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Emerging Clinical Issues in Melanoma in the Molecularly Targeted Era

  • Ryan J. Sullivan
  • Michael B. Atkins
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1102)

Abstract

The standard of care of patients with malignant melanoma is dramatically changing, hallmarked by the approval of three new agents for the treatment of malignant melanoma in 2011. In this changing therapeutic landscape, several clinical issues are emerging which will best be addressed through the application of advances in molecular analytics, diagnostics, and therapeutics. It is expected that dedicated and coordinated efforts in basic, translational, and clinical will be responsible for the next major breakthroughs in the care of patients with this dreaded disease. In this chapter, five critical, emerging clinical issues are presented with descriptions of approaches that might be expected to help solve these challenges to optimal patient care.

Key words

BRAF NRAS Predictive biomarkers Patient selection Treatment sequencing 

References

  1. 1.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2012. CA Cancer J Clin 63(1):11–30Google Scholar
  2. 2.
    Ascierto PA, Kirkwood JM (2008) Adjuvant therapy of melanoma with interferon: lessons of the past decade. J Transl Med 6:62PubMedCrossRefGoogle Scholar
  3. 3.
    Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U (2004) A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 10:1670–1677PubMedCrossRefGoogle Scholar
  4. 4.
    Eggermont AM, Suciu S, Santinami M et al (2008) Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372:117–126PubMedCrossRefGoogle Scholar
  5. 5.
    Mocellin S, Pasquali S, Rossi CR, Nitti D (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 102:493–501PubMedCrossRefGoogle Scholar
  6. 6.
    Berry DA, Cirrincione C, Henderson IC et al (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658–1667PubMedCrossRefGoogle Scholar
  7. 7.
    Peto R, Davies C, Godwin J et al (2012) Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379:432–444PubMedCrossRefGoogle Scholar
  8. 8.
    Balch CM, Buzaid AC, Soong SJ et al (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMedGoogle Scholar
  9. 9.
    Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206PubMedCrossRefGoogle Scholar
  10. 10.
    Eggermont AM, Suciu S, Testori A et al (2012) Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer 48:218–225PubMedCrossRefGoogle Scholar
  11. 11.
    Gogas H, Ioannovich J, Dafni U et al (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718PubMedCrossRefGoogle Scholar
  12. 12.
    Bouwhuis MG, Suciu S, Testori A et al (2010) Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies—EORTC 18991. J Clin Oncol 28:2460–2466PubMedCrossRefGoogle Scholar
  13. 13.
    Flaherty LE, Moon J, Atkins MB et al (2012) Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): an intergroup study of CALGB, COG, ECOG, and SWOG. J Clin Oncol 30Google Scholar
  14. 14.
    Lian B, Mao LL, Cui CL et al (2012) Phase II randomized study of high-dose interferon alfa-2b (HDI) versus chemotherapy as adjuvant therapy in patients with resected mucosal melanoma. J Clin Oncol 30Google Scholar
  15. 15.
    Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516PubMedCrossRefGoogle Scholar
  16. 16.
    Hauschild A, Grob JJ, Demidov LV et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365PubMedCrossRefGoogle Scholar
  17. 17.
    Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCrossRefGoogle Scholar
  18. 18.
    Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526PubMedCrossRefGoogle Scholar
  19. 19.
    Panka DJ, Sullivan RJ, Mier JW (2010) An inexpensive, specific and highly sensitive protocol to detect the BrafV600E mutation in melanoma tumor biopsies and blood. Melanoma Res 20:401–407PubMedGoogle Scholar
  20. 20.
    Kitago M, Koyanagi K, Nakamura T et al (2009) mRNA expression and BRAF mutation in circulating melanoma cells isolated from peripheral blood with high molecular weight melanoma-associated antigen-specific monoclonal antibody beads. Clin Chem 55:757–764PubMedCrossRefGoogle Scholar
  21. 21.
    Hoshimoto S, Faries MB, Morton DL et al (2012) Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. Ann Surg 255:357–362PubMedCrossRefGoogle Scholar
  22. 22.
    Sullivan RJ, Atkins MB (2010) Cytokine therapy in melanoma. J Cutan Pathol 37(Suppl 1):60–67PubMedCrossRefGoogle Scholar
  23. 23.
    Atkins MB, Lotze MT, Dutcher JP et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116PubMedGoogle Scholar
  24. 24.
    Atkins MB, Kunkel L, Sznol M, Rosenberg SA (2000) High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6(Suppl 1):S11–S14PubMedGoogle Scholar
