Melanoma pp 667-686 | Cite as

Targeted Therapy in Advanced Melanoma

  • Jeffrey A. Sosman
  • Douglas B. JohnsonEmail author
Reference work entry


Molecularly targeted therapy, specifically small molecule therapeutics against particular oncogenes, has transformed the treatment landscape in melanoma and other cancers. Activating mutations in BRAFV600 produce constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, causing unrestrained growth in nearly half of all melanomas. In turn, therapeutic blockade of this pathway through BRAF inhibitors produces dramatic clinical responses and improved survival compared to traditional cytotoxic chemotherapy. The addition of downstream MAPK blockade via MEK inhibition has further improved clinical outcomes. Although initial responses are impressive in most patients, and durable responses occasionally occur, acquired resistance remains a major barrier to long-term efficacy with these agents. A number of other potential therapeutic targets have been identified among other subsets of melanoma, including those with NRAS mutations, KIT mutations, and atypical BRAF alterations. Further, combinatorial regimens targeted MAPK and other pathways (including CDK4/6 and PI3K/AKT pathways) have shown early promise. This chapter reviews the development, current clinical activity, and future development directions for targeted therapy in melanoma.


BRAF Targeted therapy NRAS KIT Vemurafenib Dabrafenib Trametinib 


  1. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421CrossRefGoogle Scholar
  2. Asati V, Mahapatra DK, Bharti SK (2016) PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: structural and pharmacological perspectives. Eur J Med Chem 109:314–341CrossRefGoogle Scholar
  3. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, Van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A et al (2013) MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 14:249–256CrossRefGoogle Scholar
  4. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206CrossRefGoogle Scholar
  5. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G et al (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599CrossRefGoogle Scholar
  6. Buchbinder EI, Sosman JA, Lawrence DP, Mcdermott DF, Ramaiya NH, Van Den Abbeele AD, Linette GP, Giobbie-Hurder A, Hodi FS (2015) Phase 2 study of sunitinib in patients with metastatic mucosal or acral melanoma. Cancer 121:4007–4015CrossRefGoogle Scholar
  7. Burd CE, Liu W, Huynh MV, Waqas MA, Gillahan JE, Clark KS, Fu K, Martin BL, Jeck WR, Souroullas GP et al (2014) Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov 4:1418–1429CrossRefGoogle Scholar
  8. Cancer Genome Atlas Network (2015) Genomic classification of cutaneous melanoma. Cell 161:1681–1696CrossRefGoogle Scholar
  9. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas KS, Busam KJ, Chmielowski B, Lutzky J et al (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305:2327–2334CrossRefGoogle Scholar
  10. Carvajal RD, Lawrence DP, Weber JS, Gajewski TF, Gonzalez R, Lutzky J, O’day SJ, Hamid O, Wolchok JD, Chapman PB et al (2015) Phase II study of Nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res 21:2289–2296CrossRefGoogle Scholar
  11. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, Linette GP, Gajewski TF, Lutzky J, Lawson DH et al (2014) Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 311:2397–2405CrossRefGoogle Scholar
  12. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516CrossRefGoogle Scholar
  13. Chattopadhyay C, Ellerhorst JA, Ekmekcioglu S, Greene VR, Davies MA, Grimm EA (2012) Association of activated c-Met with NRAS-mutated human melanomas. Int J Cancer 131:E56–E65CrossRefGoogle Scholar
  14. Chen X, Wu Q, Depeille P, Chen P, Thornton S, Kalirai H, Coupland SE, Roose JP, Bastian BC (2017) RasGRP3 mediates MAPK pathway activation in GNAQ mutant uveal melanoma. Cancer Cell 31(685–696):e6Google Scholar
  15. Curtin JA, Busam K, Pinkel D, Bastian BC (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346CrossRefGoogle Scholar
  16. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, Leboit PE et al (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147CrossRefGoogle Scholar
  17. Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, Mcmahon M, Stuart DD (2013) Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494:251–255CrossRefGoogle Scholar
  18. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefGoogle Scholar
  19. Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, Woodman SE, Calderone TC, Ju Z, Lazar AJ et al (2009) Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 15:7538–7546CrossRefGoogle Scholar
  20. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA et al (2016) Activity of Selumetinib in Neurofibromatosis type 1-related plexiform Neurofibromas. N Engl J Med 375:2550–2560CrossRefGoogle Scholar
  21. Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, Demarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT et al (2012) Activity of the oral MEK inhibitor Trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 13:782–789CrossRefGoogle Scholar
