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Epidermal Growth Factor Receptor’s Function in Cutaneous Squamous Cell Carcinoma and Its Role as a Therapeutic Target in the Age of Immunotherapies

  • Skin Cancer (T Ito, Section Editor)
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Opinion statement

Recent studies have evidenced the potential of combining anti-EGFR therapies with anti-PD-1/PD-L1 checkpoint therapies. Both anti-EGFR and anti-PD-1/PD-L1 have been separately tested in the treatment of cutaneous SCC (cSCC). Here, we review recent data on EGFR in the context of cancer progression, as a prognostic and as a therapeutic target in cSCC. Anti-EGFR/checkpoint immunotherapy and other combination therapy approaches are discussed. With the advent of immunotherapy, EGFR is still a valid cSCC target.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol. 2012;166(5):1069–80. https://doi.org/10.1111/j.1365-2133.2012.10830.x.

    Article  CAS  PubMed  Google Scholar 

  2. Weedon DMM, Gross C, Nagore E, Yu LL. Pathology and genetics of skin tumors. World Health Organization Classification of tumors. Lyon: IARC Press; 2006.

    Google Scholar 

  3. Potenza C, Bernardini N, Balduzzi V, Losco L, Mambrin A, Marchesiello A, et al. A review of the literature of surgical and nonsurgical treatments of invasive squamous cells carcinoma. Biomed Res Int. 2018;2018:9489163. https://doi.org/10.1155/2018/9489163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tschetter AJ, Campoli MR, Zitelli JA, Brodland DG. Long-term clinical outcomes of patients with invasive cutaneous squamous cell carcinoma treated with Mohs surgery: a five-year, multicenter, prospective cohort study. J Am Acad Dermatol. 2019. https://doi.org/10.1016/j.jaad.2019.06.1303.

    Article  PubMed  Google Scholar 

  5. Skulsky SL, O’Sullivan B, McArdle O, Leader M, Roche M, Conlon PJ, et al. Review of high-risk features of cutaneous squamous cell carcinoma and discrepancies between the American Joint Committee on Cancer and NCCN Clinical Practice Guidelines In Oncology. Head Neck. 2017;39(3):578–94. https://doi.org/10.1002/hed.24580.

    Article  PubMed  Google Scholar 

  6. Timothy AW, Panizza B. Managing perineural and skull base involvement. In: CEP FR, Veness M, editors. Non-melanoma skin cancer of the head and neck. Berlin: Springer, Byword Books; 2015.

    Google Scholar 

  7. Ogata D, Tsuchida T. Systemic immunotherapy for advanced cutaneous squamous cell carcinoma. Curr Treat Options in Oncol. 2019;20(4):30. https://doi.org/10.1007/s11864-019-0629-2.

    Article  Google Scholar 

  8. Tanese K, Nakamura Y, Hirai I, Funakoshi T. Updates on the systemic treatment of advanced non-melanoma skin cancer. Front Med. 2019;6:160. https://doi.org/10.3389/fmed.2019.00160.

    Article  Google Scholar 

  9. Nakamura YTK, Hirai I, Kawakami Y, Funakoshi T. Carboplatin and epirubicin combination therapy for advanced malignant epithelial skin tumors: retrospective study of six patients. J Dermatol. 2018;45(7):874–5. https://doi.org/10.1111/1346-8138.14328.

    Article  PubMed  Google Scholar 

  10. Cartei G, Cartei F, Interlandi G, Meneghini G, Jop A, Zingone G, et al. Oral 5-fluorouracil in squamous cell carcinoma of the skin in the aged. Am J Clin Oncol. 2000;23(2):181–4.

    Article  CAS  PubMed  Google Scholar 

  11. Sadek H, Azli N, Wendling JL, Cvitkovic E, Rahal M, Mamelle G, et al. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer. 1990;66(8):1692–6. https://doi.org/10.1002/1097-0142(19901015)66:8<1692::aid-cncr2820660807>3.0.co;2-y.

    Article  CAS  PubMed  Google Scholar 

  12. Brewster AM, Lee JJ, Clayman GL, Clifford JL, Reyes MJ, Zhou X, et al. Randomized trial of adjuvant 13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(15):1974–8. https://doi.org/10.1200/jco.2006.05.9873.

