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Non-melanoma Skin Cancer and Cutaneous Melanoma from the Oncological Point of View

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Non-Melanoma Skin Cancer and Cutaneous Melanoma

Abstract

The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from the metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with a median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited, and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy, and combination regimens failed to show significant improvement in overall survival.

Recent advances and an in-depth understanding of the biology of melanoma have contributed to the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression-free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review, the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic and molecular-targeted agents and the clinical perspectives of these new weapons against metastatic melanoma.

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References

  1. World Health Organization. Skin cancers [database on the Internet].

    Google Scholar 

  2. Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011;16(1):5–24. Epub 2011/01/08.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bedikian AY, Johnson MM, Warneke CL, Papadopoulos NE, Kim K, Hwu WJ, et al. Prognostic factors that determine the long-term survival of patients with unresec metastatic melanoma. Cancer Investig. 2008;26(6):624–33. Epub 2008/06/28

    CAS  Google Scholar 

  4. Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26(4):527–34. Epub 2008/02/01.

    PubMed  Google Scholar 

  5. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206. Epub 2009/11/18.

    PubMed  PubMed Central  Google Scholar 

  6. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351(10):998–1012. Epub 2004/09/03.

    CAS  PubMed  Google Scholar 

  7. Carter RD, Krementz ET, Hill GJ 2nd, Metter GE, Fletcher WS, Golomb FM, et al. DTIC (NSC-45388) and combination therapy for melanoma. I. Studies with DTIC, BCNU (NSC-409962), CCNU (NSC-79037), vincristine (NSC-67574), and hydroxyurea (NSC-32065). Cancer Treat Rep. 1976;60(5):601–9. Epub 1976/05/01

    CAS  PubMed  Google Scholar 

  8. Hill GJ 2nd, Krementz ET, Hill HZ. Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma. IV. Late results after complete response to chemotherapy (central oncology group protocols 7130, 7131, and 7131A). Cancer. 1984;53(6):1299–305. Epub 1984/03/15.

    PubMed  Google Scholar 

  9. Eggermont AM, Kirkwood JM. Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? Eur J Cancer. 2004;40(12):1825–36. Epub 2004/08/04.

    CAS  PubMed  Google Scholar 

  10. Fletcher WS, Green S, Fletcher JR, Dana B, Jewell W, Townsend RA. Evaluation of cis-platinum and DTIC combination chemotherapy in disseminated melanoma. A southwest oncology group study. Am J Clin Oncol. 1988;11(5):589–93. Epub 1988/10/01

    CAS  PubMed  Google Scholar 

  11. Vorobiof DA, Sarli R, Falkson G. Combination chemotherapy with dacarbazine and vindesine in the treatment of metastatic malignant melanoma. Cancer Treat Rep. 1986;70(7):927–8. Epub 1986/07/01

    CAS  PubMed  Google Scholar 

  12. Del Prete SA, Maurer LH, O’Donnell J, Forcier RJ, LeMarbre P. Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep. 1984;68(11):1403–5. Epub 1984/11/01

    Google Scholar 

  13. Legha SS, Ring S, Eton O, Bedikian A, Buzaid AC, Plager C, et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol. 1998;16(5):1752–9. Epub 1998/05/20

    CAS  PubMed  Google Scholar 

  14. Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, et al. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002;20(6):1600–7. Epub 2002/03/16.

    CAS  PubMed  Google Scholar 

  15. Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, et al. Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Ann Oncol. 2006;17(4):571–7. Epub 2006/02/14.

    CAS  PubMed  Google Scholar 

  16. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002;20(8):2045–52. Epub 2002/04/17

    CAS  PubMed  Google Scholar 

  17. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004;22(6):1118–25. Epub 2004/03/17

    CAS  PubMed  Google Scholar 

  18. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen melanoma study group. J Clin Oncol. 2006;24(29):4738–45. Epub 2006/09/13.

    CAS  PubMed  Google Scholar 

  19. Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Brocker EB, et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006;17(4):563–70. Epub 2006/01/19

    CAS  PubMed  Google Scholar 

  20. Ermertcan AT, Ozturk F, Gunduz K. Chemotherapy. In: Morton R, editor. Treatment of metastatic melanoma. 1st ed. Croatia: InTech; 2011. p. 73–90.

    Google Scholar 

  21. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158–66. Epub 2000/01/07

    CAS  PubMed  Google Scholar 

  22. Buzaid A, Legha SS, Winn R. Cisplatin (C), vinblastine (V) and dacarbazine (D) (CVD) versus dacarbazine alone in metastatic melanoma: preliminary results of a Phase II Cancer Community Oncology Program (CCOP) trial. ASCO; 1993.

