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Role of Genetic and Molecular Profiling in Sarcomas

  • Sarcoma (SH Okuno, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The treatment of sarcomas has been challenging due to their heterogeneity, rarity in the general population, relative insensitivity to chemotherapeutics, and lack of effective targeted agents. One of the first major breakthroughs in the treatment of sarcomas was the use of imatinib to treat gastrointestinal stromal tumors (GISTs). Since then, advanced molecular techniques and genetic profiling have revolutionized the approach to sarcoma classification, diagnosis, prognosis and, most importantly, treatment. As the sarcoma genetic database continues to expand, the basis for how we classify, diagnose, and treat these challenging malignancies will be redefined. The overall goal of these types of techniques has been to determine a molecular blueprint for each sarcoma subtype and discover actionable alterations that lend themselves to targeted therapies. Other important information derived from these large genomic databases includes biomarkers, prognostic indicators, and information regarding tumorigenesis. Eventually, advanced molecular techniques will provide a personalized-medicine approach that tailors each treatment regimen to the patient’s own tumor genome.

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References and Recommended Reading

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

  1. Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol. 2005;29:1340–7.

    PubMed  Google Scholar 

  2. Thway K, Flora R, Shah C, et al. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol. 2012;36:462–9.

    PubMed  Google Scholar 

  3. Bridge JA, Cushman-Vokoun AM. Molecular diagnostics of soft tissue tumors. Arch Pathol Lab Med. 2011;135:588–601.

    CAS  PubMed  Google Scholar 

  4. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–9.

    CAS  PubMed  Google Scholar 

  5. Beck AH, Lee CH, Witten DM, et al. Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling. Oncogene. 2010;29:845–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Skubitz KM, Pambuccian S, Manivel JC, et al. Identification of heterogeneity among soft tissue sarcomas by gene expression profiles from different tumors. J Transl Med. 2008;6:23.

    PubMed Central  PubMed  Google Scholar 

  7. Skubitz KM, Francis P, Skubitz AP, et al. Gene expression identifies heterogeneity of metastatic propensity in high-grade soft tissue sarcomas. Cancer. 2012;118:4235–43.

    CAS  PubMed  Google Scholar 

  8. Antonescu CR. The role of genetic testing in soft tissue sarcoma. Histopathology. 2006;48:13–21.

    CAS  PubMed  Google Scholar 

  9. Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res Off J Am Assoc Cancer Res. 2003;9:1941–56.

    Google Scholar 

  10. Guillou L, Aurias A. Soft tissue sarcomas with complex genomic profiles. Virchows Arch. 2010;456:201–17.

    CAS  PubMed  Google Scholar 

  11. Perot G, Chibon F, Montero A, et al. Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics. Am J Pathol. 2010;177:2080–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Sharpless NE, Ferguson DO, O’Hagan RC, et al. Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol Cell. 2001;8:1187–96.

    CAS  PubMed  Google Scholar 

  13. Gisselsson D, Jonson T, Petersen A, et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci U S A. 2001;98:12683–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Scheel C, Schaefer KL, Jauch A, et al. Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene. 2001;20:3835–44.

    CAS  PubMed  Google Scholar 

  15. Bridge JA. Contribution of cytogenetics to the management of poorly differentiated sarcomas. Ultrastruct Pathol. 2008;32:63–71.

    PubMed  Google Scholar 

  16. Turc-Carel C, Aurias A, Mugneret F, et al. Chromosomes in Ewing’s sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet. 1988;32:229–38.

    CAS  PubMed  Google Scholar 

  17. Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet. 2002;359:1301–7.

    CAS  PubMed  Google Scholar 

  18. Francis P, Namlos HM, Muller C, et al. Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential. BMC Genomics. 2007;8:73.

    PubMed Central  PubMed  Google Scholar 

  19. Baird K, Davis S, Antonescu CR, et al. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 2005;65:9226–35.

    CAS  PubMed  Google Scholar 

  20. Konstantinopoulos PA, Fountzilas E, Goldsmith JD, et al. Analysis of multiple sarcoma expression datasets: implications for classification, oncogenic pathway activation and chemotherapy resistance. PLoS One. 2010;5:e9747.

