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

Suenaga, Mitsukuni; Stintzing, Sebastian; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Okazaki, Satoshi; Berger, Martin Dave; Miyamoto, Yuji; Schirripa, Marta; Soni, Shivani; Barzi, Afsaneh; Heinemann, Volker; Lenz, Heinz-Josef (2019). Role of CCL5 and CCR5 gene polymorphisms in epidermal growth factor receptor signalling blockade in metastatic colorectal cancer: analysis of the FIRE-3 trial. European journal of cancer, 107, pp. 100-114. Elsevier 10.1016/j.ejca.2018.11.019

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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.

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