    Google Scholar 

  23. Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol. 1999;17(9):2745–51. Epub 1999/11/24

    CAS  PubMed  Google Scholar 

  24. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16. Epub 2011/06/07

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature. 1983;302(5906):305–10. Epub 1983/03/24

    CAS  PubMed  Google Scholar 

  26. Smith KA. Interleukin-2: inception, impact, and implications. Science. 1988;240(4856):1169–76. Epub 1988/05/27

    CAS  PubMed  Google Scholar 

  27. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985;161(5):1169–88. Epub 1985/05/01

    CAS  PubMed  Google Scholar 

  28. Atkins MB. Cytokine-based therapy and biochemotherapy for advanced melanoma. Clin Cancer Res. 2006;12(7 Pt 2):2353s–8s. Epub 2006/04/13

    CAS  PubMed  Google Scholar 

  29. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16. Epub 1999/11/24

    CAS  PubMed  Google Scholar 

  30. Dutcher JP, Creekmore S, Weiss GR, Margolin K, Markowitz AB, Roper M, et al. A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol. 1989;7(4):477–85. Epub 1989/04/01

    CAS  PubMed  Google Scholar 

  31. Parkinson DR, Abrams JS, Wiernik PH, Rayner AA, Margolin KA, Van Echo DA, et al. Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study. J Clin Oncol. 1990;8(10):1650–6. Epub 1990/10/01

    CAS  PubMed  Google Scholar 

  32. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907–13. Epub 1994/03/23

    CAS  PubMed  Google Scholar 

  33. Balmer CM. Clinical use of biologic response modifiers in cancer treatment: an overview. Part II. Colony-stimulating factors and interleukin-2. DICP. 1991;25(5):490–8. Epub 1991/05/01

    CAS  PubMed  Google Scholar 

  34. Bruton JK, Koeller JM. Recombinant interleukin-2. Pharmacotherapy. 1994;14(6):635–56. Epub 1994/11/01

    CAS  PubMed  Google Scholar 

  35. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987;328(6127):267–70. Epub 1987/07/16

    CAS  PubMed  Google Scholar 

  36. Khattri R, Auger JA, Griffin MD, Sharpe AH, Bluestone JA. Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses. J Immunol. 1999;162(10):5784–91. Epub 1999/05/07

    CAS  PubMed  Google Scholar 

  37. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7. Epub 1995/11/01

    CAS  PubMed  Google Scholar 

  38. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–8. Epub 1995/11/10

    CAS  PubMed  Google Scholar 

  39. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459–65. Epub 1995/08/01

    CAS  PubMed  Google Scholar 

  40. Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12(12):1005–16. Epub 2005/11/12

    PubMed  PubMed Central  Google Scholar 

  41. Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23(35):8968–77. Epub 2005/10/06

    CAS  PubMed  Google Scholar 

  42. Alegre ML, Shiels H, Thompson CB, Gajewski TF. Expression and function of CTLA-4 in Th1 and Th2 cells. J Immunol. 1998;161(7):3347–56. Epub 1998/10/06

    CAS  PubMed  Google Scholar 

  43. McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol. 1999;77(1):1–10. Epub 1999/04/02.

    CAS  PubMed  Google Scholar 

  44. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002;16(1):23–35. Epub 2002/02/05

    CAS  PubMed  Google Scholar 

  45. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3(7):611–8. Epub 2002/06/28

    CAS  PubMed  Google Scholar 

  46. Hurwitz AA, Foster BA, Kwon ED, Truong T, Choi EM, Greenberg NM, et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 2000;60(9):2444–8. Epub 2000/05/16

    CAS  PubMed  Google Scholar 

  47. Kwon ED, Foster BA, Hurwitz AA, Madias C, Allison JP, Greenberg NM, et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Proc Natl Acad Sci U S A. 1999;96(26):15074–9. Epub 1999/12/28

    CAS  PubMed  PubMed Central  Google Scholar 

  48. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190(3):355–66. Epub 1999/08/03.

    PubMed  PubMed Central  Google Scholar 

  49. Espenschied J, Lamont J, Longmate J, Pendas S, Wang Z, Diamond DJ, et al. CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. J Immunol. 2003;170(6):3401–7. Epub 2003/03/11.

