K. M. Nicholson

2581 Background: Inhibitors of human epidermal receptors (HER) have shown benefit against a wide range of solid tumors. However, their use is associated with a rash in up to 90% of patients, which impacts quality of life and may lead to therapeutic dose modification or interruption. The histologic characteristics of affected skin are not clearly understood, precluding the development of rational therapies. The aim of this study is to evaluate differences in histologic and immunohistochemical (IHC) alterations in skin rash due to lapatinib, a dual HER1/2 inhibitor (iHER1/2) and the single HER1 inhibitors (iHER1) cetuximab, erlotinib, and panitumumab. Methods: Skin biopsies were collected from 8 patients with skin rash for each iHER (n=32). Two dermatopathologists performed blinded independent analysis of epidermis, dermis, follicle, and inflammatory infiltrates. In addition, specimens were stained for 17 receptor/pathway biomarkers. Blinded IHC analysis was conducted to determine percentage and intensity of expression for each biomarker and compared between four iHER. Results: A significant increase in the expression of pAKT in the epidermis and dermis when comparing iHER1/2 lapatinib, to iHER1 cetuximab, erlotinib, and panitumumab; a significant decrease in the expression of K16 and p27 in dermis; and a significantly higher expression of ERK1 in the dermis compared to erlotinib. Moreover, decreased epidermal atrophy and follicular neutrophilic infiltrate were observed in skin of patients on iHER1/2 when compared to the 3 iHER1. Conclusions: Our findings suggest a lower inhibition of epidermal kinetics and decreased follicular inflammation in iHER1/2-induced rash. These findings underscore differences in skin toxicity with specificity of HER blockade and are concordant with clinical data suggesting lower severity of skin toxicity with the iHER1/2 lapatinib, compared to iHER1 cetuximab, erlotinib, and panitumumab. Less severe skin rash may improve quality of life and ensure consistent dosing with iHER therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline