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. 2022 Sep:172:22-30.
doi: 10.1016/j.ejca.2022.05.016. Epub 2022 Jun 21.

Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials

Jingyuan Wang  1 , Yi Xiao  2 , Fotios Loupakis  3 , Sebastian Stintzing  4 , Yan Yang  2 , Hiroyuki Arai  5 , Francesca Battaglin  5 , Natsuko Kawanishi  5 , Priya Jayachandran  5 , Shivani Soni  5 , Wu Zhang  5 , Christoph Mancao  6 , Chiara Cremolini  7 , Tianshu Liu  8 , Volker Heinemann  9 , Alfredo Falcone  7 , Lin Shen  10 , Joshua Millstein  2 , Heinz-Josef Lenz  11
Affiliations

Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials

Jingyuan Wang et al. Eur J Cancer. 2022 Sep.

Abstract

Background: The activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGAS-STING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer.

Methods: Genomic DNA from blood samples of patients enrolled in FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215) was genotyped using the OncoArray-500K bead chip panel. Seven selected single nucleotide polymorphisms in 3 genes (cGAS, STING and interferon B1 (IFNB1)) were analysed for the association with overall survival and progression-free survival.

Results: In the cetuximab cohort, patients with STING rs1131769 any T allele showed significantly shorter overall survival (36.3 versus 56.1 months) than carriers of C/C in both univariate [hazard ratio (HR) = 2.08; 95% confidence interval (CI): 1.06-4.07; P = 0.03] and multivariate (HR = 2.98; 95% CI: 1.35-6.6; P = 0.0085) analyses; patients carrying IFNB1 rs1051922 G/A and A/A genotype showed a significantly shorter progression-free survival than carriers of G/G allele in both univariate (G/A versus G/G, 10.2 versus 14.1 months, HR = 1.84; 95% CI 1.23-2.76; A/A versus G/G, 10.7 versus 14.1 months, HR = 2.19; 95% CI 0.97-4.96; P = 0.0077) and multivariate analyses (G/A versus G/G, HR = 2; 95% CI 1.22-3.3; A/A versus G/G, HR = 2.19, 95% CI 0.92-5.26, P = 0.02). These associations were not observed in the bevacizumab arm of FIRE-3 or TRIBE.

Conclusion: These results suggest for the first time that germline polymorphisms in STING and IFNB1 genes may predict the outcomes of cetuximab-based treatment in patients with metastatic colorectal cancer.

Keywords: Biomarker; Cetuximab; Colorectal cancer; STING.

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Conflict of interest statement

Conflict of interest statement H.-J.L. reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. S.S. reports receiving honoraria for talks and advisory board role: AMGEN, Bayer, BMS, Pierre-Fabre, Merck KGaA; MSD, Leo-Pharma, Lilly, Sanofi, Servier, Roche, Takeda, Taiho. A.F reports receiving honoraria as consultant/advisory board for Amgen, Bayer, Bristol, Daiichi Sankyo, Incyte, Lilly, Merck, MSD, Pierre-Fabre, Roche, Servier. All remaining authors have declared no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
The potential relationship between the cGAS-STING pathway and the efficacy of cetuximab. (a) The STING pathway recognises cytoplasmic DNA through cGAS and promotes the release of type I interferon. (b) STING activation enhances cetuximab-mediated NK cell activation and DC maturation, thereby enhancing the efficacy of cetuximab. cGAS, cyclic GMP-AMP synthase; DC, dendritic cell; NK, natural killer; STING, stimulator of interferon gene.
Fig. 2.
Fig. 2.
Consort diagram. SNP, single nucleotide polymorphism.
Fig. 3.
Fig. 3.
The association of STING rs1131768 with OS (a) and IFNB1 rs1051922 (b) with PFS in the cetuximab/bevacizumab cohorts of FIRE-3 and TRIBE. OS, overall survival; PFS, progression-free survival; STING, stimulator of interferon gene.
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