    CAS  PubMed  Google Scholar 

  50. Sabel MS, Hess SD, Egilmez NK, Conway TF Jr, Chen FA, Bankert RB. CTLA-4 blockade augments human T lymphocyte-mediated suppression of lung tumor xenografts in SCID mice. Cancer Immunol Immunotherapy. 2005;54(10):944–52. Epub 2005/04/23

    CAS  Google Scholar 

  51. Paradis TJ, Floyd E, Burkwit J, Cole SH, Brunson B, Elliott E, et al. The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFN gamma. Cancer Immunol Immunother 2001;50(3):125-133. Epub 2001/06/23.

    Google Scholar 

  52. Canniff PC, Donovan CB, Burkwit JJ, et al. CP-675, 205 anti CTLA-4 antibody clinical candidate enhances IL-2 production in cancer patient T cells in vitro regardless of tumor type or stage of disease. Amer Assoc. Cancer Res. 2004;45

    Google Scholar 

  53. Bulanhagui CA, Ribas A, Dea P. Phase 1 clinical trials of CP-675, 206: tumor responses are sufficient but not necessary for prolonged survival. J Clin Oncol. 2006;24:461s.

    Google Scholar 

  54. Gomez-Navarro J, Sharma A, Vea B. Dose and schedule selection for the anti-CTLA-4 monoclonal antibody (mAb) CP-675, 206 in patients (pts) with metastatic melanoma. J Clin Oncol. 2006;(24 (suppl)):460s.

    Google Scholar 

  55. Ribas AA, Sosman J, et al. Results of a phase II clinical trial of 2 doses and schedules of CP-675, 206, an anti-CTLA-4 monocloncal antibody, in patients with advanced melanoma. J Clin Oncol. 2007;118s:25.

    Google Scholar 

  56. Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16(3):1042–8. Epub 2010/01/21

    CAS  PubMed  Google Scholar 

  57. Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–22. Epub 2013/01/09

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. Epub 2010/06/08

    Google Scholar 

  59. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26. Epub 2011/06/07

    Google Scholar 

  60. Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13(6):1810–5. Epub 2007/03/17

    CAS  PubMed  Google Scholar 

  61. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23(25):6043–53. Epub 2005/08/10

    CAS  PubMed  Google Scholar 

  62. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64. Epub 2009/12/17

    CAS  PubMed  Google Scholar 

  63. Wolchok JD, Weber JS, Hamid O, Lebbe C, Maio M, Schadendorf D, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun 2010;10:9. Epub 2010/10/21.

    Google Scholar 

  64. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10(9):909–15. Epub 2004/09/02.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364(22):2119–27. Epub 2011/06/03

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Robert C, Schadendorf D, Messina M, Hodi FS, O’Day S. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res. 2013;19(8):2232–9. Epub 2013/02/28

    Google Scholar 

  67. Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance A, et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2017;18(5):611–22.

    CAS  PubMed  Google Scholar 

  68. Eggermont AM, Robert C. New drugs in melanoma: it’s a whole new world. Eur J Cancer. 2011;47(14):2150–7. Epub 2011/08/02

    Google Scholar 

  69. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20. Epub 2009/11/26

    Google Scholar 

  70. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7. Epub 2012/05/23

    CAS  PubMed  Google Scholar 

  71. Squibb B-M. YERVOY (ipilimumab): Serious and fatal immune-mediated adverse reactions - YERVOY Risk Evaluation and Mitigation Stategy (REMS). http://www.yervoy.com/hcp/rems.aspx.

  72. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65. Epub 2012/03/30

    CAS  PubMed  Google Scholar 

  73. Diao K, Bian SX, Routman DM, Yu C, Kim PE, Wagle NA, et al. Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J Neurosurg. 2018;129(6):1397–406.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Diao K, Bian SX, Routman DM, Yu C, Ye JC, Wagle NA, et al. Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. J Neuro-Oncol. 2018;139(2):421–9.

    CAS  Google Scholar 

  75. Cohen-Inbar O, Shih HH, Xu Z, Schlesinger D, Sheehan JP. The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab. J Neurosurg. 2017;127(5):1007–14.

    PubMed  Google Scholar 

  76. Yuan J, Gnjatic S, Li H, Powel S, Gallardo HF, Ritter E, et al. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci U S A. 2008;105(51):20410–5. Epub 2008/12/17

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005;5(8):615–25. Epub 2005/07/22

    CAS  PubMed  Google Scholar 

  78. Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16(10):2861–71. Epub 2010/05/13

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled analysis of Long-term survival data from phase II and phase III trials of Ipilimumab in Unresectable or metastatic melanoma. J Clin Oncol. 2015;33(17):1889–94. Epub 2015/02/11.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hamid OHW, Richards JM, et al. Ipilimumab (Ipi) expanded access program (EAP) for patients with stage III/IV melanoma: 10mg/kg cohort interim results. J Clin Oncol. 2012;30:15s. suppl

    Google Scholar 

  81. Hodi FS, Friedlander A, Atkins MB, McDermott D, Lawrence D, Ibrahim Nea. A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2011(29 suppl).

