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Objective Epidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers. Materials and methods Five candidate miRNAs were selected, based on an earlier in vitro next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients (n = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash. Results In our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (p-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (p-value 9.01e-06 linear-trend-test). Conclusions This suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.

// Vivien Hichert 1, 7 , Catharina Scholl 1, 7 , Michael Steffens 1, 7 , Tanusree Paul 2 , Christian Schumann 3, 4 , Stefan Rudiger 3 , Stefan Boeck 5, 8 , Volker Heinemann 5, 8 , Volker Kachele 6 , Thomas Seufferlein 6 and Julia Stingl 1, 7 1 Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany 2 Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany 3 Department of Internal Medicine II, University of Ulm, Ulm, Germany 4 Pneumology, Thoracic Oncology, Sleep and Respiratory Critical Care Medicine, Clinics Kempten-Oberallgau, Kempten, Germany 5 Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany 6 Department of Internal Medicine I, University of Ulm, Ulm, Germany 7 Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany 8 DKTK, German Cancer Consortium, German Cancer Research Center, (DKFZ), Heidelberg, Germany Correspondence to: Julia Stingl, email: julia.stingl@bfarm.de Keywords: EGFR inhibitor-induced skin rash, predictive biomarkers, amphiregulin, hepatocyte growth factor, calcidiol Received: October 25, 2016 Accepted: March 22, 2017 Published: April 12, 2017 ABSTRACT Epidermal growth factor receptor overexpression in human cancer can be effectively targeted by drugs acting as specific inhibitors of the receptor, like erlotinib, gefitinib, cetuximab and panitumumab. A common adverse effect is a typical papulopustular acneiform rash, whose occurrence and severity are positively correlated with overall survival in several cancer types. We studied molecules involved in epidermal growth factor receptor signaling which are quantifiable in plasma, with the aim of identifying biomarkers for the severity of rash. With a predictive value for the rash these biomarkers may also have a prognostic value for survival and disease outcome. The concentrations of amphiregulin, hepatocyte growth factor (HGF) and calcidiol were determined by specific enzyme-linked immunosorbent assays in plasma samples from 211 patients. We observed a significant inverse correlation between the plasma concentration of HGF and overall survival in patients with an inhibitor-induced rash (p-value = 0.0075; mean overall survival low HGF: 299 days, high HGF: 240 days) but not in patients without rash. The concentration of HGF was also significantly inversely correlated with severity of rash (p-value = 0.00124). High levels of HGF lead to increased signaling via its receptor MET, which can activate numerous pathways which are normally also activated by epidermal growth factor receptor. Increased HGF/MET signaling might compensate the inhibitory effect of epidermal growth factor receptor inhibitors in skin as well as tumor cells, leading to less severe skin rash and decreased efficacy of the anti-tumor therapy, rendering the plasma concentration of HGF a candidate for predictive biomarkers.