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Correlations between serum cetuximab and EGFR-related markers, and skin disorders in head and neck cancer patients

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Abstract

Purpose

Cetuximab inhibits epidermal growth factor receptor (EGFR) signaling in cancer and skin cells, thereby inducing anti-cancer effects and skin disorders. The present study aimed to evaluate the relationships between serum cetuximab and EGFR-related markers, and adverse effects in head and neck cancer patients.

Methods

Thirty-four head and neck cancer patients receiving weekly intravenous cetuximab were enrolled. Serum cetuximab levels were determined just before dosing. Blood samples for determination of serum EGFR-related markers including soluble epidermal growth factor receptor (sEGFR) and interleukin-6 (IL-6) were obtained. The severities of skin disorders, their medications, and hypomagnesemia treatment were also assessed.

Results

Serum levels of cetuximab and sEGFR were negatively and positively correlated with that of IL-6, respectively. The serum cetuximab level was twofold higher in the patients with a grade 2–3 skin rash than with a grade 0–1 rash. The serum cetuximab cutoff value related to severe skin rash was 71 μg/mL (sensitivity, 59%; and specificity, 94%). The use of a strong topical corticosteroid for skin rash was also associated with a higher serum cetuximab level. Serum levels of sEGFR and IL-6 had no correlations with the skin disorder severities or their medications. Hypomagnesemia treatment using intravenous magnesium sulfate was not related to serum cetuximab and EGFR-related markers.

Conclusions

Head and neck cancer patients with a higher serum IL-6 level tended to have a lower serum cetuximab level. Serum cetuximab had positive correlations to skin rash severity and its medication in the study population.

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Availability of data and materials

The data that support the findings of the present study are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Abbreviations

EGFR:

Epidermal growth factor receptor

sEGFR:

Soluble EGFR

STAT3:

Signal transducer and activator of transcription 3

JAK2:

Janus kinase 2

IL-6:

Interleukin-6

CRP:

C-reactive protein

LC–MS/MS:

Liquid chromatography system coupled to a tandem mass spectrometry

ELISA:

Enzyme-linked immunosorbent assay

ROC:

Receiver-operating characteristic

OR:

Odds ratios

95% CI:

95% Confidence intervals

IQR:

Interquartile range

AUC:

Area under the curve

TRPM6:

Transient receptor potential melastatin 6

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Acknowledgements

This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant number JP19H00398 and a Research Grant provided by the Japan Research Foundation for Clinical Pharmacology.

Funding

Kaito Shibata received financial support from the Japan Society for the Promotion of Science (JSPS) (KAKENHI, Grant Number JP19H00398). Takafumi Naito received funding from the Japan Research Foundation for Clinical Pharmacology.

Author information

Authors and Affiliations

  1. Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Kaito Shibata, Takafumi Naito, Koji Suzuki & Junichi Kawakami

  2. Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Satoshi Hirakawa

  3. Department of Otorhinolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Seiji Hosokawa & Hiroyuki Mineta

Authors
  1. Kaito Shibata
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  2. Takafumi Naito
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  3. Satoshi Hirakawa
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  4. Koji Suzuki
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  7. Junichi Kawakami
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Contributions

KS and TN conceptualized the study with input from SH and JK. KS and TN funded the study. KS and KS recruited patients and performed blood sampling with assistance from SH and HM. KS measured drug and biomarker levels. SH evaluated clinical symptoms. KS curated drug and biomarker level results and analyzed and interpreted data with assistance of TN and SH. KS and TN wrote the manuscript and all the coauthors reviewed and contributed to the manuscript.

Corresponding author

Correspondence to Takafumi Naito.

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The authors declare there are no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

The present study was conducted in accordance with the Declaration of Helsinki, its amendments, and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. The study protocol was approved by the Ethics Committee of Hamamatsu University School of Medicine. All patients were fully informed of the scientific aim of this study and each patient provided written informed consent before study enrollment.

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Shibata, K., Naito, T., Hirakawa, S. et al. Correlations between serum cetuximab and EGFR-related markers, and skin disorders in head and neck cancer patients. Cancer Chemother Pharmacol 87, 555–565 (2021). https://doi.org/10.1007/s00280-020-04228-4

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