  22. Fedorenko IV, Gibney GT, Smalley KS (2012) NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene 32(25):3009CrossRefGoogle Scholar
  23. Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, Zaidi MR, Ksander BR, Merlino G, Sodhi A et al (2014) Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 25:831–845CrossRefGoogle Scholar
  24. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N et al (2012a) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New Engl J Med 367:1694CrossRefGoogle Scholar
  25. Flaherty KT, Puzanov I, Kim KB, Ribas A, Mcarthur GA, Sosman JA, O’dwyer PJ, Lee RJ, Grippo JF, Nolop K et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363:809–819CrossRefGoogle Scholar
  26. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P et al (2012b) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114CrossRefGoogle Scholar
  27. Gajewski TF, Salama AK, Niedzwiecki D, Johnson J, Linette G, Bucher C, Blaskovich MA, Sebti SM, Haluska F (2012) Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). J Transl Med 10:246CrossRefGoogle Scholar
  28. Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, Li H, Sheng X 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 29:2904–2909CrossRefGoogle Scholar
  29. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:1410–1413CrossRefGoogle Scholar
  30. Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM (2013) Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet 45:133–135CrossRefGoogle Scholar
  31. Harding JJ, Catalanotti F, Munhoz RR, Cheng DT, Yaqubie A, Kelly N, Mcdermott GC, Kersellius R, Merghoub T, Lacouture ME et al (2015) A retrospective evaluation of Vemurafenib as treatment for BRAF-mutant melanoma brain metastases. Oncologist 20:789–797CrossRefGoogle Scholar
  32. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365CrossRefGoogle Scholar
  33. Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, Friedlander P, Gonzalez R, Weber JS, Gajewski TF et al (2013) Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 31:3182–3190CrossRefGoogle Scholar
  34. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C et al (2012) A landscape of driver mutations in melanoma. Cell 150:251–263CrossRefGoogle Scholar
  35. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, Moriceau G, Hong A, Dahlman KB, Johnson DB et al (2015) Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162:1271–1285CrossRefGoogle Scholar
  36. Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, Vnencak-Jones CL, Ross JS, Pietenpol JA, Sosman JA et al (2013) BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res 19:6696–6702CrossRefGoogle Scholar
  37. Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH et al (2014) Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol 32(33):3697CrossRefGoogle Scholar
  38. Johnson DB, Puzanov I (2015) Treatment of NRAS-mutant melanoma. Curr Treat Options Oncol 16:15CrossRefGoogle Scholar
  39. Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, Mcarthur GA, Hwu P et al (2013) Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 31:482–489CrossRefGoogle Scholar
  40. Klein O, Clements A, Menzies AM, O’toole S, Kefford RF, Long GV (2013) BRAF inhibitor activity in V600R metastatic melanoma. Eur J Cancer 49(5):1073–1079CrossRefGoogle Scholar
  41. Komatsubara KM, Manson DK, Carvajal RD (2016) Selumetinib for the treatment of metastatic uveal melanoma: past and future perspectives. Future Oncol 12:1331–1344CrossRefGoogle Scholar
  42. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, Mccusker JP, Cheng E, Davis MJ, Goh G, Choi M et al (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44:1006–1014CrossRefGoogle Scholar
  43. Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, Jakubosky D, Genovese G, Muller FL, Jeong JH et al (2012) Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 18(10):1503CrossRefGoogle Scholar
  44. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, Mandala M, Demidov L, Stroyakovskiy D, Thomas L et al (2014) Combined Vemurafenib and Cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867–1876CrossRefGoogle Scholar
  45. Lim SM, Park HS, Kim S, Kim S, Ali SM, Greenbowe JR, Yang IS, Kwon NJ, Lee JL, Ryu MH et al (2016) Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. Oncotarget 7:10547–10556PubMedPubMedCentralGoogle Scholar
  46. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, De Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ et al (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386:444–451CrossRefGoogle Scholar
  47. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A et al (2012) Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 13:1087CrossRefGoogle Scholar
  48. Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, Sosman JA, Hamid O, Schuchter L, Cebon J et al (2016) Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving Dabrafenib combined with Trametinib. J Clin Oncol 34:871–878CrossRefGoogle Scholar
