Characterisation of the cutaneous pathology in non-small cell lung cancer (NSCLC) patients treated with the EGFR tyrosine kinase inhibitor erlotinib

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Abstract

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.

Introduction

EGFR-targeted drugs emerged as robust therapeutic agents against various malignancies.1 Unlike standard chemotherapy that acts on replicating cells, EGFR inhibitors (EGFRIs) target only cells expressing the cognate receptor.2, 3, 4, 5 Therefore, these drugs have different pharmacologic actions and systemic side-effects compared with standard chemotherapeutic drugs.6 Erlotinib (Tarceva®; OSI-774) is a potent, selective small-molecule EGFRI approved for NSCLC and pancreatic cancer.7, 8

The increasing clinical usage of EGFRIs has led to the identification of commonly occurring side effects which are most evident in tissues dependent on EGFR signalling for normal function, such as the skin.1 Unique skin toxicity was reported as follicular, ‘acneiform’ rash.1, 9, 10, 11, 12 Although this rash resembles acne vulgaris, it is predominantly pustular, not associated with comedones, may involve different body areas and is pathologically distinct from acne vulgaris.1, 9, 13 Most patients exhibit mild skin symptoms, but moderate to severe toxicities, leading to dose adjustment or interruption of therapy, occur in 8–17% of patients.7 The clinical benefit of EGFRIs has been suggested to correlate with severity of this characteristic rash, rendering rash a potential marker of drug activity.13, 14 The optimum management of this rash remains somewhat anecdotal, as the rash does not typically respond to anti-acne agents, but sometimes to anti-inflammatory, antibiotic and immunomodulatory agents.1, 13, 15, 16, 17

The high frequency of cutaneous manifestations with EGFRIs may reflect the function of EGFR in epithelial or mesenchymal cells associated with the epidermis, sweat gland apparatus, hair follicle and periungual tissues.18, 19, 20 Studies in mice lacking EGFR at these sites showed a central role of EGFR in normal differentiation and development of the hair follicle, as these mice presented disorganised hair follicle phenotypes.21, 22, 23 While EGF attenuates hair follicle growth and differentiation, it has pleiotropic effects on cultured keratinocytes.24, 25 In vitro models using organ cultures established a role for EGF and TGF-α in the regulation of sebocyte and keratinocyte differentiation in human pilosebaceous unit.26

Cutaneous inflammation in several disease models is linked to inflammatory dendritic cells (DCs),27 where myeloid DCs are greatly increased over background resident DCs in the skin. These DCs accumulate in parallel with T-cells, have T-cell stimulatory activity and produce direct inflammatory mediators, such as inducible nitric oxide (iNOS), TNF-α and chemokines.27

Although prior EGFRI studies reported skin findings, these did not usually integrate cutaneous biology and histology, possibly precluding a clear understanding of patho-physiological mechanisms of these side effects, and adequate treatment guidelines.1 The present study is the first in which patients with advanced NSCLC were given escalating doses of EGFRI in order to induce a mechanistic rash for studying its associated pathology. We identified profound alterations in growth and differentiation of appendegeal epithelium, including sebaceous glands, in affected and unaffected skin. Inflammation was associated with a mononuclear infiltrate, including TRAIL-positive cells with a DC morphology. This cell type has been previously shown to have cytotoxic function in mouse and human cancers.28, 29

Section snippets

Material and methods

A multi-centre, open-label, phase 2 study (NCT00072631) was conducted to determine the feasibility of intrapatient dose escalation to induce a characteristic target rash (TR) and evaluate the effect on objective tumour response rate in patients with advanced NSCLC. TR was defined as a grade 2 rash, symptomatic, albeit tolerable rash, which required intervention with oral minocycline.

Results

Forty-two patients (28 males, 14 females), median age 63 years (range 41–78), participated in the study. The clinical results were previously presented and will be published separately.30 Forty-one (98%) of 42 enrolled patients experienced rash (Table 1); 24 (59%) of 41 patients with rash experienced a TR and had biopsies performed. Biopsies paired with matching clinical photographs were available from 23 (95%) patients with a TR. For 19 (83%) of these patients, the TR first occurred at the

Discussion

The present study analyses the largest reported patient series treated with an EGFRI to specifically induce a typical drug-associated rash and study its cellular basis. Unlike previous reports, the effects of EGFRI were studied in paired biopsies of ‘affected’ (‘rash’) and unaffected skin.

The ‘acneiform’ rash induced by EGFR inhibitors has been most commonly characterised as a suppurative folliculitis dominated by neutrophils within and around hair follicles that may also contain keratin-plugs

Conflict of interest statement

Authors Sean McCarthy and Kenneth Iwata are employed and own stock in OSI Pharmaceuticals, the sponsor of the phase 2 study from which biopsies were obtained for this characterisation study.

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