Title

 

Authors

G. Bocci^1,3, C. Cremolini^2,3, A. Fioravanti^1,3, P. Orlandi^1,3, L. Salvatore^2,3, G. Masi^2,3, M. Schirripa^2,3, B. Canu^1,3, T. Di Desidero^1,3, G. Fontanini⁴, F. Basolo⁴, R. Danesi^1,3,A. Falcone^2,3, F. Loupakis^2,3

Div. of Pharmacology, Dept. of Internal Medicine, University of Pisa, Italy; ²Dept. of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy; ³Institute Tumors Tuscany; ⁴Dept. of Surgery, University of Pisa.

 

Abstract

To determine the circulating levels of EGFR ligands occurring in mCRC patients (pts) during the treatment with cetuximab and irinotecan and to explore the potential clinical implication of plasma level variations as pharmacodynamic markers of intrinsic and acquired resistance to anti-EGFRs. Plasma concentrations of Amphiregulin (AR), Epidermal Growth Factor (EGF), Transforming Growth Factor-α (TGF-α) and Heparin Binding-EGF (HB-EGF) were assessed in 45 chemorefractory mCRC pts, treated with cetuximab and irinotecan. Plasma levels were measured before (d1), one hour after the first administration of cetuximab (d1-1hr), before (d15) and one hour after the second administration (d15-1hr), before the third (d29) and the fifth (d57) cycle. KRAS and BRAF mutational status, as well as tissue AR expression, were determined. EGFR ligand plasma levels were differently modulated according to KRAS and BRAF mutational status. In KRAS wildtype (wt) patients (N=34), AR and EGF early increased and higher increases were associated with worse clinical outcome. Among KRAS and BRAF wt patients (N=27), also TGF-α rapid increase was related to worse prognosis. By adopting a cut-off value, identified by a ROC curve, “d1-1hr-AR high” pts had worse response rate, progression free survival and overall survival compared to “d1-1hr-AR low”. At the time of radiographic assessment (d57), higher levels of EGFR ligands were found in non-responders compared to responders. EGFR ligands were significantly modulated by the administration of cetuximab and irinotecan. Pharmacodynamic approaches might help to disclose possible mechanisms of resistance to anti-EGFRs, leading foundations toward innovative therapeutic strategies.