    PubMed Central  PubMed  Google Scholar 

  21. Mills AM, Beck AH, Montgomery KD, et al. Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry. Am J Surg Pathol. 2011;35:583–9.

    PubMed Central  PubMed  Google Scholar 

  22. Italiano A, Largarde P, Brulard C, et al. Genetic Profiling Identifies Two Classes of Soft-Tissue Leiomyosarcomas with Distinct Clinical Characteristics. Clin Cancer Res Off J Am Assoc Cancer Res. 2013.

  23. Skubitz KM, Skubitz AP. Differential gene expression in leiomyosarcoma. Cancer. 2003;98:1029–38.

    CAS  PubMed  Google Scholar 

  24. Edris B, Fletcher JA, West RB, et al. Comparative gene expression profiling of benign and malignant lesions reveals candidate therapeutic compounds for leiomyosarcoma. Sarcoma. 2012;2012:805614. In this study, a novel approach to finding targeted therapies in sarcomas was developed. This study exemplifies how preexisting genetic data on sarcomas can be used to discover and test targeted therapies in a genetically-driven manner.

  25. Davidson B, Abeler VM, Forsund M, et al. Gene expression signatures of primary and metastatic uterine leiomyosarcoma. Hum Pathol. 2014;45:691–700.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Singer S, Socci ND, Ambrosini G, et al. Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma. Cancer Res. 2007;67:6626–36.

    CAS  PubMed  Google Scholar 

  27. Tap WD, Eilber FC, Ginther C, et al. Evaluation of well-differentiated/de-differentiated liposarcomas by high-resolution oligonucleotide array-based comparative genomic hybridization. Genes Chromosom Cancer. 2011;50:95–112.

    CAS  PubMed  Google Scholar 

  28. Ferrari A, Bisogno G, Alaggio R, et al. Synovial sarcoma of children and adolescents: the prognostic role of axial sites. Eur J Cancer. 2008;44:1202–9.

    PubMed  Google Scholar 

  29. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.

    PubMed  Google Scholar 

  30. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.

    CAS  PubMed  Google Scholar 

  31. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726–34.

    CAS  PubMed  Google Scholar 

  32. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res BCR. 2006;8:R25.

    PubMed  Google Scholar 

  33. Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;28:1829–34.

    PubMed  Google Scholar 

  34. Lee YF, John M, Falconer A, et al. A gene expression signature associated with metastatic outcome in human leiomyosarcomas. Cancer Res. 2004;64:7201–4.

    CAS  PubMed  Google Scholar 

  35. Chibon F, Lagarde P, Salas S, et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med. 2010;16:781–7. This study was able to create a prognostic gene expression signature that was created in a large training set data (183 samples) and tested on a separate, independent set of 127 sarcoma samples. This 67-gene predictor and grading system, called CINSARC, was shown to be better at predicting metastatic outcomes compared to the FNCLCC grading system.

    CAS  PubMed  Google Scholar 

  36. Lagarde P, Przybyl J, Brulard C, et al. Chromosome instability accounts for reverse metastatic outcomes of pediatric and adult synovial sarcomas. J Clin Oncol. 2013;31:608–15. The CINSARC grading system and Genomic Index created by Chibon et al was tested on Synovial Sarcomas and found to be independent prognostic indicators. Besides karyotype status, which has been met with controversy, this is the first validated genetic expression profile with prognostic capabilities in Synovial Sarcomas.

    CAS  PubMed  Google Scholar 

  37. Scotlandi K, Remondini D, Castellani G, et al. Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol. 2009;27:2209–16.

    CAS  PubMed  Google Scholar 

  38. Ohali A, Avigad S, Zaizov R, et al. Prediction of high risk Ewing’s sarcoma by gene expression profiling. Oncogene. 2004;23:8997–9006.

    CAS  PubMed  Google Scholar 

  39. Schaefer KL, Eisenacher M, Braun Y, et al. Microarray analysis of Ewing’s sarcoma family of tumours reveals characteristic gene expression signatures associated with metastasis and resistance to chemotherapy. Eur J Cancer. 2008;44:699–709.

