Таргетная терапия сарком мягких тканей и десмоидных опухолей

Саркомы мягких тканей – группа редких злокачественных опухолей, характеризующихся высокими частотой рецидивов и летальностью. За последние десятилетия достигнут незначительный прогресс в лечении данной патологии. Хирургическое лечение с адъювантной/неоадъювантной лучевой терапией или без нее по-прежнему является терапией 1-й линии при локализованных саркомах мягких тканей, а химиотерапия – дополнительным вариантом для пациентов с высоким риском развития рецидива болезни. Тем не менее не у всех больных с распространенными или метастатическими саркомами мягких тканей наблюдается эффект от традиционной химиотерапии. Саркомы мягких тканей характеризуются высокой гетерогенностью биологического поведения и разнообразием генетических мутаций, что указывает на перспективность персонализированного лечения на основе гистотипа опухоли, генетических и молекулярных характеристик и новых малых молекул-ингибиторов сигнальных путей. В данной статье представлен обзор исследований, посвященных эффективности таргетной терапии наиболее часто встречающихся сарком мягких тканей и десмоидных опухолей.

1. Sung H., Ferlay J., Siegel R.L. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209–49. DOI: 10.3322/caac.21660

2. Океанов А.Е., Моисеев П.И., Левин Л.Ф. и др. Рак в Беларуси: цифры и факты. Анализ данных Белорусского канцер-регистра за 2010–2019 гг. Под ред. С.Л. Полякова. Минск: Национальная библиотека Беларуси, 2020. 298 с.

3. Young R.J., Natukunda A., Litière S. et al. First-line anthracyclinebased chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials. Eur J Cancer 2014;50(18):3178–86. DOI: 10.1016/j.ejca.2014.10.004

4. Savina M., Le Cesne A., Blay J.Y. et al. Patterns of care and outcomes of patients with metastatic soft tissue sarcoma in a real-life setting: the metasarc observational study. BMC Med 2017;15(1):78. DOI: 10.1186/s12916-017-0831-7

5. Judson I., Verweij J., Gelderblom H. et al. European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014;15(4):415–23. DOI: 10.1016/S1470-2045(14)70063-4

6. Wunder J.S., Nielsen T.O., Maki R.G. et al. Opportunities for improving the therapeutic ratio for patients with sarcoma. Lancet Oncol 2007;8(6):513–24. DOI: 10.1016/S1470-2045(07)70169-9

7. Juan J., Li X., Yu S. Molecular targeted therapy for advanced or metastatic soft tissue sarcoma. Cancer Control 2021;28:10732748211038424. DOI: 10.1177/10732748211038424

8. Crago A.M., Brennan M.F. Principles in management of soft tissue sarcoma. Adv Surg 2015;49(1):107–22. DOI: 10.1016/j.yasu.2015.04.002

9. Schöffski P., Chawla S., Maki R.G. et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 2016;387(10028):1629–37. DOI: 10.1016/S0140-6736(15)01283-0

10. Demetri G.D., von Mehren M., Jones R.L. et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol 2016;34(8):786–93. DOI: 10.1200/JCO.2015.62.4734

11. Konecny G.E. Cyclin-dependent kinase pathways as targets for women's cancer treatment. Curr Opin Obstet Gynecol 2016;28(1):42–8. DOI: 10.1097/GCO.0000000000000243

12. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. DOI: 10.1016/j.cell.2011.02.013

13. Binh M.B., 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(10):1340–7. DOI: 10.1097/01.pas.0000170343.09562.39

14. Dickson M.A., Tap W.D., Keohan M.L. et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 2013;31(16):2024–8. DOI: 10.1200/JCO.2012.46.5476

15. Dickson M.A., Schwartz G.K., Keohan M.L. et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol 2016;2(7):937–40. DOI: 10.1001/jamaoncol.2016.0264

16. Dickson M.A., Koff A., Sandra P. et al. Phase 2 study of the CDK4 inhibitor abemaciclib in dedifferentiated liposarcoma. J Clin Oncol 2019;37(Suppl. 15):11004. DOI: 10.1200/JCO.2019.37.15 suppl.11004

17. Mahmood S.T., Agresta S., Vigil C.E. et al. Phase II study of sunitinib malate, a multitargeted tyrosine kinase inhibitor in patients with relapsed or refractory soft tissue sarcomas. Focus on three prevalent histologies: leiomyosarcoma, liposarcoma and malignant fibrous histiocytoma. Int J Cancer 2011;129(8):1963–9. DOI: 10.1002/ijc.25843