    Article  CAS  Google Scholar 

  13. Behshad R, Garcia-Zuazaga J, Bordeaux JS. Systemic treatment of locally advanced nonmetastatic cutaneous squamous cell carcinoma: a review of the literature. Br J Dermatol. 2011;165(6):1169–77. https://doi.org/10.1111/j.1365-2133.2011.10524.x.

    Article  CAS  PubMed  Google Scholar 

  14. Wollina U. Update of cetuximab for non-melanoma skin cancer. Expert Opin Biol Ther. 2014;14(2):271–6. https://doi.org/10.1517/14712598.2013.876406.

    Article  CAS  PubMed  Google Scholar 

  15. Gaffney DC, Soyer HP, Simpson F. The epidermal growth factor receptor in squamous cell carcinoma: an emerging drug target. Aust J Dermatol. 2014;55(1):24–34. https://doi.org/10.1111/ajd.12025.

    Article  Google Scholar 

  16. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103(2):211–25.

    Article  CAS  PubMed  Google Scholar 

  17. Schlessinger J. Receptor tyrosine kinases: legacy of the first two decades. Cold Spring Harb Perspect Biol. 2014;6(3):a008912. https://doi.org/10.1101/cshperspect.a008912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12(1):3–20. https://doi.org/10.1002/1878-0261.12155.

    Article  PubMed  Google Scholar 

  19. •• Caldieri G, Malabarba MG, Di Fiore PP, Sigismund S. EGFR Trafficking in Physiology and Cancer. Prog Mol Subcell Biol. 2018;57:235–72. https://doi.org/10.1007/978-3-319-96704-2_9. This book chapter discusses deeply the EGFR signaling and trafficking as well as the impact of EGFR dysregulation in different types of cancer.

    Article  CAS  PubMed  Google Scholar 

  20. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34. https://doi.org/10.1016/j.cell.2010.06.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Joseph SR, Endo-Munoz L, Gaffney DC, Saunders NA, Simpson F. Dysregulation of epidermal growth factor receptor in actinic keratosis and squamous cell carcinoma. Basel: Actinic Keratosis. Karger Publishers; 2015. p. 20–7.

    Google Scholar 

  22. Boucrot E, Ferreira AP, Almeida-Souza L, Debard S, Vallis Y, Howard G, et al. Endophilin marks and controls a clathrin-independent endocytic pathway. Nature. 2015;517(7535):460–5. https://doi.org/10.1038/nature14067.

    Article  CAS  PubMed  Google Scholar 

  23. Orth JD, Krueger EW, Weller SG, McNiven MA. A novel endocytic mechanism of epidermal growth factor receptor sequestration and internalization. Cancer Res. 2006;66(7):3603–10. https://doi.org/10.1158/0008-5472.can-05-2916.

    Article  CAS  PubMed  Google Scholar 

  24. Sorkin A, Goh LK. Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res. 2009;315(4):683–96.

    Article  CAS  PubMed  Google Scholar 

  25. Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci U S A. 2005;102(8):2760–5. https://doi.org/10.1073/pnas.0409817102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sigismund S, Algisi V, Nappo G, Conte A, Pascolutti R, Cuomo A, et al. Threshold-controlled ubiquitination of the EGFR directs receptor fate. EMBO J. 2013;32(15):2140–57. https://doi.org/10.1038/emboj.2013.149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Caldieri G, Barbieri E, Nappo G, Raimondi A, Bonora M, Conte A, et al. Reticulon 3-dependent ER-PM contact sites control EGFR nonclathrin endocytosis. Science. 2017;356(6338):617–24. https://doi.org/10.1126/science.aah6152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Polo S, Di Fiore PP, Sigismund S. Keeping EGFR signaling in check: ubiquitin is the guardian. Cell Cycle. 2014;13(5):681–2. https://doi.org/10.4161/cc.27855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Reuter CWM, Morgan MA, Eckardt A. Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck. Br J Cancer. 2007;96(3):408–16. https://doi.org/10.1038/sj.bjc.6603566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. El-Abaseri TB, Putta S, Hansen LA. Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis. 2006;27(2):225–31. https://doi.org/10.1093/carcin/bgi220.