    CAS  PubMed  Google Scholar 

  40. Gobble RM, Qin LX, Brill ER, et al. Expression profiling of liposarcoma yields a multigene predictor of patient outcome and identifies genes that contribute to liposarcomagenesis. Cancer Res. 2011;71:2697–705.

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Kawai A, Woodruff J, Healey JH, et al. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med. 1998;338:153–60.

  42. Ladanyi M, Antonescu CR, Leung DH, et al. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res. 2002;62:135–40.

    CAS  PubMed  Google Scholar 

  43. Guillou L, Benhattar J, Bonichon F, et al. Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol. 2004;22:4040–50.

    PubMed  Google Scholar 

  44. Przybyl J, Sciot R, Wozniak A, et al. Metastatic potential is determined early in synovial sarcoma development and reflected by tumor molecular features. Int J Biochem Cell Biol. 2014;53:505–13. This study demonstrated the importance of aCGH and gene expression profiling in determining a genetic expression profile more prone to metastasis.

    CAS  PubMed  Google Scholar 

  45. Mayr MI, Hummer S, Bormann J, et al. The human kinesin Kif18A is a motile microtubule depolymerase essential for chromosome congression. Curr Biol CB. 2007;17:488–98.

    CAS  PubMed  Google Scholar 

  46. Zhang C, Zhu C, Chen H, et al. Kif18A is involved in human breast carcinogenesis. Carcinogenesis. 2010;31:1676–84.

    CAS  PubMed  Google Scholar 

  47. Nagahara M, Nishida N, Iwatsuki M, et al. Kinesin 18A expression: clinical relevance to colorectal cancer progression. Int J Cancer. 2011;129:2543–52.

    CAS  PubMed  Google Scholar 

  48. Corson TW, Zhu CQ, Lau SK, et al. KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13:3229–34.

  49. Collins MH, Zhao H, Womer RB, et al. Proliferative and apoptotic differences between alveolar rhabdomyosarcoma subtypes: a comparative study of tumors containing PAX3-FKHR or PAX7-FKHR gene fusions. Med Pediatr Oncol. 2001;37:83–9.

  50. Barr FG. The role of chimeric paired box transcription factors in the pathogenesis of pediatric rhabdomysarcoma. Cancer Res. 1999;59:1711s-5s.

    Google Scholar 

  51. Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol. 2002;20:2672–9.

    CAS  PubMed  Google Scholar 

  52. Davicioni E, Finckenstein FG, Shahbazian V, et al. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res. 2006;66:6936–46.

  53. Missiaglia E, Williamson D, Chisholm J, et al. PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol. 2012;30:1670–7. Two large, separate sample groups were used in this study and showed that, when genetic data is combined with other factors (TNM staging, age, etc.), more accurate risk-stratification methods can be developed. In particular, it demonstrated the importance of fusion status as a marker of prognosis in ARMS, which is relatively cheap to determine and therefore more accessible in the clinical setting.

    PubMed  Google Scholar 

  54. Scurr M. Histology-driven chemotherapy in soft tissue sarcomas. Curr Treat Options in Oncol. 2011;12:32–45.

    Google Scholar 

  55. Svancarova L, Blay JY, Judson IR, et al. Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2002;38:556–9.

    CAS  PubMed  Google Scholar 

  56. Okuno S, Ryan LM, Edmonson JH, et al. Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer. 2003;97:1969–73.

  57. Patel SR, Gandhi V, Jenkins J, et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol. 2001;19:3483–9.

    CAS  PubMed  Google Scholar 

  58. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20:2824–31.

    CAS  PubMed  Google Scholar 

  59. Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11:1269–75.

    CAS  PubMed  Google Scholar 

  60. Le Cesne A, Antoine E, Spielmann M, et al. High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol. 1995;13:1600–8.

    PubMed  Google Scholar 

  61. Rosen G, Forscher C, Lowenbraun S, et al. Synovial sarcoma. Uniform response of metastases to high dose ifosfamide. Cancer. 1994;73:2506–11.