    Google Scholar 

  82. Amin A, Lawson DH, Salama AK, Koon HB, Guthrie T Jr, Thomas SS, et al. Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. J Immunother Cancer. 2016;4:44.

    PubMed  PubMed Central  Google Scholar 

  83. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51. Epub 1999/09/15.

    CAS  PubMed  Google Scholar 

  84. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19(7):813–24. Epub 2007/07/04.

    CAS  PubMed  Google Scholar 

  85. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9. Epub 1999/12/02.

    CAS  PubMed  Google Scholar 

  86. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34. Epub 2000/10/04.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193(7):839–46. Epub 2001/04/03.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–8. Epub 2001/02/27.

    CAS  PubMed  Google Scholar 

  89. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800. Epub 2002/07/02.

    CAS  PubMed  Google Scholar 

  90. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293–7. Epub 2002/09/10

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–77. Epub 2008/05/27

    CAS  PubMed  Google Scholar 

  92. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med. 2003;9(5):562–7. Epub 2003/04/22

    CAS  PubMed  Google Scholar 

  93. Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol. 2009;10(11):1185–92. Epub 2009/09/29

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54. Epub 2012/06/05

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65. Epub 2012/06/05

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. Epub 2013/06/04.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17. Epub 2014/07/19

    CAS  PubMed  Google Scholar 

  98. Daud A, Ribas A, Robert C, Hodi FS, Wolchok JD, Joshua AM, et al. Long-term efficacy of pembrolizumab in a pooled analysis of 655 patients with advanced melanoma enrolled in KEYNOTE-001. ASCO; 2015.

    Google Scholar 

  99. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015;16(8):908-918. Epub 2015/06/28.

    Google Scholar 

  100. Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, et al. Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017;86:37–45.

    CAS  PubMed  Google Scholar 

  101. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84. Epub 2015/03/22.

    Google Scholar 

  102. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521–32. Epub 2015/04/22

    CAS  PubMed  Google Scholar 

  103. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. Epub 2014/11/18.

    CAS  PubMed  Google Scholar 

  104. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17. Epub 2015/04/22

    PubMed  PubMed Central  Google Scholar 

  105. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. Epub 2015/06/02

    PubMed  PubMed Central  Google Scholar 

  106. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. Epub 2013/06/04.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92.

    CAS  PubMed  Google Scholar 

  108. Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018;19(5):672–81.

    CAS  PubMed  Google Scholar 

  109. Hu JC, Coffin RS, Davis CJ, Graham NJ, Groves N, Guest PJ, et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006;12(22):6737–47. Epub 2006/11/24

    CAS  PubMed  Google Scholar 

  110. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–8. Epub 2015/05/28

    CAS  PubMed  Google Scholar 

  111. Puzanov I, Milhem MM, Minor D, Hamid O, Li A, Chen L, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol. 2016;34(22):2619–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. https://clinicaltrials.gov. Accessed 18 Mar 2019.

  113. Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011;104(3):392–8. Epub 2010/12/09

    CAS  PubMed  Google Scholar 

  114. Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL, et al. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res. 2003;63(4):756–9. Epub 2003/02/20

    CAS  PubMed  Google Scholar 

  115. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47. Epub 2005/11/18.

    CAS  PubMed  Google Scholar 

  116. Flaherty KT, Brose M, Schucter L, editors. Phase I/II trial of BAY 43-9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma. Virginia: ASCO; 2004.

    Google Scholar 

  117. McDermott DF, Sosman JA, Gonzalez R, Hodi FS, Linette GP, Richards J, et al. Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 study group. J Clin Oncol. 2008;26(13):2178–85. Epub 2008/05/01

    CAS  PubMed  Google Scholar 

  118. Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27(17):2823–30. Epub 2009/04/08.

    CAS  PubMed  Google Scholar 

  119. Flaherty K. Final results of E2603: a double-blind, randomized phase III trial comparing carboplatin (C)/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma. J Clin Oncol. 2010;20(15). suppl

    Google Scholar 

  120. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19. Epub 2010/09/08.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Ribas A, Kim KB, Schuchter LM. al. e. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation positive metastatic melanoma. J Clin Oncol. 2011;29(suppl)

    Google Scholar 

  122. Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014;15(4):436–44. Epub 2014/03/04.

