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Association of VEGFA and CCL4L2 polymorphisms with hand-foot skin reaction and survival of regorafenib in Japanese patients with colorectal cancer

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Abstract

Purpose

Treatment with regorafenib, which inhibits vascular endothelial growth factor (VEGF) receptor, frequently results in hand-foot skin reaction (HFSR), requiring treatment discontinuation or dose reduction. In our prospective study of regorafenib on patients with metastatic colorectal cancer, 17% of patients developed grade 3 HFSR. Herein, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe HFSR.

Methods

To identify associated polymorphisms, exploratory whole-exome sequencing focusing on factors related to VEGF-mediated signaling pathways was first performed in seven patients each, with grade 3 HFSR and without HFSR. The identified HFSR-associated polymorphisms were analyzed in all the 40 patients.

Results

The genotype frequency of rs3025009 G/A or A/A in the gene encoding VEGF-A (VEGFA) in patients with ≥ grade 2 HFSR was significantly higher than in other patients (P = 0.0257, Pc = 0.0771 [Bonferroni correction]). The frequency of C–C motif of chemokine ligand 4-like 2 (CCL4L2) rs3744596 A/T or T/T in patients with grade 3 HFSR was significantly lower than in others (P = 0.00894, Pc = 0.0268). The combination of the risk genotypes VEGFA rs3025009 G/A or A/A and CCL4L2 rs3744596 A/A was significantly associated with a higher incidence of grade 3 (P = 0.000614, Pc = 0.00246) and a longer median progression-free survival (P = 0.0234) than others.

Conclusions

These VEGF-related polymorphisms were found to be associated with HFSR and the survival benefits of regorafenib treatment.

Trial registration number and date

UMIN000013939, registered on May 12, 2014, when 6 months after the approval by the Institutional Review Board of Showa University.

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Availability of data and material

All data generated or analyzed during this study are included in this published article and electronic supplementary material.

Code availability

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Funding

This study was supported in part by a JSPS Grant-in-Aid for Scientific Research (C) Grant Number 19K07204 to K.F.

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Authors and Affiliations

  1. Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Koutaro Ono, Remi Murase, Natsumi Matsumoto & Ken-ichi Fujita

  2. Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Yutaro Kubota

  3. Division of Medical Oncology, Showa University Northern Yokohama Hospital, 35-1 Chigasakichuo, Tsuzuki-ku, Yokohama, 224-8503, Japan

    Hiroo Ishida

Authors
  1. Koutaro Ono
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  4. Yutaro Kubota
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  5. Hiroo Ishida
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  6. Ken-ichi Fujita
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Contributions

K.O., R.M., and K.F. wrote the manuscript; K.O., R.M., and K.F. designed the study; K.O., R.M., N.M., Y.K., H.I., and K.F. performed the research; and K.O., R.M., N.M., Y.K., H.I., and K.F. analyzed the data.

Corresponding author

Correspondence to Ken-ichi Fujita.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Showa University. The study was registered with the University Hospital Medical Information Network-Clinical Trials Registry for Japan on May 12, 2014 (UMIN000013939), when 6 months after the approval by the Institutional Review Board of Showa University.

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All patients gave written informed consent for the use of their peripheral blood samples and medical information for research purposes.

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All patients gave written informed consent regarding publishing their data.

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Ono, K., Murase, R., Matsumoto, N. et al. Association of VEGFA and CCL4L2 polymorphisms with hand-foot skin reaction and survival of regorafenib in Japanese patients with colorectal cancer. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04649-5

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