    Article  CAS  PubMed  Google Scholar 

  31. Li YY, Hanna GJ, Laga AC, Haddad RI, Lorch JH, Hammerman PS. Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin Cancer Res. 2015;21(6):1447–56. https://doi.org/10.1158/1078-0432.ccr-14-1773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ridd K, Bastian BC. Somatic mutation of epidermal growth factor receptor in a small subset of cutaneous squamous cell carcinoma. J Investig Dermatol. 2010;130(3):901–3. https://doi.org/10.1038/jid.2009.312.

    Article  CAS  PubMed  Google Scholar 

  33. Picard A, Pedeutour F, Peyrade F, Saudes L, Duranton-Tanneur V, Chamorey E, et al. Association of oncogenic mutations in patients with advanced cutaneous squamous cell carcinomas treated with cetuximab. JAMA Dermatol. 2017;153(4):291–8. https://doi.org/10.1001/jamadermatol.2017.0270.

    Article  PubMed  Google Scholar 

  34. Al-Rohil RN, Tarasen AJ, Carlson JA, Wang K, Johnson A, Yelensky R, et al. Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies. Cancer. 2016;122(2):249–57. https://doi.org/10.1002/cncr.29738.

    Article  CAS  PubMed  Google Scholar 

  35. Egashira S, Jinnin M, Ajino M, Shimozono N, Okamoto S, Tasaki Y, et al. Chronic sun exposure-related fusion oncogenes EGFR-PPARGC1A in cutaneous squamous cell carcinoma. Sci Report. 2017;7(1):12654. https://doi.org/10.1038/s41598-017-12,836-z.

    Article  Google Scholar 

  36. Sand M, Bechara FG, Sand D, Gambichler T, Hahn SA, Bromba M, et al. Expression profiles of long noncoding RNAs in cutaneous squamous cell carcinoma. Epigenomics. 2016;8(4):501–18. https://doi.org/10.2217/epi-2015-0012.

    Article  CAS  PubMed  Google Scholar 

  37. Mei XL, Zhong S. Long noncoding RNA LINC00520 prevents the progression of cutaneous squamous cell carcinoma through the inactivation of the PI3K/Akt signaling pathway by downregulating EGFR. Chin Med J. 2019;132(4):454–65. https://doi.org/10.1097/cm9.0000000000000070.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhang Y, Gao L, Ma S, Ma J, Wang Y, Li S, et al. MALAT1-KTN1-EGFR regulatory axis promotes the development of cutaneous squamous cell carcinoma. Cell Death Differ. 2019;26(10):2061–73. https://doi.org/10.1038/s41418-019-0288-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. •• Canueto J, Cardenoso E, Garcia JL, Santos-Briz A, Castellanos-Martin A, Fernandez-Lopez E, et al. Epidermal growth factor receptor expression is associated with poor outcome in cutaneous squamous cell carcinoma. Br J Dermatol. 2017;176(5):1279–87. https://doi.org/10.1111/bjd.14936. This paper describes the most recent analysis of EGFR expression in a large cohort of 94 cSCC patients. The authors used different techniques such as IHC, FISH, and qPCR and showed a correlation between EGFR expression and disease progression.

    Article  CAS  PubMed  Google Scholar 

  40. Nanney LB, Magid M, Stoscheck CM, King LE Jr. Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J Investig Dermatol. 1984;83(5):385–93. https://doi.org/10.1111/1523-1747.ep12264708.

    Article  CAS  PubMed  Google Scholar 

  41. Reigneau M, Robert C, Routier E, Mamelle G, Moya-Plana A, Tomasic G, et al. Efficacy of neoadjuvant cetuximab alone or with platinum salt for the treatment of unresectable advanced nonmetastatic cutaneous squamous cell carcinomas. Br J Dermatol. 2015;173(2):527–34. https://doi.org/10.1111/bjd.13741.

