele in rs2069837 in late-onset Alzheimer's disease, cervical cancer, chronic hepatitis B virus infection, colorectal cancer, and hepatocellular carcinoma (11)(12)(13)(14)(15).…”

“…The Takayasu arteritis associated risk allele in this variant is associated with longevity, spastic tetraplegia, cerebral palsy, and antipsychotic-induced weight gain (7)(8)(9)(10). In contrast, the Takayasu arteritis risk allele in rs2069837 was shown to be protective against late-onset Alzheimer's disease, cervical cancer, chronic hepatitis B virus infection, colorectal cancer, and hepatocellular carcinoma (11)(12)(13)(14)(15).…”