Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA; Gastroenterology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA; Medical Oncology 1 Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.
Clin Colorectal Cancer. 2018 Jun;17(2):e395-e414. doi: 10.1016/j.clcc.2018.02.010. Epub 2018 Feb 27.
The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib.
We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing.
CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026).
Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy.
C-C 基序趋化因子配体 5/C-C 基序趋化因子受体 5（CCL5/CCR5）通路已被证明可诱导内皮祖细胞迁移，从而增加血管内皮生长因子 A 的表达。我们假设 CCL5/CCR5 通路中的遗传多态性可预测接受regorafenib 治疗的转移性结直肠癌（mCRC）患者的疗效和毒性。
我们分析了来自接受regorafenib 治疗的 2 个不同患者队列的 229 个肿瘤样本中的基因组 DNA：一个来自 79 名日本患者的评估队列和一个来自 150 名意大利患者的验证队列。通过基于 PCR 的直接测序分析 CCL5/CCR5 通路相关基因的单核苷酸多态性。
CCL4 rs1634517 和 CCL3 rs1130371 与评估队列的无进展生存期相关（风险比 [HR] 1.54，P=0.043；HR 1.48，P=0.064），以及验证队列的无进展生存期（HR 1.74，P<0.001；HR 1.66，P=0.002）和总生存期（HR 1.65，P=0.004；HR 1.65，P=0.004）。CCL5 单核苷酸多态性的等位基因频率在评估和验证队列之间存在差异（rs2280789 中的 G/G 变体，21.5%比 1.3%，P<0.001；rs3817655 中的 T/T 变体，22.8%比 2.7%，P<0.001）。在评估队列中，与任何 A 等位基因相比，rs2280789 中的 G/G 变体的患者发生 3 级以上手足皮肤反应的发生率更高（53%比 27%，P=0.078），与 rs3817655 中的 T/T 变体相比也是如此（56%比 26%，P=0.026）。
CCL5/CCR5 通路中的遗传变异可能作为预后标志物，并可预测接受regorafenib 治疗的 mCRC 患者发生严重手足皮肤反应。