    CAS  PubMed  Google Scholar 

  62. Movva S, Chen W, Millis SZ, et al. Predictive biomarker profiling of> 1,900 sarcomas: Identification of potential novel treatment modalities. Journal of Clinical Oncology 2014;32:5s, 2014 (suppl; abstr 10509). As one of the largest genetic studies on sarcomas done to date (with > 1,900 patient samples), this study added an immense amount of genetic information about sarcomas such as EGFR gene amplification that was found to be present in a wide variety of sarcomas. It also identified multiple potential chemotherapeutic biomarkers providing a basis for several future studies.

  63. Jour G, Scarborough JD, Jones RL, et al. Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics. Hum Pathol. 2014;45:1563–71.

    CAS  PubMed  Google Scholar 

  64. Egas-Bejar D, Anderson PM, Agarwal R, et al. Theranostic profiling for actionable aberrations in advanced high risk osteosarcoma with aggressive biology reveals high molecular diversity: the human fingerprint hypothesis. Oncoscience. 2014;1:167–79.

    PubMed Central  PubMed  Google Scholar 

  65. Cote G, Shen J, Morgan J, et al. Genomic analysis of over 400 sarcomas Connective Tissue Oncology Society. New York, NY; 2013.

  66. Choy E, Hornicek F, MacConaill L, et al. High-throughput genotyping in osteosarcoma identifies multiple mutations in phosphoinositide-3-kinase and other oncogenes. Cancer. 2012;118:2905–14.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Salas S, Jezequel P, Campion L, et al. Molecular characterization of the response to chemotherapy in conventional osteosarcomas: predictive value of HSD17B10 and IFITM2. Int J Cancer. 2009;125:851–60. In this study, advanced molecular techniques were used to discover new genes that were more responsive to chemotherapy and that HSD17B10 may be a therapeutic target.

    CAS  PubMed  Google Scholar 

  68. Gardner K, Leahy M, et al. Activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in alveolar soft part sarcoma. J Clin Oncol. 2009;27:10523.

    Google Scholar 

  69. Kummar S, Monks A, et al. An evaluation of cediranib as a new agent for alveolar soft part sarcoma (ASPS). J Clin Oncol. 2011;29:10001.

    Google Scholar 

  70. Stacchiotti S, Negri T, Zaffaroni N, et al. Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2011;22:1682–90.

    CAS  Google Scholar 

  71. Wagner AJ, Goldberg JM, Dubois SG, et al. Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial. Cancer. 2012;118:5894–902.

    CAS  PubMed  Google Scholar 

  72. Maki RG, D’Adamo DR, Keohan ML, et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol. 2009;27:3133–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. von Mehren M, Rankin C, Goldblum JR, et al. Phase 2 Southwest Oncology Group-directed intergroup trial (S0505) of sorafenib in advanced soft tissue sarcomas. Cancer. 2012;118:770–6.

    Google Scholar 

  74. Agulnik M, Von Mehren M, et al. An open-label multicenter phase II study of bevacizumab for the treatment of angiosarcoma. J Clin Oncol. 2009; Orlando, Florida.

  75. Agios Pharmaceuticals I. Study of Orally Administered AG-120 in Subjects with Advanced Solid Tumors, Including Glioma, with an IDH1 Mutation 2015.

  76. Agios Pharmaceuticals I. Study of Orally Administered AG-221 in subjects with advanced solid tumors, including glioma, and with angioimmunoblastic T-cell lymphoma, with an IDH2 Mutation. 2014;NCT02273739.

  77. Akhavan-Sigari R, Gaab MR, Rohde V, et al. Expression of PDGFR-alpha, EGFR and c-MET in spinal chordoma: a series of 52 patients. Anticancer Res. 2014;34:623–30.

  78. Pharmaceuticals N. Efficacy and Safety of Imatinib in Chordoma. 2012;NCT00150072

  79. Center MSKC. Sunitinib in treating patients with metastatic, locally advanced, or locally recurrent sarcomas. 2013;NCT00474994.

  80. McArthur GA, Demetri GD, van Oosterom A, et al. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol. 2005;23:866–73.

