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Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2790-2792 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.16.0077
The Koebner-Phenomenon in Epidermal Growth Factor Receptor Inhibitor–Induced Cutaneous Adverse EffectsDepartment of Dermatology, Heinrich-Heine University, Düsseldorf, Germany To the Editor: A 41-year-old female patient with metastatic non–small-cell lung cancer was treated with erlotinib, a small molecule inhibitor directed against the tyrosinkinase of the epidermal growth factor receptor (EGFR). After 12 weeks of erlotinib 150 mg orally once daily, the patient presented to our clinic with a characteristic papulopustular eruption located exclusively to the dorsal side of both of her forearms (Fig 1A). The patient reported that over a period of 1 week before the appearance of the rash she had received considerable ultraviolet (UV) exposure to her forearms while wearing sleeveless shirts on sunny days. She had not been applying any sunscreen.
A 76-year-old male patient with metastatic non–small-cell lung cancer was treated with erlotinib 150 mg orally once daily for 12 weeks. Ten days after initiation of erlotinib therapy, the patient presented to our clinic with a characteristic papulopustular rash located to his face and upper trunk. On initial presentation, clinical documentation and the excision of a skin biopsy were performed. One week later, the patient was re-evaluated displaying aggravated papulopustular eruptions located to two strictly confined areas of approximately 3 x 3 cm2 (Fig 1B and 1C). Interestingly, aggravated skin eruptions were limited to previously traumatized areas. Concerning the lesions occurring on the patient`s chest, a port-needle and band-aid had been stripped off, respectively, 3 days before (Fig 1B). The aggravated rash on the abdomen was confined to the area where the excision of the skin biopsy and subsequent changes of band-aids had been performed earlier (Fig 1C). Cutaneous adverse effects are the most common adverse effect associated with the use of EGFR inhibitors (EGFRI), occurring in far more than 50% of the patients.1 Within the first week of administration patients develop characteristic pruritic, papulopustular eruptions (the so-called "acneiform rash") located mainly to the seborrhoic areas of face and trunk. While recent studies demonstrate a positive correlation of the severity of EGFRI-induced rash and efficacy of the therapy,2,3 triggering factors of the rash have remained largely unnoticed. Recently, Luu et al4 for the first time described photosensitivity of an erlotinib-induced rash in a 75-year-old male patient. However, the cases presented here demonstrate that EGFRI-induced papulopustular eruptions can be provoked not only by UV exposure, but also by other physical traumata. This effect, namely the provocation or aggravation of disease-specific skin lesions by trauma, is referred to as Koebner or isomorphic phenomenon. The Koebner phenomenon, probably one of the most well-known entities in dermatology, has been documented in a number of skin diseases including psoriasis, vitiligo, or lichen planus. In susceptible individuals, Koebnerization can be induced by a variety of triggers, all of which cause predominantly epidermal cell injury or inflammation. Trigger factors include burns, freezing, friction, pressure, ionizing irradiation, and pulsed dye lasers, or, as presented in our cases, tape stripping, surgical incision, and UV light.5 The documentation of the Koebner phenomenon in EGFRI-induced cutaneous adverse effects provides interesting new insights into the pathogenesis of these novel skin toxicities. It has been demonstrated that the EGFR regulates proliferation, differentiation, migration, and survival in tumor tissue and human keratinocytes.6-9 So far, the pathogenesis of EGFRI-induced cutaneous toxicities remains largely unknown. Whereas mechanisms of cutaneous adverse effects have initially been introduced by Lacouture in 2006,1 today new clinical and in vitro observations present a wider and more complex spectrum of adverse effects and should be incorporated into the molecular and cellular concepts. Notably, two studies demonstrated that the blockade of the EGFR induces a dysregulated cytokine expression in primary human keratinocytes and results in markedly enhanced skin inflammation in mouse models for contact hypersensitivity.10,11 Moreover, inhibition of the EGFR has been reported to increase the expression of genes that stimulate inflammation and apoptosis.6 Interestingly, our group and other authors have recently reported transient, as well as permanent prevention of the EGFRI-induced skin rash in preirradiated areas.12,13 While high irradiation dosages may cause a permanent rash prevention due to chronic radiation–induced adverse effects (like extensive fibrosis and a destruction and scarring of hair follicles and sebaceous glands), moderate irradiation dosages may result in a reversible rash prevention due to a transient depletion of EGFR-harboring basal layer stem cells and a transient immunosupression. In summary, the observations presented in this paragraph for the first time, to our knowledge, outline the importance of the EGFR for the control of cutaneous inflammatory processes and provide interesting links to the underlying mechanisms of the inflammatory phenotype of EGFRI-induced cutaneous adverse effects. Next to its role in inflammation, the EGFR has been reported to also regulate keratinocyte growth and survival. In particular, EGFRI have been demonstrated to inhibit DNA synthesis and induce growth arrest,14,15 as well as to induce extensive cell death16,17 in cultured human keratinocytes. Similar effects have been observed for a combination of EGFRI and UV-radiation.18,19 Inhibition of EGFR in tumor tissue during radiotherapy results in an enhanced radiation toxicity, mainly through inhibition of DNA