Abstract
The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR–216G/T and –191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wheeler DL, Dunn EF, Harari PM . Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol 2010; 7: 493–507.
Mendelsohn J, Baselga J . Epidermal growth factor receptor targeting in cancer. Semin Oncol 2006; 33: 369–385.
Harandi A, Zaidi AS, Stocker AM, Laber DA . Clinical Efficacy and Toxicity of Anti-EGFR Therapy in Common Cancers. J Oncol 2009; 2009: 567486.
Segaert S, Van Cutsem E . Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005; 16: 1425–1433.
Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC . Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006; 55: 657–670.
Bianchini D, Jayanth A, Chua YJ, Cunningham D . Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker. Clin Colorectal Cancer 2008; 7: 33–43.
Perez-Soler R, Saltz L . Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005; 23: 5235–5246.
Van Cutsem E . Challenges in the use of epidermal growth factor receptor inhibitors in colorectal cancer. Oncologist 2006; 11: 1010–1017.
Giovannetti E, Zucali PA, Peters GJ, Cortesi F, D’Incecco A, Smit EF et al. Association of polymorphisms in AKT1 and EGFR with clinical outcome and toxicity in non-small cell lung cancer patients treated with gefitinib. Mol Cancer Ther 2010; 9: 581–593.
Klinghammer K, Knodler M, Schmittel A, Budach V, Keilholz U, Tinhofer I . Association of epidermal growth factor receptor polymorphism, skin toxicity, and outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment. Clin Cancer Res 2010; 16: 304–310.
Liu G, Gurubhagavatula S, Zhou W, Wang Z, Yeap BY, Asomaning K et al. Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib. Pharmacogenomics J 2008; 8: 129–138.
McKibbin T, Zhao W, Tagen M, Daw NC, Furman WL, McGregor LM et al. Epidermal growth factor receptor polymorphisms and risk for toxicity in paediatric patients treated with gefitinib. Eur J Cancer 2010; 46: 2045–2051.
Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol 2008; 26: 1119–1127.
Tiseo M, Capelletti M, De Palma G, Franciosi V, Cavazzoni A, Mozzoni P et al. Epidermal growth factor receptor intron-1 polymorphism predicts gefitinib outcome in advanced non-small cell lung cancer. J Thorac Oncol 2008; 3: 1104–1111.
Huang CL, Yang CH, Yeh KH, Hu FC, Chen KY, Shih JY et al. EGFR intron 1 dinucleotide repeat polymorphism is associated with the occurrence of skin rash with gefitinib treatment. Lung Cancer 2009; 64: 346–351.
Gregorc V, Hidalgo M, Spreafico A, Cusatis G, Ludovini V, Ingersoll RG et al. Germline polymorphisms in EGFR and survival in patients with lung cancer receiving gefitinib. Clin Pharmacol Ther 2008; 83: 477–484.
Tan AR, Steinberg SM, Parr AL, Nguyen D, Yang SX . Markers in the epidermal growth factor receptor pathway and skin toxicity during erlotinib treatment. Ann Oncol 2008; 19: 185–190.
Cancer Therapy Evaluation Program Common Toxicity Criteria: http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf [cited; Available from: http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf.
Nomura M, Shigematsu H, Li L, Suzuki M, Takahashi T, Estess P et al. Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers. PLoS Med 2007; 4: e125.
Pettersson FH, Anderson CA, Clarke GM, Barrett JC, Cardon LR, Morris AP et al. Marker selection for genetic case-control association studies. Nat Protoc 2009; 4: 743–752.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.
Liu W, Innocenti F, Wu MH, Desai AA, Dolan ME, Cook EH et al. A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter. Cancer Res 2005; 65: 46–53.
Liu W, Wu X, Zhang W, Montenegro RC, Fackenthal DL, Spitz JA et al. Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor inhibitors in the NCI60 cell lines. Clin Cancer Res 2007; 13: 6788–6795.
Heist RS, Christiani D . EGFR-targeted therapies in lung cancer: predictors of response and toxicity. Pharmacogenomics 2009; 10: 59–68.
Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D et al. Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. J Clin Oncol 2004; 22: 3238–3247.
Faehling M, Eckert R, Kuom S, Kamp T, Stoiber KM, Schumann C . Benefit of erlotinib in patients with non-small-cell lung cancer is related to smoking status, gender, skin rash and radiological response but not to histology and treatment line. Oncology 2010; 78: 249–258.
Kris MG, Natale RB, Herbst RS, Lynch Jr TJ, Prager D, Belani CP et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. Jama 2003; 290: 2149–2158.
Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ . 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 2007; 13: 3913–3921.
Herbst RS, Arquette M, Shin DM, Dicke K, Vokes EE, Azarnia N et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 2005; 23: 5578–5587.
Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24: 4914–4921.
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345.
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960–1966.
Xiong HQ, Rosenberg A, LoBuglio A, Schmidt W, Wolff RA, Deutsch J et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. J Clin Oncol 2004; 22: 2610–2616.
Lacouture ME . Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6: 803–812.
Moriai T, Kobrin MS, Hope C, Speck L, Korc M . A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci U S A 1994; 91: 10217–10221.
Wang WS, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC et al. Epidermal growth factor receptor R497 K polymorphism is a favorable prognostic factor for patients with colorectal carcinoma. Clin Cancer Res 2007; 13: 3597–3604.
Amador ML, Oppenheimer D, Perea S, Maitra A, Cusatis G, Iacobuzio-Donahue C et al. An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res 2004; 64: 9139–9143.
Thrash BR, Menges CW, Pierce RH, McCance DJ . AKT1 provides an essential survival signal required for differentiation and stratification of primary human keratinocytes. J Biol Chem 2006; 281: 12155–12162.
Janes SM, Ofstad TA, Campbell DH, Eddaoudi A, Warnes G, Davies D et al. PI3-kinase-dependent activation of apoptotic machinery occurs on commitment of epidermal keratinocytes to terminal differentiation. Cell Res 2009; 19: 328–339.
Sayama K, Yamasaki K, Hanakawa Y, Shirakata Y, Tokumaru S, Ijuin T et al. Phosphatidylinositol 3-kinase is a key regulator of early phase differentiation in keratinocytes. J Biol Chem 2002; 277: 40390–40396.
Acknowledgements
This study was financially supported by a research Grant from the Wilhelm Sander Foundation (Grant No 2008.017.1). We would like to thank Professor Dr Konstanze Döhner and Marianne Habdank for technical support in genotyping the EGFR CA repeat. SP is a fellow of the International Graduate School in Molecular Medicine, Ulm.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
PowerPoint slides
Rights and permissions
About this article
Cite this article
Parmar, S., Schumann, C., Rüdiger, S. et al. Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity. Pharmacogenomics J 13, 181–188 (2013). https://doi.org/10.1038/tpj.2011.51
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2011.51
Keywords
This article is cited by
-
Clinical Pharmacokinetics and Pharmacodynamics of the Epidermal Growth Factor Receptor Inhibitor Panitumumab in the Treatment of Colorectal Cancer
Clinical Pharmacokinetics (2018)
-
Determinants of Gefitinib toxicity in advanced non-small cell lung cancer (NSCLC): a pharmacogenomic study of metabolic enzymes and transporters
The Pharmacogenomics Journal (2017)
-
TruSight Cancer Sequencing Panel reveals pharmacogenetic variants associated with sensitivity to chemotherapy in lung cancer
memo - Magazine of European Medical Oncology (2016)