18. Samuels B.L., Chawla S.P., Somaiah N. et al. Results of a prospective phase 2 study of pazopanib in patients with advanced intermediategrade or high-grade liposarcoma. Cancer 2017;123(23):4640–7. DOI: 10.1002/cncr.30926

19. Chi Y., Fang Z., Hong X. et al. Safety and efficacy of anlotinib, a multikinase angiogenesis inhibitor, in patients with refractory metastatic soft-tissue sarcoma. Clin Cancer Res 2018;24(21):5233–8. DOI: 10.1158/1078-0432.CCR-17-376

20. Riedel R.F., Ballman K.V., Lu Y. et al. Double-blind, placebo-controlled, phase II study of regorafenib versus placebo in advanced/ metastatic, treatment-refractory liposarcoma: results from the SARC024 study. Oncologist 2020;25(11):e1655–62. DOI: 10.1634/theoncologist.2020-0679

21. Thway K., Fisher C. Synovial sarcoma: defining features and diagnostic evolution. Ann Diagn Pathol 2014;18(6):369–80. DOI: 10.1016/j.anndiagpath.2014.09.002

22. 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(20):4040–50. DOI: 10.1200/JCO.2004.11.093

23. Judson I., Verweij J., Gelderblom H. et al. Doxorubicin alone vs. intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomized controlled phase 3 trial. Lancet Oncol 2014;15(4):415–23. DOI: 10.1016/S1470-2045(14)70063-4

24. Vlenterie M., Litiere S., Rizzo E. et al. Outcome of chemotherapy in advanced synovial sarcoma patients: review of 15 clinical trials from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group; setting a new landmark for studies in this entity. Eur J Cancer 2016;58:62–72. DOI: 10.1016/j.ejca.2016.02.002

25. 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 organization for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62,043). J Clin Oncol 2009;27(19):3126–32. DOI: 10.1200/JCO.2008.21.3223

26. Van der Graaf W.T., Blay J.Y., Chawla S.P. et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomized, doubleblind, placebocontrolled phase 3 trial. Lancet 2012;379(9829):1879–86. DOI: 10.1016/S0140-6736(12)60651-5

27. Mir O., Brodowicz T., Italiano A. et al. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomized, double-blind, placebocontrolled, phase 2 trial. Lancet Oncol 2016;17(12):1732–42. DOI: 10.1016/S1470-2045(16)30507-1

28. Kotecki N., Brodowicz T., Le Cesne A. et al. Post-cross-over activity of regorafenib (RE) in soft tissue sarcoma: analysis from the REGOSARC trial. J Clin Oncol 2017;35(Suppl. 15):11052. DOI: 10.1200/JCO.2017.35.15_suppl.11052

29. Xie L., Guo W., Wang Y. et al. Apatinib for advanced sarcoma: results from multiple institutions' off-label use in China. BMC Cancer 2018;18(1):396. DOI: 10.1186/s12885-018-4303-z

30. Maki R.G., D’Adamo D.R., Keohan M.L. et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 2009;27(19):3133–40. DOI: 10.1200/JCO.2008.20.4495

31. Vincenzi B., Silletta M., Schiavon G. et al. Sorafenib and dacarbazine in soft tissue sarcoma: a single institution experience. Expert Opin Investig Drugs 2013;22(1):1–7. DOI: 10.1517/13543784.2013.742886

32. Schöffski P., Adkins D., Blay J.Y. et al. An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or ewing family of tumours. Eur J Cancer 2013;49(15):3219–28. DOI: 10.1016/j.ejca.2013.06.010

33. Pappo A.S., Vassal G., Crowley J.J. et al. A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study. Cancer 2014;120(16):2448–56. DOI: 10.1002/cncr.28728

34. D’Adamo D.R., Dickson M.A., Keohan M.L. et al. A phase II trial of sorafenib and dacarbazine for leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Oncologist 2019;24(6):857–63. DOI: 10.1634/theoncologist.2018-0160

35. Tap W.D., Jones R.L., Van Tine B.A. et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet 2016;388(10043):488–97. DOI: 10.1016/S0140-6736(16)30587-6

36. Tap W.D., Wagner A.J., Papai Z. et al. ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS). J Clin Oncol 2019;37(18). DOI: 10.1200/JCO.2019.37.18_suppl.LBA3

37. Kadoch C., Crabtree G.R. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013;153(1):71–85. DOI: 10.1016/j.cell.2013.02.036

38. Kawano S., Grassian A.R., Tsuda M. et al. Preclinical evidence of anti-tumor activity induced by EZH2 inhibition in human models of synovial sarcoma. PLoS One 2016;11(7):e0158888. DOI: 10.1371/journal.pone.0158888

