Top

Published in:

01-01-2020 | Cutaneous Squamous Cell Carcinoma | Skin Cancer (T Ito, Section Editor)

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

Authors: Priscila Oliveira de Lima, Shannon Joseph, Benedict Panizza, Fiona Simpson

Published in: Current Treatment Options in Oncology | Issue 1/2020

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.

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.CrossRefPubMed

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

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.

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.CrossRef

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

16.

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

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.

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.CrossRefPubMed

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.CrossRefPubMed

24.

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

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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%.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRef

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.PubMed

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.

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.PubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

Title: Epidermal Growth Factor Receptor’s Function in Cutaneous Squamous Cell Carcinoma and Its Role as a Therapeutic Target in the Age of Immunotherapies
Authors: Priscila Oliveira de Lima
Shannon Joseph
Benedict Panizza
Fiona Simpson
Publication date: 01-01-2020
Publisher: Springer US
Keywords: Cutaneous Squamous Cell Carcinoma
Radiotherapy
Cutaneous Squamous Cell Carcinoma
Erlotinib
Cetuximab
Published in: Current Treatment Options in Oncology / Issue 1/2020
Print ISSN: 1527-2729
Electronic ISSN: 1534-6277
DOI: https://doi.org/10.1007/s11864-019-0697-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Opinion statement

Please log in to get access to this content

Other articles of this Issue 1/2020

Prognosticating for Adult Patients With Advanced Incurable Cancer: a Needed Oncologist Skill

The Microbiota in Hematologic Malignancies

Opioids in Cancer Development, Progression and Metastasis: Focus on Colorectal Cancer

Chemotherapy-Induced Sarcopenia

Multimodal Therapy for Sinonasal Malignancies: Updates and Review of Current Treatment

Current and Future Molecular Targets for Acute Myeloid Leukemia Therapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer