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.
Highlights
The epidermal growth factor receptor (EGFR, HER1) belongs to the ErbB family of receptor tyrosine kinases
Administered inhibitors which are specific for EGFR (EGFRIs) are the tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib and the monoclonal antibodies cetuximab and panitumumab
Occurrence and severity of EGFRI-induced skin rash show a positive correlation with patient outcome, rendering this rash a potential marker for drug efficacy [12, 13, 16]
Summary
The epidermal growth factor receptor (EGFR, HER1) belongs to the ErbB family of receptor tyrosine kinases. Occurrence and severity of the EGFRI-induced skin rash have been shown in several independent studies to be positively correlated with patients’ outcome [12, 13] and have been tested as surrogate marker for drug efficacy and suitable dosing [14,15,16]. Determinable predictive biomarkers for the severity of EGFRI-induced rash would allow to start early with preventive treatment of the rash and still allow prediction of EGFRI efficacy. Such biomarkers might indicate whether clinicians should intensify therapy and monitoring (e.g. by more frequent tumor imaging).
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