Research Papers:

Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash

Vivien Hichert, Catharina Scholl, Michael Steffens, Tanusree Paul, Christian Schumann, Stefan Rüdiger, Stefan Boeck, Volker Heinemann, Volker Kächele, Thomas Seufferlein and Julia Stingl _

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Oncotarget. 2017; 8:35193-35204. https://doi.org/10.18632/oncotarget.17060

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Vivien Hichert1,7, Catharina Scholl1,7, Michael Steffens1,7, Tanusree Paul2, Christian Schumann3,4, Stefan Rüdiger3, Stefan Boeck5,8, Volker Heinemann5,8, Volker Kächele6, Thomas Seufferlein6 and Julia Stingl1,7

1Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany

2Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany

3Department of Internal Medicine II, University of Ulm, Ulm, Germany

4Pneumology, Thoracic Oncology, Sleep and Respiratory Critical Care Medicine, Clinics Kempten-Oberallgäu, Kempten, Germany

5Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany

6Department of Internal Medicine I, University of Ulm, Ulm, Germany

7Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany

8DKTK, German Cancer Consortium, German Cancer Research Center, (DKFZ), Heidelberg, Germany

Correspondence to:

Julia Stingl, email: [email protected]

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


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.

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