    CAS  PubMed  Google Scholar 

  123. Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31(26):3205–11. Epub 2013/08/07

    Google Scholar 

  124. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65. Epub 2012/06/28

    CAS  PubMed  Google Scholar 

  125. Dummer R, Robert C, Chapman PB, et al. AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol. 2008;26

    Google Scholar 

  126. Comparison of AZD6244 in combination with dacarbazine versus (vs) dacarbazine alone in BRAF mutation positive melanoma patients. [database on the Internet]; 2010. [cited June 11, 2010]. http://clinicaltrials.gov/ct2/show/.

  127. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32. Epub 2014/02/11.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Hauschild A, Grob JJ. Demidov LV, al. e. an update on BREAK-3, a phase III, randomized trial: dabrafeniv (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol. 2013;31(Suppl)

    Google Scholar 

  129. Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20(7):1965–77. Epub 2014/01/28

    CAS  PubMed  Google Scholar 

  130. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4(1):94–109. Epub 2013/11/23

    PubMed  Google Scholar 

  131. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4(1):80–93. Epub 2013/11/23

    CAS  PubMed  Google Scholar 

  132. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5. Epub 2010/02/05.

    CAS  PubMed  Google Scholar 

  133. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427–30. Epub 2010/02/25

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140(2):209–21. Epub 2010/02/10.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med. 2012;367(24):2316–21. Epub 2012/11/09

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207–15. Epub 2012/01/20

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Oberholzer PA, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2012;30(3):316–21. Epub 2011/11/10

    CAS  PubMed  Google Scholar 

  138. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703. Epub 2012/10/02

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88. Epub 2014/09/30

    PubMed  Google Scholar 

  140. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444–51. Epub 2015/06/04.

    CAS  PubMed  Google Scholar 

  141. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9. Epub 2014/11/18.

    PubMed  Google Scholar 

  142. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76. Epub 2014/09/30

    PubMed  Google Scholar 

  143. Hoeflich KP, Merchant M, Orr C, Chan J, Den Otter D, Berry L, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012;72(1):210–9. Epub 2011/11/16.

    CAS  PubMed  Google Scholar 

  144. Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014;15(9):954–65. Epub 2014/07/20

    CAS  PubMed  Google Scholar 

  145. Delord JP, Robert C, Nyakas M, McArthur GA, Kudchakar R, Mahipal A, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor Encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res. 2017;23(18):5339–48.

    CAS  PubMed  Google Scholar 

  146. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–15.

    CAS  PubMed  Google Scholar 

  147. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315–27.

    CAS  PubMed  Google Scholar 

  148. NCCN Guidelines Version 1.2019.

    Google Scholar 

  149. Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol. 1994;30:774–8.

    CAS  PubMed  Google Scholar 

  150. Gorlin RJ. Nevoid basal cell carcinoma syndrome. Medicine (Baltimore). 1987;66:98–113.

    CAS  Google Scholar 

  151. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668–71.

    CAS  PubMed  Google Scholar 

  152. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841–51.

    CAS  PubMed  Google Scholar 

  153. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78–81.

    CAS  PubMed  Google Scholar 

  155. Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998;110:885–8.

    CAS  PubMed  Google Scholar 

  156. Ling G, Ahmadian A, Persson A, Undén AB, Afink G, Williams C, et al. PATHCED and p53 gene alterations in sporadic and hereditary basal cell cancer. Oncogene. 2001;20:7770–8.

    CAS  PubMed  Google Scholar 

  157. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.

    Google Scholar 

  158. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–9. https://doi.org/10.1056/NEJMoa1113713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180–8. https://doi.org/10.1056/NEJMoa1113538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Casey D, Demko S, Shord S, Zhao H, Chen H, He K, Putman A, Helms WS, et al. FDA approval summary: sonidegib for locally advanced basal cell carcinoma. Clin Cancer Res. 2017; https://doi.org/10.1158/1078-0432.CCR-16-2051.

  161. Dummer R, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. The 12-month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol. 2016;75(1):113–125.e5. https://doi.org/10.1016/j.jaad.2016.02.1226.