  25. 25.
    Joseph RW, Sullivan RJ, Harrell R et al (2012) Correlation of NRAS mutations with clinical response to high-dose IL-2 in patients with advanced melanoma. J Immunother 35:66–72PubMedCrossRefGoogle Scholar
  26. 26.
    Sullivan RJ, Hoshida Y, Brunet J et al (2009) A single center experience with high-dose IL-2 treatment for patients with advanced melanoma and pilot investigation of a novel gene expression signature as a predictor of response. J Clin Oncol 27(suppl): abstr 9003Google Scholar
  27. 27.
    Sabatino M, Kim-Schulze S, Panelli MC et al (2009) Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 27:2645–2652PubMedCrossRefGoogle Scholar
  28. 28.
    Wolchok JD, Saenger Y (2008) The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist 13(suppl 4):2–9PubMedCrossRefGoogle Scholar
  29. 29.
    Wolchok JD, Neyns B, Linette G et al (2010) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11:155–164PubMedCrossRefGoogle Scholar
  30. 30.
    Wolchok JD, Weber JS, Hamid O et al (2010) Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun 10:9PubMedGoogle Scholar
  31. 31.
    Weber JS, Kahler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30:2691–2697PubMedCrossRefGoogle Scholar
  32. 32.
    Yuan J, Adamow M, Ginsberg BA et al (2011) Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc Natl Acad Sci USA 108: 16723–16728PubMedCrossRefGoogle Scholar
  33. 33.
    Breunis WB, Tarazona-Santos E, Chen R, Kiley M, Rosenberg SA, Chanock SJ (2008) Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother 31: 586–590PubMedCrossRefGoogle Scholar
  34. 34.
    Hamid O, Schmidt H, Nissan A et al (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204PubMedCrossRefGoogle Scholar
  35. 35.
    Shahabi V, Whitney G, Hamid O et al (2012) Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother 61:733–737PubMedCrossRefGoogle Scholar
  36. 36.
    Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264PubMedCrossRefGoogle Scholar
  37. 37.
    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454PubMedCrossRefGoogle Scholar
  38. 38.
    Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465PubMedCrossRefGoogle Scholar
  39. 39.
    Taube JM, Anders RA, Young GD et al (2012) Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4:127–137CrossRefGoogle Scholar
  40. 40.
    Sosman JA, Kim KB, Schuchter L et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714PubMedCrossRefGoogle Scholar
  41. 41.
    Smith FO, Goff SL, Klapper JA et al (2007) Risk of bowel perforation in patients receiving interleukin-2 after therapy with anti-CTLA 4 monoclonal antibody. J Immunother 30:130PubMedCrossRefGoogle Scholar
  42. 42.
    Ackerman A, McDermott DF, Lawrence DP et al (2012) Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after vemurafenib. J Clin Oncol 30:8569Google Scholar
  43. 43.
    Flaherty KT, Robert C, Hersey P et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367(2):107–114PubMedCrossRefGoogle Scholar
  44. 44.
    Hauschild A, Agarwala SS, Trefzer U et al (2009) 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 27:2823–2830PubMedCrossRefGoogle Scholar
  45. 45.
    Falchook GS, Long GV, Kurzrock R et al (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379:1893–1901PubMedCrossRefGoogle Scholar
  46. 46.
    Flaherty KT, Puzanov I, Kim KB et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363: 809–819PubMedCrossRefGoogle Scholar
  47. 47.
    Sullivan RJ, Flaherty K (2013) MAP kinase signaling and inhibition in melanoma. Oncogene 32(19):2373–2379PubMedCrossRefGoogle Scholar
  48. 48.
    Nathanson KL, Martin A, Letrero R, D’Andrea KP, O’Day S, Infante JR, Falchook GS, Millward M, Curtis CM, Ma B, Gagnon RC, Lebowitz PF, Long GV, Kefford RF (2011) Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436). In: ASCO, 2011, Chicago. J Clin Oncol (suppl): abstr 8501Google Scholar
  49. 49.
    Smalley KS, Lioni M, Dalla Palma M et al (2008) Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 7:2876–2883PubMedCrossRefGoogle Scholar
  50. 50.
    Straussman R, Morikawa T, Shee K et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487:500–504PubMedCrossRefGoogle Scholar
  51. 51.
    Wilson TR, Fridlyand J, Yan Y et al (2012) Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487:505–509PubMedCrossRefGoogle Scholar
  52. 52.
    Bollag G, Hirth P, Tsai J et al (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599PubMedCrossRefGoogle Scholar
  53. 53.
    Johannessen CM, Boehm JS, Kim SY et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972PubMedCrossRefGoogle Scholar
  54. 54.
    Nazarian R, Shi H, Wang Q et al (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977PubMedCrossRefGoogle Scholar