39. Schoffski P., Agulnik M., Stacchiotti S. et al. Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with synovial sarcoma (NCT02601950). J Clin Oncol 2017;35(Suppl. 15):11057. DOI: 10.1200/JCO.2017.35.15_suppl.11057

40. Roberts M.E., Aynardi J.T., Chu C.S. Uterine leiomyosarcoma: a review of the literature and update on management options. Gynecol Oncol 2018;151(3):562–72. DOI: 10.1016/j.ygyno.2018.09.010

41. Italiano A., Kind M., Stoeckle E. et al. Temsirolimus in advanced leiomyosarcomas: patterns of response and correlation with the activation of the mammalian target of rapamycin pathway. Anticancer Drugs 2011;22(5):463–7. DOI: 10.1097/CAD.0b013e3283442074

42. Chawla S.P., Staddon A.P., Baker L.H. et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 2012;30(1):78–84. DOI: 10.1200/JCO.2011.35.6329

43. Okuno S., Bailey H., Mahoney M.R. et al. A phase 2 study of temsirolimus (CCI-779) in patients with soft tissue sarcomas: a study of the Mayo phase 2 consortium (P2C). Cancer 2011;117(15):3468–75. DOI: 10.1002/cncr.25928

44. Schwartz G.K., Tap W.D., Qin L.X. et al. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 2013;14(4):371–82. DOI: 10.1016/S1470-2045(13)70049-4

45. Martin-Liberal J., López-Pousa A., Martínez-Trufero J. et al. Phase II study of gemcitabine plus sirolimus in previously treated patients with advanced soft-tissue sarcoma: a spanish group for research on sarcomas (GEIS) study. Target Oncol 2018;13(1):81–7. DOI: 10.1007/s11523-017-0539-9

46. Trucco M.M., Meyer C.F., Thornton K.A. et al. A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas. Clin Sarcoma Res 2018;8:21. DOI: 10.1186/s13569-018-0107-9

47. Santoro A., Comandone A., Basso U. et al. Phase II prospective study with sorafenib in advanced soft tissue sarcomas after anthracycline-based therapy. Ann Oncol 2013;24(4):1093–8. DOI: 10.1093/annonc/mds607

48. Escobar C., Munker R., Thomas J.O. et al. Update on desmoid tumors. Ann Oncol 2012;23(3):562–9. DOI: 10.1093/annonc/mdr386

49. Li C., Bapat B., Alman B.A. Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor). Am J Pathol 1998;153(3):709– 14. DOI: 10.1016/s0002-9440(10)65614-3

50. Messersmith W.A., Shapiro G.I., Cleary J.M. et al. A Phase I, dosefinding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014. Clin Cancer Res 2015;21(1):60–7. DOI: 10.1158/1078-0432.CCR-14-0607

51. Kummar S., O’Sullivan Coyne G., Do K.T. et al. Clinical activity of the γ-secretase inhibitor PF-03084014 in adults with desmoid tumors (aggressive fibromatosis). J Clin Oncol 2017;35(14):1561–9. DOI: 10.1200/JCO.2016.71.1994

52. Penel N., Le Cesne A., Bui B. et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/ French Sarcoma Group phase II trial with a long-term follow-up. Ann Oncol 2011;22(2):452–7. DOI: 10.1093/annonc/mdq341

53. Gounder M.M., Lefkowitz R.A., Keohan M.L. et al. Activity of sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res 2011;17(12):4082–90. DOI: 10.1158/1078-0432.CCR-10-3322

54. Gounder M.M., Mahoney M.R., Van Tine B.A. et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med 2018;379(25):2417–28. DOI: 10.1056/NEJMoa1805052

55. Szucs Z., Messiou C., Wong H. Pazopanib, a promising option for the treatment of aggressive fibromatosis. Anticancer Drugs 2017;28(4):421–6. DOI: 10.1097/CAD.0000000000000474

56. Toulmonde M., Pulido M., Ray-Coquard I. et al. Pazopanib or methotrexate-vinblastine combination chemotherapy in adult patients with progressive desmoid tumours (DESMOPAZ): a non-comparative, randomised, open-label, multicentre, phase 2 study. Lancet Oncol 2019;20(9):1263–72. DOI: 10.1016/S1470-2045(19)30276-1

57. Miano S.T., Francini G., Civitelli S. et al. Clinical outcomes of sunitinib (Su) for patients (pts) with desmoid tumors (DT). J Clin Oncol 2019;37:11052. DOI:10.1200/JCO.2019.37.15_suppl.11052