"Histopathologic and Immunohistochemical Characterization of Rash to Human Epidermal Growth Factor Receptor 1 (HER1) and HER1/2 Inhibitors in Cancer Patients

Introduction: Human epidermal receptor (HER) 1 inhibitors and HER 1/2 inhibitors have shown benefit against a wide range of solid tumors. However, their use is associated with rash in 40-90% of patients, which impacts quality of life and interrupts antineoplastic therapy. The pathologic characteristics of affected skin remain unclear, precluding development of rational therapies. The aim of this study is to evaluate differences in histologic and immunohistochemical (IHC) alterations in rash caused by lapatinib, a dual HER1/2 inhibitor (HER1/2i), and the single HER1 inhibitors (HER1i) cetuximab, erlotinib, and panitumumab. Material and Methods: For each of the four drugs, skin biopsies were collected and analyzed from 8 patients with skin rash (n=32). Blinded independent histologic analysis and automated measurement of 17 skin biomarkers involved in proliferation, differentiation, and inflammation was conducted. Results: Increased expression of pAKT and decreased dermal K16 and p27 for HER1/2i when compared to each of the HER1i were observed. In addition, decreased epidermal atrophy and follicular neutrophilic infiltrate were evidenced in the skin of patients on HER1/2i when compared to HER1i. Conclusions: We found a lower inhibition of epidermal kinetics and decreased inflammation in HER1/2i-induced rash. These findings underscore differences in skin toxicity as related to specificity of HER blockade, concordant with clinical tolerability and decreased severity of skin toxicity seen with the HER1/2i lapatinib compared to the HER1 inhibitors cetuximab, erlotinib and panitumumab.