Introduction: EGFR inhibitors (EGFRIs) have been shown to be clinically effective in various cancers. Unique skin toxicity is commonly observed with EGFRIs and a correlation between the clinical benefit of EGFRIs and this characteristic rash has been reported. Erlotinib is a potent EGFRI approved for treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer. Methods: This is the first time in which patients were given increasing doses of an EGFRI to induce a mechanistic rash and study its associated pathology in skin. Biopsies were collected during treatment from both rash-affected and unaffected skin of 23 NSCLC patients and compared with pre-treatment biopsies. Results: Altered differentiation of appendegeal epithelium (hair follicles and sebaceous glands) was remarkable in both affected and unaffected skin, although epidermal growth was not significantly reduced. A predominantly mononuclear leucocyte infiltrate was detected in the interfollicular dermis or around skin appendages. This infiltrate included TRAIL-positive cells with a dendritic cell (DC) morphology, although T-cells, antigen-presenting DCs and macrophages were also evident. This is the first report showing the involvement of a dendritic cell subtype with EGFRI skin toxicity. Conclusions: Altered differentiation of pilosebaceous epithelium is evident in both rash-affected and unaffected skin and constitutes the primary process of EGFRI in human skin. We propose that this eventually triggers inflammation and the EGFRI rash. TRAIL-positive inflammatory cells could link rash development and immune-triggered apoptosis of epithelial cells, including those of underlying carcinomas.

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Keywords EGFRI, Erlotinib, Rash, T lymphocyte, adult, aged, antigen presenting cell, article, cancer chemotherapy, cell infiltration, cell structure, clinical article, dendritic cell, dermis, drug dose escalation, erlotinib, female, hair follicle, human, lung non small cell cancer, macrophage, male, mononuclear cell, priority journal, rash, sebaceous gland, skin, skin appendage, skin biopsy, tumor necrosis factor related apoptosis inducing ligand
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Guttman-Yassky, E., mita, A., de Jonge, M.J.A., Matthews, L., McCarthy, S., Iwata, K.K., … Krueger, J.G.. (2010). Characterisation of the cutaneous pathology in non-small cell lung cancer (NSCLC) patients treated with the EGFR tyrosine kinase inhibitor erlotinib. European Journal of Cancer, 46(11), 2010–2019. doi:10.1016/j.ejca.2010.04.028