    Article  CAS  PubMed  Google Scholar 

  42. Jenni D, Karpova MB, Muhleisen B, Mangana J, Dreier J, Hafner J, et al. A prospective clinical trial to assess lapatinib effects on cutaneous squamous cell carcinoma and actinic keratosis. ESMO open. 2016;1(1):e000003. https://doi.org/10.1136/esmoopen-2015-000003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lavrijsen AP, Tieben LM, Ponec M, van der Schroeff JG, van Muijen GN. Expression of EGF receptor, involucrin, and cytokeratins in basal cell carcinomas and squamous cell carcinomas of the skin. Arch Dermatol Res. 1989;281(2):83–8. https://doi.org/10.1007/bf00426583.

    Article  CAS  PubMed  Google Scholar 

  44. Liu B, Zhang H, Li S, Chen W, Li R. The expression of c-erbB-1 and c-erbB-2 oncogenes in basal cell carcinoma and squamous cell carcinoma of skin. Chin Med Sci J. 1996;11(2):106–9.

    CAS  PubMed  Google Scholar 

  45. Fogarty GB, Conus NM, Chu J, McArthur G. Characterization of the expression and activation of the epidermal growth factor receptor in squamous cell carcinoma of the skin. Br J Dermatol. 2007;156(1):92–8. https://doi.org/10.1111/j.1365-2133.2006.07603.x.

    Article  CAS  PubMed  Google Scholar 

  46. Wee KB, Aguda BD. Akt versus p53 in a network of oncogenes and tumor suppressor genes regulating cell survival and death. Biom J. 2006;91(3):857–65. https://doi.org/10.1529/biophysj.105.077693.

    Article  CAS  Google Scholar 

  47. Wee KB, Surana U, Aguda BD. Oscillations of the p53-Akt network: implications on cell survival and death. PLoS One. 2009;4(2):e4407. https://doi.org/10.1371/journal.pone.0004407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(9):1803–10. https://doi.org/10.1200/jco.2005.08.037.

    Article  CAS  Google Scholar 

  49. •• Joseph SR, Gaffney D, Barry R, Hu L, Banushi B, Wells JW, et al. An Ex Vivo Human Tumor Assay Shows Distinct Patterns of EGFR Trafficking in Squamous Cell Carcinoma Correlating to Therapeutic Outcomes. J Investig Dermatol. 2019;139(1):213–23. https://doi.org/10.1016/j.jid.2018.06.190. This paper describes an imaging method that allows ex vivo examination of EGFR internalization and shows that EGFR polarization is altered in cSCC. Authors found a strong association between EGFR internalization and poor responses to anti-EGFR therapies. They also suggested that these tumors can be classified based on their ability of EGFR internalization in response to ligand.

    Article  CAS  PubMed  Google Scholar 

  50. Mutch LJ, Howden JD, Jenner EP, Poulter NS, Rappoport JZ. Polarised clathrin-mediated endocytosis of EGFR during chemotactic invasion. Traffic. 2014;15(6):648–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Belleudi F, Scrofani C, Torrisi MR, Mancini P. Polarized endocytosis of the keratinocyte growth factor receptor in migrating cells: role of Src-signaling and cortactin. PLoS One. 2011;6(12):e29159. https://doi.org/10.1371/journal.pone.0029159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Research CfDEa. Clinical pharmacology and biopharmaceutics review - BLA125084. In: Administration USFaD, editor.2004.

  53. Srivastava RM, Lee SC, Andrade Filho PA, Lord CA, Jie HB, Davidson HC, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T cell immunity in head and neck cancer patients. Clin Cancer Res. 2013;19(7):1858–72. https://doi.org/10.1158/1078-0432.ccr-12-2426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kimura H, Sakai K, Arao T, Shimoyama T, Tamura T, Nishio K. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 2007;98(8):1275–80. https://doi.org/10.1111/j.1349-7006.2007.00510.x.

    Article  CAS  PubMed  Google Scholar 

  55. Patel D, Guo X, Ng S, Melchior M, Balderes P, Burtrum D, et al. IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab. Hum Antibodies. 2010;19(4):89–99. https://doi.org/10.3233/hab-2010-0232.