    Article  CAS  PubMed  Google Scholar 

  162. Iyer JG, Blom A, Doumani R, Lewis C, Tarabadkar ES, Anderson A, et al. Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med. 2016;5(9):2294–301. https://doi.org/10.1002/cam4.815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Tai PT, Yu E, Winquist E, Hammond A, Stitt L, Tonita J, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review: of 204 cases. J Clin Oncol. 2000;18(12):2493–9.

    CAS  PubMed  Google Scholar 

  164. Paulson KG, Iyer JG, Blom A, Warton EM, Sokil M, Yelistratova L, et al. Systemic immune suppression predicts diminished Merkel cell carcinoma-specificsurvival independent of stage. J Invest Dermatol. 2013;133(3):642–6. https://doi.org/10.1038/jid.2012.388. Epub 2012 Nov 29

    Article  CAS  PubMed  Google Scholar 

  165. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096–100. https://doi.org/10.1126/science.1152586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Iyer JG, Afanasiev OK, McClurkan C, Paulson K, Nagase K, Jing L, et al. Merkel cell polyomavirus-specific CD8+ and CD4+ T-cell responses identified inMerkel cell carcinomas and blood. Clin Cancer Res. 2011;17(21):6671–80. https://doi.org/10.1158/1078-0432.CCR-11-1513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Afanasiev OK, Yelistratova L, Miller N, Nagase K, Paulson K, Iyer JG, et al. Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res. 2013;19(19):5351–60. https://doi.org/10.1158/1078-0432.CCR-13-0035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Paulson KG, Carter JJ, Johnson LG, Cahill KW, Iyer JG, Schrama D, et al. Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden inmerkel cell carcinoma patients. Cancer Res. 2010;70(21):8388–97. https://doi.org/10.1158/0008-5472.CAN-10-2128. Epub 2010 Oct 19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wong SQ, Waldeck K, Vergara IA, Schröder J, Madore J, Wilmott JS, et al. UV-associated mutations underlie the etiology of MCV-negative merkel cell carcinomas. Cancer Res. 2015;75(24):5228–34. https://doi.org/10.1158/0008-5472.CAN-15-1877.

    Article  CAS  PubMed  Google Scholar 

  170. Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM, Dhanasekaran SM, et al. The distinctive mutational spectra of polyomavirus-negative merkel cell carcinoma. Cancer Res. 2015;75(18):3720–7. https://doi.org/10.1158/0008-5472.CAN-15-0702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Goh G, Walradt T, Markarov V, Blom A, Riaz N, Doumani R, et al. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget. 2016;7(3):3403–15. https://doi.org/10.18632/oncotarget.6494.

    Article  PubMed  Google Scholar 

  172. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37. https://doi.org/10.1126/scitranslmed.3003689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lipson EJ, Vincent JG, Loyo M, Kagohara LT, Luber BS, Wang H, Xu H, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res. 2013;1:54–63. https://doi.org/10.1158/2326-6066.CIR-13-0034.

    Article  CAS  PubMed  Google Scholar 

  174. Dowlatshahi M, Huang V, Gehad AE, Jiang Y, Calarese A, Teague JE, et al. Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T-cell exhaustion in reducing T-cell responses. J Invest Dermatol. 2013;133(7):1879–89. https://doi.org/10.1038/jid.2013.75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al. PD-1 blockade with Pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med. 2016;374(26):2542–52. https://doi.org/10.1056/NEJMoa1603702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Walocko FM, Scheier BY, Harms PW, Fecher LA, Lao CD. Metastatic Merkel cell carcinoma response to nivolumab. J Immunother Cancer. 2016;4:79.

    PubMed  PubMed Central  Google Scholar 

  177. Mantripragada K, Bimbaum A. Response to anti-PD-1 therapy in metastatic merkel cell carcinoma metastatic to the heart and pancreas. Cureus. 2015;7(12):e403. https://doi.org/10.7759/cureus.403.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Kaufman HL, Russell JS, Hamid O, Bhatia S, Terheyden P, D’Angelo SP, et al. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer. 2018;6(1):7.

    Google Scholar 

  179. Kelly K, Infante JR, Taylor MH, Patel MR, Wong DJ, Iannotti N, et al. Safety profile of avelumab in patients with advanced solid tumors: a pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. Cancer. 2018;124(9):2010–7.

    CAS  PubMed  Google Scholar 

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Gogas, H., Diamantopoulos, P., Polyzos, A. (2020). Non-melanoma Skin Cancer and Cutaneous Melanoma from the Oncological Point of View. In: Papadopoulos, O., Papadopulos, N.A., Champsas, G. (eds) Non-Melanoma Skin Cancer and Cutaneous Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-030-18797-2_2

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