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Clinical Trial
. 2019 Jan:107:100-114.
doi: 10.1016/j.ejca.2018.11.019. Epub 2018 Dec 14.

Role of CCL5 and CCR5 gene polymorphisms in epidermal growth factor receptor signalling blockade in metastatic colorectal cancer: analysis of the FIRE-3 trial

Mitsukuni Suenaga  1 , Sebastian Stintzing  2 , Shu Cao  3 , Wu Zhang  4 , Dongyun Yang  3 , Yan Ning  4 , Satoshi Okazaki  4 , Martin D Berger  4 , Yuji Miyamoto  4 , Marta Schirripa  4 , Shivani Soni  4 , Afsaneh Barzi  4 , Volker Heinemann  2 , Heinz-Josef Lenz  4
Affiliations
Clinical Trial

Role of CCL5 and CCR5 gene polymorphisms in epidermal growth factor receptor signalling blockade in metastatic colorectal cancer: analysis of the FIRE-3 trial

Mitsukuni Suenaga et al. Eur J Cancer. 2019 Jan.

Abstract

Background: Epidermal growth factor receptor signalling blockade increases CCL5 expression that regulates either the anti-tumour immune response or tumour progression. We investigated the potential role of CCL5/CCR5 axis in cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients.

Patients and methods: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC from the FIRE-3 trial: an evaluation cohort of 244 patients receiving cetuximab plus FOLFIRI and a control cohort of 247 patients receiving bevacizumab plus FOLFIRI. Single-nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analysed by polymerase chain reaction-based direct sequencing.

Results: Patients in the evaluation cohort with any CCL5 rs2280789G allele had shorter overall survival (OS) compared with those with the A/A variant (hazard ratio 1.56, P = 0.024). Patients carrying any CCR5 rs1799988T allele had a trend toward lower response rate than those with the C/C variant (68 vs. 81%, P = 0.078). In the analysis based on primary tumour location (left-sided [L]: right-sided [R]), remarkable differences in outcomes were observed between patients with L-CCR5 SNPs C/C variant (L-C/C), L-any T, R-T/T and R-any C as follows: median OS, 38.5, 30.6, 27.1 and 15.8 months, P < 0.001; response rate, 91, 66, 92 and 48%, P < 0.001. Median OS for CCL5 SNPs including L-A/A, L-any G, R-A/A and R-any G groups were 38.3, 21.7, 21.9 and 18.3 months, P < 0.001. The findings were not significant in the control cohort.

Conclusion: Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC patients receiving cetuximab-based treatment depending on tumour location.

Keywords: CCL5; CCR5; Cetuximab; Metastatic colorectal cancer; Primary tumour location.

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Conflict of interest statement

Disclosure

The authors have no conflicts of interest to declare in this work.

Figures

Fig. 1.
Fig. 1.
Models combining tumor location with CCL5 rs2280789 (Model 1) and CCR5 rs1799988 (Model 2).
Fig. 2.
Fig. 2.
A novel classification composed of CCL5 rs2280789 and CCR5 rs1799988 based on tumor location regarding clinical outcome in the evaluation cohort, which was finally divided into three categories: Group I, Group II and Group III.
Fig. 3.
Fig. 3.
Progression-free survival (PFS) and overall survival (OS) according to the novel classification consisting of CCL5/CCR5 SNPs and tumor location in the evaluation cohort: (A) PFS in KRAS wild-type; (B) OS in KRAS wild-type; (C) OS in RAS wild-type. (D) OS by the novel classification and stratified by treatment arms in the FIRE-3 trial. CET, cetuximab; BEV, bevacizumab.
Fig. A. 1.
Fig. A. 1.
Role of CCL5/CCR5 axis in EGFR signaling.
See this image and copyright information in PMC

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