    Article  CAS  PubMed  Google Scholar 

  56. Miller K, Sherman W, Ratner D. Complete clinical response to cetuximab in a patient with metastatic cutaneous squamous cell carcinoma. Dermatol Surg: official publication for American Society for Dermatologic Surgery [et al]. 2010;36(12):2069–74. https://doi.org/10.1111/j.1524-4725.2010.01786.x.

    Article  CAS  Google Scholar 

  57. Kim S, Eleff M, Nicolaou N. Cetuximab as primary treatment for cutaneous squamous cell carcinoma to the neck. Head Neck. 2011;33(2):286–8. https://doi.org/10.1002/hed.21299.

    Article  PubMed  Google Scholar 

  58. Goppner D, Nekwasil S, Franke I, Gollnick H, Leverkus M. Successful combination therapy of a locally advanced squamous cell carcinoma of the skin with cetuximab and gamma-irradiation. J Dtsch Dermatol Ges. 2010;8(10):826–8. https://doi.org/10.1111/j.1610-0387.2010.07526.x.

    Article  PubMed  Google Scholar 

  59. • Joseph K, Alkaabi K, Warkentin H, Ghosh S, Jha N, Smylie M, et al. Cetuximab-radiotherapy combination in the management of locally advanced cutaneous squamous cell carcinoma. J Med Imaging Radiat Oncol. 2019;63(2):257–63. https://doi.org/10.1111/1754-9485.12842. This is recent study shows the efficacy of cetuximab in combination with radiotherapy for the treatment of 8 advanced cSCC cases. Complete response was observed in 6/8 patients with overall survival and progression-free survival rates of 87.5% and 83.3%, respectively.

    Article  PubMed  Google Scholar 

  60. Capalbo C, Belardinilli F, Filetti M, Parisi C, Petroni M, Colicchia V, et al. Effective treatment of a platinum-resistant cutaneous squamous cell carcinoma case by EGFR pathway inhibition. Mol Clini Oncol. 2018;9(1):30–4. https://doi.org/10.3892/mco.2018.1634.

    Article  CAS  Google Scholar 

  61. Conen KL, Fischer N, Hofbauer GF, Shafaeddin-Schreve B, Winterhalder R, Rochlitz C, et al. Cetuximab in metastatic squamous cell cancer of the skin: a Swiss case series. Dermatology (Basel, Switzerland). 2014;229(2):97–101. https://doi.org/10.1159/000362384.

    Article  CAS  Google Scholar 

  62. Falivene S, Giugliano FM, Grimaldi AM, Di Franco R, Toledo D, Muto M, et al. Tomotherapy concomitant with cetuximab, followed by cetuximab as single-agent therapy for unresectable squamous cell carcinoma of the skin: a case report. BMC Dermatol. 2014;14:15. https://doi.org/10.1186/1471-5945-14-15.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Preneau S, Rio E, Brocard A, Peuvrel L, Nguyen JM, Quereux G, et al. Efficacy of cetuximab in the treatment of squamous cell carcinoma. J Dermatol Treat. 2014;25(5):424–7. https://doi.org/10.3109/09546634.2012.751481.

    Article  CAS  Google Scholar 

  64. Samstein RM, Ho AL, Lee NY, Barker CA. Locally advanced and unresectable cutaneous squamous cell carcinoma: outcomes of concurrent cetuximab and radiotherapy. J Skin Cancer. 2014;2014:284582. https://doi.org/10.1155/2014/284582.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Carthon BC, Ng CS, Pettaway CA, Pagliaro LC. Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis. BJU Int. 2014;113(6):871–7. https://doi.org/10.1111/bju.12450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Foote MC, McGrath M, Guminski A, Hughes BG, Meakin J, Thomson D, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Annal Oncol: official journal of the European Society for Medical Oncology. 2014;25(10):2047–52. https://doi.org/10.1093/annonc/mdu368.

