Mitsukuni Suenaga1, Sebastian Stintzing2, Shu Cao3, Wu Zhang4, Dongyun Yang3, Yan Ning4, Satoshi Okazaki4, Martin D Berger4, Yuji Miyamoto4, Marta Schirripa4, Shivani Soni4, Afsaneh Barzi4, Volker Heinemann2, Heinz-Josef Lenz4. 1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. Electronic address: m.suenaga1972@gmail.com. 2. Department of Medicine III, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany. 3. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA. 4. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
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 receivingbevacizumab 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.
RCT Entities:
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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