  55. 55.
    Villanueva J, Vultur A, Lee JT et al (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683–695PubMedCrossRefGoogle Scholar
  56. 56.
    Wagle N, Emery C, Berger MF et al (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29:3085–3096PubMedCrossRefGoogle Scholar
  57. 57.
    Poulikakos PI, Persaud Y, Janakiraman M et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–390PubMedCrossRefGoogle Scholar
  58. 58.
    Shi H, Moriceau G, Kong X et al (2012) Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3:724PubMedCrossRefGoogle Scholar
  59. 59.
    Tap WD, Gong KW, Dering J et al (2010) Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma. Neoplasia 12:637–649PubMedGoogle Scholar
  60. 60.
    Emery CM, Vijayendran KG, Zipser MC et al (2009) MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci USA 106:20411–20416PubMedCrossRefGoogle Scholar
  61. 61.
    Weber JS, Flaherty KT, Infante JR, Falchook GS, Kefford R, Daud A, Hamid O, Gonzalez R, Kudchadkar RR, Lawrence DP, Burris HA, Long GV, Algazi AP, Lewis KD, Kim KB, Puzanov I, Sun P, Little SM, Patel K, Sosman JA (2012) Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. In: ASCO, 2012, Chicago. J Clin Oncol (suppl): abstr 8510Google Scholar
  62. 62.
    Koya RC, Mok S, Otte N et al (2012) BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res 72:3928–3937PubMedCrossRefGoogle Scholar
  63. 63.
    Boni A, Cogdill AP, Dang P et al (2010) Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 70: 5213–5219PubMedCrossRefGoogle Scholar
  64. 64.
    Wilmott JS, Long GV, Howle JR et al (2012) Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res 18:1386–1394PubMedCrossRefGoogle Scholar
  65. 65.
    Comin-Anduix B, Chodon T, Sazegar H et al (2010) The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin Cancer Res 16:6040–6048PubMedCrossRefGoogle Scholar
  66. 66.
    Omholt K, Platz A, Kanter L, Ringborg U, Hansson J (2003) NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 9:6483–6488PubMedGoogle Scholar
  67. 67.
    McArthur GA, Young RJ, Sheppard KE et al (2012) Clinical significance of genomic alterations of the CDK4-pathway and sensitivity to the CDK4 inhibitor PD 0332991 in melanoma. J Clin Oncol 30Google Scholar
  68. 68.
    Solit DB, Garraway LA, Pratilas CA et al (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362PubMedCrossRefGoogle Scholar
  69. 69.
    Adjei AA, Cohen RB, Franklin W et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–2146PubMedCrossRefGoogle Scholar
  70. 70.
    Banerji U, Camidge DR, Verheul HM et al (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16:1613–1623PubMedCrossRefGoogle Scholar
  71. 71.
    Ascierto PA, Berking C, Agawala SS et al (2012) Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations. In: ASCO, 2012, Chicago. J Clin OncolGoogle Scholar
  72. 72.
    Curtin JA, Fridlyand J, Kageshita T et al (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147PubMedCrossRefGoogle Scholar
  73. 73.
    Curtin JA, Busam K, Pinkel D, Bastian BC (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346PubMedCrossRefGoogle Scholar
  74. 74.
    Carvajal RD, Antonescu CR, Wolchok JD et al (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305:2327–2334PubMedCrossRefGoogle Scholar
  75. 75.
    Guo J, Si L, Kong Y et al (2011) Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29:2904–2909PubMedCrossRefGoogle Scholar
  76. 76.
    Wyman K, Atkins MB, Prieto V et al (2006) Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 106:2005–2011PubMedCrossRefGoogle Scholar
  77. 77.
    Van Raamsdonk CD, Bezrookove V, Green G et al (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:599–602PubMedCrossRefGoogle Scholar
  78. 78.
    Van Raamsdonk CD, Griewank KG, Crosby MB et al (2010) Mutations in GNA11 in uveal melanoma. N Engl J Med 363:2191–2199PubMedCrossRefGoogle Scholar
  79. 79.
    Harbour JW, Onken MD, Roberson ED et al (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:1410–1413PubMedCrossRefGoogle Scholar
  80. 80.
    Hodis E, Watson IR, Kryukov GV et al (2012) A landscape of driver mutations in melanoma. Cell 150:251–263PubMedCrossRefGoogle Scholar
  81. 81.
    Krauthammer M, Kong Y, Ha BH et al (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44:1006–1014PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, New York 2014

Authors and Affiliations

  • Ryan J. Sullivan
    • 1
  • Michael B. Atkins
    • 2
  1. 1.Center for Melanoma, Massachusetts General Hospital Cancer CenterBostonUSA
  2. 2.Georgetown-Lombardi Comprehensive Cancer CenterWashington, DCUSA

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