    Article  CAS  Google Scholar 

  67. Read WL, Brumund KT, Weisman RA, Nguyen AQ. Squamous cell carcinomas of the skin responsive to erlotinib: 5 cases. JAAD Case Rep. 2015;1(3):153–6. https://doi.org/10.1016/j.jdcr.2015.02.014.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Seber S, Gonultas A, Ozturk O, Yetisyigit T. Recurrent squamous cell carcinoma of the skin treated successfully with single agent cetuximab therapy. Onco Targets Ther. 2016;9:945–8. https://doi.org/10.2147/OTT.S96227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. William WN Jr, Feng L, Ferrarotto R, Ginsberg L, Kies M, Lippman S, et al. Gefitinib for patients with incurable cutaneous squamous cell carcinoma: a single-arm phase II clinical trial. J Am Acad Dermatol. 2017;77(6):1110–3.e2. https://doi.org/10.1016/j.jaad.2017.07.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. • Gold KA, Kies MS, William WN Jr, Johnson FM, Lee JJ, Glisson BS. Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase 2 clinical trial. Cancer. 2018;124(10):2169–73. https://doi.org/10.1002/cncr.31346. This study describes a recent single-arm phase II clinical trial evaluating the efficacy of erlotinib (EGFR TKI). Disease control rates was 72% with a 1-year overall survival of 53% and a 3-year overall survival of 19%.

    Article  CAS  PubMed  Google Scholar 

  71. Strickley JD, Spalding AC, Haeberle MT, Brown T, Stevens DA, Jung J. Metastatic squamous cell carcinoma of the skin with clinical response to lapatinib. Exp Hematol Oncol. 2018;7:20. https://doi.org/10.1186/s40164-018-0111-z.

    Article  PubMed  PubMed Central  Google Scholar 

  72. • Chen A, Ali N, Boasberg P, Ho AS. Clinical remission of cutaneous squamous cell carcinoma of the auricle with cetuximab and nivolumab. J Clin Med. 2018;7(1):E10. https://doi.org/10.3390/jcm7010010. This article describes a recent case report of invasive cSCC treated with combination of cetuximab and nivolumab. Complete remission was achieved after 6 months with no recurrence after 1 year.

    Article  CAS  PubMed  Google Scholar 

  73. Cavalieri S, Perrone F, Miceli R, Ascierto PA, Locati LD, Bergamini C, et al. Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer. Eur J Cancer (Oxford, England: 1990). 2018;97:7–15. https://doi.org/10.1016/j.ejca.2018.04.004.

    Article  CAS  Google Scholar 

  74. Cavalieri S, Perrone F, Milione M, Bianco A, Alfieri S, Locati LD, et al. PD-L1 Expression in unresectable locally advanced or metastatic skin squamous cell carcinoma treated with anti-epidermal growth factor receptor agents. Oncology. 2019;97(2):112–8. https://doi.org/10.1159/000500246.

    Article  CAS  PubMed  Google Scholar 

  75. Maubec E, Petrow P, Scheer-Senyarich I, Duvillard P, Lacroix L, Gelly J, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(25):3419–26. https://doi.org/10.1200/jco.2010.34.1735.

    Article  CAS  Google Scholar 

  76. Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res. 2000;6(6):2166–74.

    CAS  PubMed  Google Scholar 

  77. Bonner JA, Raisch KP, Trummell HQ, Robert F, Meredith RF, Spencer SA, et al. Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neck cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2000;18(21 Suppl):47s–53s.

    CAS  Google Scholar 

  78. Lewis CM, Glisson BS, Feng L, Wan F, Tang X, Wistuba II, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res: an official journal of the American Association for Cancer Research. 2012;18(5):1435–46. https://doi.org/10.1158/1078-0432.ccr-11-1951.

    Article  CAS  Google Scholar 

  79. Wang J, Wang C, Hu X, Yu C, Zhou L, Ding Z, et al. Gefitinib-mediated apoptosis is enhanced via inhibition of autophagy by chloroquine diphosphate in cutaneous squamous cell carcinoma cells. Oncol Lett. 2019;18(1):368–74. https://doi.org/10.3892/ol.2019.10308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. • Wollina U, Tchernev G, Lotti T. Chimeric Monoclonal Antibody Cetuximab Targeting Epidermal Growth Factor-Receptor in Advanced Non-Melanoma Skin Cancer Open Access Maced. J Med Sci. 2018;6(1):152–5. https://doi.org/10.3889/oamjms.2018.022. This review summarizes the specific use of cetuximab in NMSC from 2011 to 2017.