    CAS  PubMed  Google Scholar 

  81. Rutkowski P, Van Glabbeke M, Rankin CJ, et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol. 2010;28:1772–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Brooks MD, Ebbs SR, Colletta AA, et al. Desmoid tumours treated with triphenylethylenes. Eur J Cancer. 1992;28A:1014–8.

  83. Chugh R, Wathen JK, Patel SR, et al. Efficacy of imatinib in aggressive fibromatosis: results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res Off J Am Assoc Cancer Res. 16:4884–91.

  84. Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17:4082–90.

    CAS  Google Scholar 

  85. Amant F, De Knijf A, Van Calster B, et al. Clinical study investigating the role of lymphadenectomy, surgical castration and adjuvant hormonal treatment in endometrial stromal sarcoma. Br J Cancer. 2007;97:1194–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Amant F, Coosemans A, Debiec-Rychter M, et al. Clinical management of uterine sarcomas. Lancet Oncol. 2009;10:1188–98.

  87. Chu MC, Mor G, Lim C, et al. Low-grade endometrial stromal sarcoma: hormonal aspects. Gynecol Oncol. 2003;90:170–6.

  88. Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2013;24:257–63.

    CAS  Google Scholar 

  89. Tolkach Y, Petrov S, Lerut E, et al. Epithelioid hemangioendothelioma of the kidney treated with sunitinib. Onkologie. 2012;35:376–8.

  90. van der Ent W, Jochemsen AG, Teunisse AF, et al. Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53. J Pathol. 2014;233:415–24.

    PubMed  Google Scholar 

  91. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626–32.

    CAS  PubMed  Google Scholar 

  92. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–5.

    CAS  PubMed  Google Scholar 

  93. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–38.

    CAS  PubMed  Google Scholar 

  94. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302.

    CAS  PubMed  Google Scholar 

  95. Thomas D, Carriere P, Jacobs I. Safety of denosumab in giant-cell tumour of bone. Lancet Oncol. 2010;11:815.

    PubMed  Google Scholar 

  96. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14:901–8.

    CAS  PubMed  Google Scholar 

  97. Kimbara S, Takeda K, Fukushima H, et al. A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib. Jpn J Clin Oncol. 2014;44:868–71.

    PubMed  Google Scholar 

  98. Jacob SV, Reith JD, Kojima AY, et al. An unusual case of systemic inflammatory myofibroblastic tumor with successful treatment with ALK-inhibitor. Case Rep Pathol. 2014;2014:470340.

  99. Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363:1727–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Barretina J, Taylor BS, Banerji S, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet. 2010;42:715–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Grignani G, Palmerini E, Dileo P, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2012;23:508–16.

    CAS  Google Scholar 

  102. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010;28:835–40.

    CAS  PubMed  Google Scholar 

  103. Gennatas C, Michalaki V, Kairi PV, et al. Successful treatment with the mTOR inhibitor everolimus in a patient with perivascular epithelioid cell tumor. World J Surg Oncol. 2012;10:181.

  104. Ravi V, Araujo DM. Imatinib in the treatment of tenosynovial giant-cell tumor and pigmented villonodular synovitis. J Clin Oncol. 2010:10011.

  105. Cassier PA, Gelderblom H, Stacchiotti S, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer. 2012;118:1649–55.

    CAS  PubMed  Google Scholar 

  106. Tap WD, Schwartz GK. That’s the “GIST” of it: use of adjuvant imatinib after resection of a primary GI stromal tumor. J Clin Oncol. 2014;32:1543–6.

    CAS  PubMed  Google Scholar 

  107. Stacchiotti S, Negri T, Palassini E, et al. Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol Cancer Ther. 2010;9:1286–97.

    CAS  PubMed  Google Scholar 

  108. Stacchiotti S, Tortoreto M, Bozzi F, et al. Dacarbazine in solitary fibrous tumor: a case series analysis and preclinical evidence vis-a-vis temozolomide and antiangiogenics. Clin Cancer Res Off J Am Assoc Cancer Res. 2013;19:5192–201.

    CAS  Google Scholar 

  109. Park MS, Patel SR, Ludwig JA, et al. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor. Cancer. 2011;117:4939–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009;27:3126–32.

    CAS  PubMed  Google Scholar 

  111. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917–24.