repair, enhanced apoptosis and reduced angiogenesis and repopulation.20 In line with these findings is a recent report by Budach et al21 that displays a novel phenotype of EGFRI-associated cutaneous adverse effects of extreme severity. The authors observed a severe erosive and ulcerative dermatitis during the combined regimen of radiotherapy and the monoclonal EGFR-antibody cetuximab.21 Since the severity of the dermatitis could not be assigned solely to radiation-induced toxicity, the authors assumed that the EGFRI increased the susceptibility of the patient to the adverse effects of ionizing radiation. Based on these recent findings and the cases presented here, we propose the following model for the development of EGFRI-induced cutaneous adverse effects: under homeostatic conditions the EGFR controls inflammatory skin responses and provides survival signals to epithelial cells such as epidermal keratinocytes. Pharmacologic inhibition of the EGFR signaling pathway causes enhanced inflammation on skin trauma/injury and increases the susceptibility of epithelial cells for apoptotic events. Herein, an EGFRI-mediated enhanced production of proinflammatory mediators leads to the recruitment of leukocytes that release enzymes, finally inducing apoptosis and subsequent necrosis in keratinocytes and other structural cells of the skin. Lacking the inhibitory function of the EGFR, inflammation induces more apoptosis/necrosis and vice versa, resulting in a self-sustaining cycle of inflammation. Skin lesions can initiate de novo or on unspecific trauma (Koebnerization). Simultaneously, the balance of the predominant pathogenetic mechanism (inflammation v trauma) as well as the resulting severity of skin lesions (provocation/aggravation of acneiform rash to ulcerative dermatitis) is shifted according to the intensity of the trauma (mechanical trauma to ionizing irradiation). Our model presents interesting new aspects toward the pathogenesis of EGFRI-induced cutaneous adverse effects. However, further research is needed to improve the understanding of these novel toxicities. The conclusions of this report should be considered in the counseling of EGFRI-treated patients. Sun protection is strongly recommended. Additional trigger factors of Koebnerization in EGFRI-induced cutaneous adverse effects need to be reported. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Bernhard Homey, Roche Pharmaceuticals (C) Stock Ownership: None Honoraria: Peter Arne Gerber, Roche Pharmaceuticals; Bernhard Homey, Roche Pharmaceuticals Research Funding: None Expert Testimony: None Other Remuneration: None
REFERENCES 1. Lacouture ME: Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803-812, 2006[CrossRef][Medline] 2. Soler R, Chachoua A, Hammond LA, et al: Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol 22:3238-3247, 2004 3. Wacker B, Nagrani T, Weinberg J, et al: Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 13:3913-3921, 2007 4. Luu M, Lai SE, Patel J, et al: Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed 23:42-45, 2007[CrossRef][Medline] 5. Weiss G, Shemer A, Trau H: The Koebner phenomenon: Review of the literature. J Eur Acad Dermatol Venereol 16:241-248, 2002[CrossRef][Medline] 6. Woodworth CD, Michael E, Marker D, et al: Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Mol Cancer Ther 4:650-658, 2005 7. Jost M, Kari C, Rodeck U: The EGF receptor: An essential regulator of multiple epidermal functions. Eur J Dermatol 10:505-510, 2000[Medline] 8. Arteaga CL: The epidermal growth factor receptor: From mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 19:32S-40S, 2001 9. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787-2799, 2003 10. Mascia F, Mariani V, Girolomoni G, et al: Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol 163:303-312, 2003 11. Pastore S, Mascia F, Mariotti F, et al: ERK1/2 regulates epidermal chemokine expression and skin inflammation. J Immunol 174:5047-5056, 2005 12. Mitra SS, Simcock R: Erlotinib induced skin rash spares skin in previous radiotherapy field. J Clin Oncol 24:e28-29, 2006 13. Gerber PA, Enderlein E, Homey B, et al: Radiation-induced prevention of erlotinib-induced skin rash is transient: A new aspect toward the understanding of epidermal growth factor receptor inhibitor associated cutaneous adverse effects. J Clin Oncol 25:4697-4698, 2007; author reply 4698-4699 14. Peus D, Hamacher L, Pittelkow MR: EGF-receptor tyrosine kinase inhibition induces keratinocyte growth arrest and terminal differentiation. J Invest Dermatol 109:751-756, 1997[CrossRef][Medline] 15. Kobayashi T, Hashimoto K, Okumura H, et al: Endogenous EGF-family growth factors are necessary for the progression from the G1 to S phase in human keratinocytes. J Invest Dermatol 111:616-620, 1998[CrossRef][Medline] 16. Stoll SW, Benedict M, Mitra R, et al: EGF receptor signaling inhibits keratinocyte apoptosis: Evidence for mediation by Bcl-XL. Oncogene 16:1493-1499, 1998[CrossRef][Medline] 17. Rodeck U, Jost M, Kari C, et al: EGF-R dependent regulation of keratinocyte survival. J Cell Sci 110:113-121, 1997[Abstract] 18. Peus D, Vasa RA, Meves A, et al: UVB-induced epidermal growth factor receptor phosphorylation is critical for downstream signaling and keratinocyte survival. Photochem Photobiol 72:135-140, 2000[CrossRef][Medline] 19. Jost M, Gasparro FP, Jensen PJ, et al: Keratinocyte apoptosis induced by ultraviolet B radiation and CD95 ligation–differential protection through epidermal growth factor receptor activation and Bcl-x(L) expression. J Invest Dermatol 116:860-866, 2001[CrossRef][Medline] 20. Sartor CI: Mechanisms of disease: Radiosensitization by epidermal growth factor receptor inhibitors. Nat Clin Pract Oncol 1:80-87, 2004[CrossRef][Medline] 21. Budach W, Bolke E, Homey B: Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med 357:514-515, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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