    Article  Google Scholar 

  81. Orditura M, De Vita F, Galizia G, Lieto E, Vecchione L, Vitiello F, et al. Correlation between efficacy and skin rash occurrence following treatment with the epidermal growth factor receptor inhibitor cetuximab: a single institution retrospective analysis. Oncol Rep. 2009;21(4):1023–8. https://doi.org/10.3892/or_00000319.

    Article  CAS  PubMed  Google Scholar 

  82. Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(1):77–85. https://doi.org/10.1200/jco.2004.06.075.

    Article  CAS  Google Scholar 

  83. Holcmann M, Sibilia M. Mechanisms underlying skin disorders induced by EGFR inhibitors. Mol Cell Oncol. 2015;2(4):e1004969–e. https://doi.org/10.1080/23723556.2015.1004969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res. 2005;11(1):397–405.

    CAS  PubMed  Google Scholar 

  85. • Chen L, Aria AB, Silapunt S, Migden MR. Emerging nonsurgical therapies for locally advanced and metastatic nonmelanoma skin cancer. Dermatol Surg. 2019;45(1):1–16. https://doi.org/10.1097/dss.0000000000001601. This review summarizes findings about the canonical ligand-induced EGFR signaling pathway and noncanonical EGFR functions with potential therapeutic approaches.

    Article  PubMed  Google Scholar 

  86. Choi FD, Kraus CN, Elsensohn AN, Carley SK, Lehmer LM, Nguyen RT, et al. PD-1 and PD-L1 inhibitors in the treatment of non-melanoma skin cancer: a systematic review. J Am Acad Dermatol. 2019. https://doi.org/10.1016/j.jaad.2019.05.077.

    Article  PubMed  Google Scholar 

  87. •• Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, et al. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N Engl J Med. 2018;379(4):341–51. https://doi.org/10.1056/NEJMoa1805131. This article describes the evaluation of the first anti-PD-1 antibody, cemiplimab, recently approved for the treatment of cSCC. Response to the treatment was observed in 50% of advanced or metastatic patients and 47% of the metastatic patients during the phase 1 and 2 studies, respectively.

    Article  CAS  PubMed  Google Scholar 

  88. Chang AL, Kim J, Luciano R, Sullivan-Chang L, Colevas AD. A case report of unresectable cutaneous squamous cell carcinoma responsive to pembrolizumab, a programmed cell death protein 1 inhibitor. JAMA Dermatol. 2016;152(1):106–8. https://doi.org/10.1001/jamadermatol.2015.2705.

    Article  PubMed  Google Scholar 

  89. Maubec E, Boubaya M, Petrow P, Basset-Seguin N, Grob JJ, Dréno B, et al. Pembrolizumab as first-line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC): phase 2 results from CARSKIN. J Clin Oncol. 2019;37(15_suppl):9547. https://doi.org/10.1200/JCO.2019.37.15_suppl.9547.

    Article  Google Scholar 

  90. Degache E, Crochet J, Simon N, Tardieu M, Trabelsi S, Moncourier M, et al. Major response to pembrolizumab in two patients with locally advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol. 2018;32(7):e257–e8. https://doi.org/10.1111/jdv.14371.

    Article  CAS  PubMed  Google Scholar 

  91. van Baar MLM, Guminski AD, Ferguson PM, Martin LK. Pembrolizumab for cutaneous squamous cell carcinoma: report of a case of inoperable squamous cell carcinoma with complete response to pembrolizumab complicated by granulomatous inflammation. JAAD Case Rep. 2019;5(6):491–4. https://doi.org/10.1016/j.jdcr.2019.04.006.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Borradori L, Sutton B, Shayesteh P, Daniels GA. Rescue therapy with anti-programmed cell death protein 1 inhibitors of advanced cutaneous squamous cell carcinoma and basosquamous carcinoma: preliminary experience in five cases. Br J Dermatol. 2016;175(6):1382–6. https://doi.org/10.1111/bjd.14642.

