Original Study
Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand–Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib

https://doi.org/10.1016/j.clcc.2018.02.010Get rights and content

Abstract

Background

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.

Patients and Methods

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.

Results

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).

Conclusion

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.

Introduction

Regorafenib, an oral multikinase inhibitor, confers the benefit of longer survival to patients with refractory metastatic colorectal cancer (mCRC).1, 2 Tumor mutation status, plasma DNA concentration, and plasma protein concentration, including its target protein kinases, have been examined by a retrospective exploration of the CORRECT study to identify predictive markers of this agent, while real-time circulating DNA analysis has shown potential prognostic markers for clinical outcomes.3 However, no validated predictive markers of efficacy and/or toxicity have been identified. Hand–foot skin reaction (HFSR) is a well-known toxicity of regorafenib that obliges patients to interrupt treatment, and an ethnic difference in the frequency of HFSR has been reported between Japanese and non-Japanese patients in the CORRECT study.4

A recent study that investigated whether serum cytokine levels are associated with clinical outcomes in mCRC patients receiving regorafenib reported that baseline serum C-C motif chemokine ligand 5 (CCL5) levels and decrease of serum vascular endothelial growth factor (VEGF) A levels after start of treatment predicted the efficacy of regorafenib in refractory mCRC. Furthermore, low CCL5 levels were associated with the onset of HFSR.5 C-C motif chemokine receptor 5 (CCR5) is a receptor of CCL5, and CCL5 can promote endothelial progenitor cell (EPC) migration in a CCR5-dependent manner. The CCL5/CCR5 pathway is involved in VEGF-A production via EPC migration.6 CCL5 is characterized as late expression after T-cell activation, and it localizes with tumor-infiltrating leukocytes.7 It is also known as regulated on activation, normal T-cell expressed and secreted (RANTES). Krüppel-like transcription factor (KLF) 13 is a transcription factor that regulates RANTES expression in T lymphocytes; it is known as RANTES factor of late activated T lymphocytes 1 (RFLAT-1).8 Other CCR5 ligands—C-C motif chemokine ligand-3 (CCL3) and -4 (CCL4)—also participate in EPC migration via binding to CCR5; however, a recent in vitro study showed that CCL5 is the most potent chemoattractant of EPCs.9 The CCL5/CCR5 signaling pathway positively activates protein kinase Cδ (PKCδ), c-Src, and hypoxia-inducible factor 1α (HIF1A) in activating VEGF-A expression (Figure 1).6

We therefore tested whether genetic polymorphisms in the CCL5/CCR5 pathway are associated with clinical outcomes and toxicity, particularly HFSR, in patients with refractory mCRC treated with regorafenib.

Section snippets

Study Design and Patients

This study investigated 2 independent cohorts composed of patients with refractory, histologically confirmed mCRC: an evaluation cohort of 79 patients treated with regorafenib at the Cancer Institute Hospital in Japan between May 2013 and December 2015, and a validation cohort of 150 patients treated with regorafenib at Azienda Ospedaliero–Universitaria Pisana (Pisa, Italy) and Istituto Oncologico Veneto (Padua, Italy) between August 2010 and November 2015. All patients met the eligibility

Patient and Tumor Baseline Characteristics

In the evaluation cohort, the median follow-up time was 15.3 months, and median PFS and OS were 2.0 and 8.7 months, respectively. In the validation cohort, the median follow-up time was 36.4 months, and median PFS and OS were 2.1 and 6.0 months, respectively. The baseline characteristics of the evaluation and validation are summarized in Supplemental Table 2 in the online version. The associations between baseline characteristics and clinical outcomes are summarized in Supplemental Tables 3 and

Discussion

Our data provide the first evidence that SNPs of genes in the CCL5/CCR5 signaling pathway are associated with not only clinical outcomes of but also HFSR caused by regorafenib in mCRC patients.

The CCL5/CCR5 axis is involved in the immune microenvironment and is exploited for network-enabling tumor progression.10 CCL5 is expressed and localized within CD8+ T cells and CXCL10 in tumor cells and macrophages within the invasive margin. CCL3 and CCL4, macrophage inflammatory protein 1 proteins, are

Disclosure

The authors have stated that they have no conflict of interest.

Acknowledgments

Supported in part by the National Cancer Institute (P30CA014089), the Gloria Borges Wunderglo Project, the Dhont Family Foundation, the Dave Butler Research Fund, and the Call to Cure Research Fund. M.S. is the recipient of Takashi Tsuruo Memorial Fund and JSPS KAKENHI grant 15K06860. M.D.B. received a grant from the Swiss Cancer League (BIL KLS-3334-02-2014) and the Werner and Hedy Berger-Janser Foundation for cancer research. Y.M. received a grant from Japan Society for the Promotion of

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