  49. Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M, Giobbie-Hurder A, Lawrence DP, Ibrahim N, Ott PA et al (2013) Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer 119(20):3687CrossRefGoogle Scholar
  50. Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S et al (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 3:742–750CrossRefGoogle Scholar
  51. Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, Tiwari S, Kong L, Hanrahan AJ, Yao Z et al (2014) Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res 74:2340–2350CrossRefGoogle Scholar
  52. Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y et al (2015) Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell 28:384–398CrossRefGoogle Scholar
  53. Posch C, Cholewa BD, Vujic I, Sanlorenzo M, Ma J, Kim ST, Kleffel S, Schatton T, Rappersberger K, Gutteridge R et al (2015) Combined inhibition of MEK and Plk1 has synergistic antitumor activity in NRAS mutant melanoma. J Invest Dermatol 135:2475–2483CrossRefGoogle Scholar
  54. Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K et al (2014) Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol 15:954–965CrossRefGoogle Scholar
  55. Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, Haydu LE, Mijatov B, Becker TM, Boyd SC et al (2014) BRAF inhibitor resistance mechanisms in metastatic melanoma: Spectrum and clinical impact. Clin Cancer Res 20:1965–1977CrossRefGoogle Scholar
  56. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L et al (2014) Improved overall survival in melanoma with combined Dabrafenib and Trametinib. New Engl J Med 372(1):30CrossRefGoogle Scholar
  57. Robert L, Ribas A, Hu-Lieskovan S (2016) Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2? Semin Immunol 28:73CrossRefGoogle Scholar
  58. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, Dummer R, North J, Pincus L, Ruben B et al (2015) The genetic evolution of melanoma from precursor lesions. N Engl J Med 373:1926–1936CrossRefGoogle Scholar
  59. Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB et al (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4:80–93CrossRefGoogle Scholar
  60. Smith MP, Brunton H, Rowling EJ, Ferguson J, Arozarena I, Miskolczi Z, Lee JL, Girotti MR, Marais R, Levesque MP et al (2016) Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29:270–284CrossRefGoogle Scholar
  61. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, Mcarthur GA, Hutson TE, Moschos SJ, Flaherty KT et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714CrossRefGoogle Scholar
  62. Sosman JA, Kittaneh M, MPJ L, Postow MA, Schwartz G et al (2014) A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity. J Clin Oncol 32:9009CrossRefGoogle Scholar
  63. Stephen AG, Esposito D, Bagni RK, Mccormick F (2014) Dragging RAS back in the ring. Cancer Cell 25:272–281CrossRefGoogle Scholar
  64. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT et al (2012a) RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366:207–215CrossRefGoogle Scholar
  65. Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, Short SP, Sobolik T et al (2012b) RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res 18:2184–2198CrossRefGoogle Scholar
  66. Thomas NE, Edmiston SN, Alexander A, Groben PA, Parrish E, Kricker A, Armstrong BK, Anton-Culver H, Gruber SB, From L et al (2015) Association between NRAS and BRAF mutational status and melanoma-specific survival among patients with higher-risk primary melanoma. JAMA Oncol 1:359–368CrossRefGoogle Scholar
  67. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV et al (2014) The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 4:94–109CrossRefGoogle Scholar
  68. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’brien JM, Simpson EM, Barsh GS, Bastian BC (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:599–602CrossRefGoogle Scholar
  69. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N et al (2010) Mutations in GNA11 in uveal melanoma. N Engl J Med 363:2191–2199CrossRefGoogle Scholar
  70. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D et al (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867CrossRefGoogle Scholar
  71. Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B et al (2015) RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 526:583–586CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Northwestern University and Robert H. Lurie Comprehensive Cancer CenterChicagoUSA
  2. 2.Vanderbilt University Medical Center and Vanderbilt Ingram Cancer CenterNashvilleUSA

Section editors and affiliations

  • Keith T. Flaherty
    • 1
  • Boris Bastian
    • 2
  • Hensin Tsao
    • 3
    • 4
  • F. Stephen Hodi
    • 5
    • 6
  1. 1.Henri and Belinda Termeer Center for Targeted TherapiesMGH Cancer CenterBostonUSA
  2. 2.Departments of Dermatology and PathologyUniversity of California, San FranciscoSan FranciscoUSA
  3. 3.AuburndaleUSA
  4. 4.Harvard-MIT Health Sciences and TechnologyCambridgeUSA
  5. 5.FraminghamUSA
  6. 6.Department of Medicine, Brigham and Women's HospitalDana-Farber Cancer InstituteBostonUSA

Personalised recommendations