    Article  CAS  PubMed  Google Scholar 

  93. Blum V, Muller B, Hofer S, Pardo E, Zeidler K, Diebold J, et al. Nivolumab for recurrent cutaneous squamous cell carcinoma: three cases. Eur J Dermatol. 2018;28(1):78–81. https://doi.org/10.1684/ejd.2017.3209.

    Article  PubMed  Google Scholar 

  94. Miller DM, Faulkner-Jones BE, Stone JR, Drews RE. Complete pathologic response of metastatic cutaneous squamous cell carcinoma and allograft rejection after treatment with combination immune checkpoint blockade. JAAD Case Rep. 2017;3(5):412–5. https://doi.org/10.1016/j.jdcr.2017.06.005.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Day F, Kumar M, Fenton L, Gedye C. Durable response of metastatic squamous cell carcinoma of the skin to ipilimumab immunotherapy. J Immunother. 2017;40(1):36–8. https://doi.org/10.1097/cji.0000000000000146.

    Article  PubMed  Google Scholar 

  96. •• Li X, Lian Z, Wang S, Xing L, Yu J. Interactions between EGFR and PD-1/PD-L1 pathway: implications for treatment of NSCLC. Cancer Lett. 2018;418:1–9. https://doi.org/10.1016/j.canlet.2018.01.005. This review describes the mechanisms underlying the modulation of antitumor immunity by EGFR signaling. The authors also analyze the effect of PD-L1 on efficacy of EGFR inhibitors with important consideration for future trials.

    Article  CAS  PubMed  Google Scholar 

  97. •• Ahn MJ, Sun JM, Lee SH, Ahn JS, Park K. EGFR TKI combination with immunotherapy in non-small cell lung cancer. Expert opinion on drug safety. Expert Opin Drug Saf. 2017;16(4):465–9. https://doi.org/10.1080/14740338.2017.1300656. This article discusses the rationale for concomitant blockage of EGFR and immune checkpoints.

    Article  CAS  PubMed  Google Scholar 

  98. Su S, Zhao J, Xing Y, Zhang X, Liu J, Ouyang Q, et al. Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages. Cell. 2018;175(2):442–57.e23. https://doi.org/10.1016/j.cell.2018.09.007.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, Queensland, Australia

    Priscila Oliveira de Lima, Shannon Joseph & Fiona Simpson

  2. Faculty of Medicine, University of Queensland, Woolloongabba, Queensland, Australia

    Benedict Panizza

  3. Otolaryngology-Head and Neck Surgery Department, Princess Alexandra Hospital, Brisbane, Queensland, Australia

    Benedict Panizza

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  1. Priscila Oliveira de Lima
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  2. Shannon Joseph
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  3. Benedict Panizza
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  4. Fiona Simpson
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Correspondence to Fiona Simpson.

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Conflict of Interest

Priscila Oliveira de Lima declares that she has no conflict of interest.

Shannon Joseph has a patent pending 2015 Methods for Classifying Tumors and Uses Therefore (Simpson F, Joseph S).

Benedict Panizza declares that he has no conflict of interest.

Fiona Simpson recently completed an investigator-led contract with Merck KgAa on avelumab; has an issued patent 2015 WO2014063206-A1 “classifying epidermal growth factor receptor-positive tumor into subtype, e.g., epidermal growth factor receptor antagonist sensitive subtype, involves analyzing ligand-induced epidermal growth factor receptor internalization status of tumor” (Simpson F, Saunders NA); has an issued patent 2015 WO2014063205-A1 “composition useful in kit for treating tumor, preferably cell surface antigen-positive tumor, e.g., cancerous tumors, comprises antibody that binds to cell surface antigen of tumor and inhibitor of receptor-mediated endocytosis” (Simpson F, Saunders NA); and has a patent pending 2015 Methods for Classifying Tumors and Uses Therefore (Simpson F, Joseph S).

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de Lima, P.O., Joseph, S., Panizza, B. et al. Epidermal Growth Factor Receptor’s Function in Cutaneous Squamous Cell Carcinoma and Its Role as a Therapeutic Target in the Age of Immunotherapies. Curr. Treat. Options in Oncol. 21, 9 (2020). https://doi.org/10.1007/s11864-019-0697-3

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