Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Department of Medicine III, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Eur J Cancer. 2019 Jan;107:100-114. doi: 10.1016/j.ejca.2018.11.019. Epub 2018 Dec 14.
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.
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.
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.
Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC patients receiving cetuximab-based treatment depending on tumour location.
表皮生长因子受体信号通路阻断会增加 CCL5 的表达，从而调节抗肿瘤免疫反应或肿瘤进展。我们研究了 CCL5/CCR5 轴在基于西妥昔单抗的转移性结直肠癌（mCRC）患者治疗中的潜在作用。
从 FIRE-3 试验的两个不同队列中提取 491 例 KRAS 野生型 mCRC 样本的基因组 DNA：评估队列中 244 例接受西妥昔单抗联合 FOLFIRI 治疗，对照组 247 例接受贝伐珠单抗联合 FOLFIRI 治疗。采用聚合酶链反应直接测序法分析 CCL5 和 CCR5 基因的单核苷酸多态性（SNP）。
评估队列中任何 CCL5 rs2280789G 等位基因的患者总生存期（OS）短于 A/A 变异型（风险比 1.56，P=0.024）。携带任何 CCR5 rs1799988T 等位基因的患者与 C/C 变异型（68%比 81%）相比，缓解率呈下降趋势（P=0.078）。基于原发肿瘤位置（左：右）的分析中，L-CCR5 SNPs C/C 变异型（L-C/C）、L-任何 T、R-T/T 和 R-任何 C 的患者之间的结局存在显著差异：中位 OS 分别为 38.5、30.6、27.1 和 15.8 个月，P<0.001；缓解率分别为 91%、66%、92%和 48%，P<0.001。CCL5 SNPs 的中位 OS 包括 L-A/A、L-任何 G、R-A/A 和 R-任何 G 组为 38.3、21.7、21.9 和 18.3 个月，P<0.001。在对照组中，这些发现没有统计学意义。
CCL5 和 CCR5 SNP 的遗传变异可能根据肿瘤位置预测接受西妥昔单抗治疗的 mCRC 患者的结局。
