Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients.

Suenaga, Mitsukuni; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Okazaki, Satoshi; Berger, Martin Dave; Miyamoto, Yuji; Schirripa, Marta; Soni, Shivani; Barzi, Afsaneh; Yamaguchi, Toshiharu; Lenz, Heinz-Josef (2019). Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients. International journal of cancer, 144(10), pp. 2567-2577. Wiley-Blackwell 10.1002/ijc.31968

[img] Text
Suenaga_et_al-2018-International_Journal_of_Cancer.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (577kB) | Request a copy

Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24-0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26-0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

28 Feb 2019 15:27

Last Modified:

23 Oct 2019 15:47

Publisher DOI:

10.1002/ijc.31968

PubMed ID:

30411783

Uncontrolled Keywords:

CCL5 CCR5 VEGF-A bevacizumab metastatic colorectal cancer

BORIS DOI:

10.7892/boris.124078

URI:

https://boris.unibe.ch/id/eprint/124078

Actions (login required)

Edit item Edit item
Provide Feedback