    PubMed Central  PubMed  Google Scholar 

  112. Dickson MA, Tap WD, et al. Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified liposarcoma. J Clin Oncol. 2012;30:10002.

    Google Scholar 

  113. Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012;13:1133–40.

    CAS  PubMed  Google Scholar 

  114. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.

    CAS  PubMed  Google Scholar 

  115. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001;61:8118–21.

    CAS  PubMed  Google Scholar 

  116. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052–6.

    CAS  PubMed  Google Scholar 

  117. Bikker JA, Brooijmans N, Wissner A, et al. Kinase domain mutations in cancer: implications for small molecule drug design strategies. J Med Chem. 2009;52:1493–509.

  118. DiNitto JP, Deshmukh GD, Zhang Y, et al. Function of activation loop tyrosine phosphorylation in the mechanism of c-Kit auto-activation and its implication in sunitinib resistance. J Biochem. 2010;147:601–9.

    CAS  PubMed  Google Scholar 

  119. Pierotti MA, Tamborini E, Negri T, et al. Targeted therapy in GIST: in silico modeling for prediction of resistance. Nat Rev Clin Oncol. 2011;8:161–70.

  120. Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15:7510–8.

    CAS  Google Scholar 

  121. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764–74.

    CAS  PubMed  Google Scholar 

  122. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11:4182–90.

    CAS  Google Scholar 

  123. Guo T, Hajdu M, Agaram NP, et al. Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Clin Cancer Res. 2009;15:6862–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Songdej N, von Mehren M. GIST treatment options after tyrosine kinase inhibitors. Curr Treat Options in Oncol. 2014;15:493–506.

    Google Scholar 

  125. Guo T, Zhang L, Chang NE, et al. Consistent MYC and FLT4 gene amplification in radiation-induced angiosarcoma but not in other radiation-associated atypical vascular lesions. Genes Chromosom Cancer. 2011;50:25–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Manner J, Radlwimmer B, Hohenberger P, et al. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol. 2010;176:34–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Behjati S, Tarpey PS, Sheldon H, et al. Recurrent PTPRB and PLCG1 mutations in angiosarcoma. 2014;46:376–9.

  128. Park MS, Ravi V, Araujo DM. Inhibiting the VEGF-VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma/solitary fibrous tumor. Curr Opin Oncol. 2010;22:351–5.

    CAS  PubMed  Google Scholar 

  129. Antonescu CR, Yoshida A, Guo T, et al. KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res. 2009;69:7175–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Ray-Coquard I, Italiano A, Bompas E, et al. Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the French Sarcoma Group (GSF/GETO). Oncologist. 2012;17:260–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Ravi V. Whole-exome and targeted sequencing of angiosarcomas: target identification and treatment implications. ASCO J Clin Oncol. 2014. As one of the few studies down in sarcomas comparing molecularly targeted therapy to non-molecularly targeted therapy, this study showed that 9 patients able to receive targeted treatments had improved PFS and CBR. Their study design is a model for future investigations into personalized-medicine approaches.

  132. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008;27:5511–26.

    CAS  PubMed  Google Scholar 

  133. Lim HJ, Crowe P, Yang JL. Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer. J Cancer Res Clin Oncol. 2014.

  134. Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224:334–43.

    CAS  PubMed  Google Scholar 

  135. Lu C, Venneti S, Akalin A, et al. Induction of sarcomas by mutant IDH2. Genes Dev. 2013;27:1986–98.

    CAS  PubMed Central  PubMed  Google Scholar 

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Scott M. Norberg and Sujana Movva declare that they have no conflict of interest.

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  1. Department of Internal Medicine, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA, 19140, USA

    Scott M. Norberg D.O.

  2. Department of Medical Oncology and Hematology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA

    Sujana Movva M.D.

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  1. Scott M. Norberg D.O.
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  2. Sujana Movva M.D.
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Correspondence to Sujana Movva M.D..

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Norberg, S.M., Movva, S. Role of Genetic and Molecular Profiling in Sarcomas. Curr. Treat. Options in Oncol. 16, 24 (2015). https://doi.org/10.1007/s11864-015-0339-3

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