Bone and soft tissue sarcomas, tumors of the skinBone and soft tissue sarcomas, tumors of the skinСаркомы костей, мягких тканей и опухоли кожи2219-46142782-3687Publishing House ABV Press58110.17650/2782-3687-2022-14-4-13-21EDITORIALОТ РЕДАКЦИИTargeted therapies for soft tissue sarcomas and desmoid tumorsТаргетная терапия сарком мягких тканей и десмоидных опухолейhttps://orcid.org/0000-0003-0592-7182KonoplyaN. E.КонопляН. Е.
Belarus

ag. Forest 223040, Minsk

Минский район, 223040 аг. Лесной

https://orcid.org/0000-0001-5946-9100ZhukovetsA. G.ЖуковецА. Г.
Belarus

Bld. 3, 3 Petrus Brovki St., Minsk 220013

220013 Минск, ул. Петруся Бровки, 3, корп. 3

https://orcid.org/0000-0002-3885-1148BogdayevYu. M.БогдаевЮ. М.
Belarus

ag. Forest 223040, Minsk

Минский район, 223040 аг. Лесной

https://orcid.org/0000-0002-5696-9481ZhilyaevA. V.ЖиляевА. В.
Belarus

ag. Forest 223040, Minsk

Минский район, 223040 аг. Лесной

zhilyaevanton1988@gmail.comN.N. Aleksandrov Republican Scientific and Practical Center of Oncology and Medical RadiologyГУ «Республиканский научно-практический центр онкологии и медицинской радиологии им. Н.Н. Александрова»Belarusian Medical Academy of Postgraduate EducationГУО «Белорусская медицинская академия последипломного образования»2212202214413212012202220122022Copyright ©; 2022, Konoplya N.E., Zhukovets A.G., Bogdayev Y.M., Zhilyaev A.V.Copyright ©; 2022, Конопля Н.Е., Жуковец А.Г., Богдаев Ю.М., Жиляев А.В.2022Konoplya N.E., Zhukovets A.G., Bogdayev Y.M., Zhilyaev A.V.Конопля Н.Е., Жуковец А.Г., Богдаев Ю.М., Жиляев А.В.https://creativecommons.org/licenses/by/4.0https://sarbon.abvpress.ru/jour/article/view/581

Soft tissue sarcomas are a group of rare malignant tumors with a high recurrence and mortality rate. Little progress has been made in the treatment of this pathology over the past decades. Surgery with or without adjuvant/neoadjuvant radiotherapy is still the first-line therapy for localized soft tissue sarcomas, and chemotherapy is an additional option for high-risk patients. However, not all patients with advanced or metastatic soft tissue sarcomas benefit from conventional chemotherapy. Soft tissue sarcomas are characterized by high heterogeneity of biological behavior and a variety of genetic mutations, which indicates the perspective of personalized therapy based on tumor histotype, genetic and molecular characteristics, and new small molecule inhibitors of signaling pathways. This article provides an overview of studies on the effectiveness of targeted therapy for the most common soft tissue sarcomas and desmoid tumors.

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.

soft tissue sarcomasdesmoid tumorsmolecular targeting therapiesclinical trialtyrosine kinase inhibitorsсаркомы мягких тканейдесмоидная опухольтаргетная терапияклинические испытанияингибиторы тирозинкиназSung 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.21660Okeanov A.E., Moiseev P.I., Levin L.F. et al. Cancer in Belarus: facts and figures. Analysis of the data of the Belarusian Cancer Register for 2010–2019. Edited by S.L. Polyakov. Minsk: National Library of Belarus, 2020. 298 p. (In Russ.).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.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.2014.10.004Savina 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/s12916-017-0831-7Judson 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)70063-4Wunder 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)70169-9Juan J., Li X., Yu S. Molecular targeted therapy for advanced or metastatic soft tissue sarcoma. Cancer Control 2021;28:10732748211038424. DOI: 10.1177/10732748211038424Crago A.M., Brennan M.F. Principles in management of soft tissue sarcoma. Adv Surg 2015;49(1):107–22. DOI: 10.1016/j.yasu.2015.04.002Schöffski 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)01283-0Demetri 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.2015.62.4734Konecny 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.0000000000000243Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. DOI: 10.1016/j.cell.2011.02.013Binh 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.0000170343.09562.39Dickson 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.2012.46.5476Dickson 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.2016.0264Dickson 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.11004Mahmood 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.25843Samuels 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.30926Chi 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-17-376Riedel 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.2020-0679Thway K., Fisher C. Synovial sarcoma: defining features and diagnostic evolution. Ann Diagn Pathol 2014;18(6):369–80. DOI: 10.1016/j.anndiagpath.2014.09.002Guillou 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.2004.11.093Judson 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)70063-4Vlenterie 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.2016.02.002Sleijfer 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.2008.21.3223Van 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)60651-5Mir 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)30507-1Kotecki 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.11052Xie 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-zMaki 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.2008.20.4495Vincenzi 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: 10.1517/13543784.2013.742886Schöffski 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.2013.06.010Pappo 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.28728D’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.2018-0160Tap 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)30587-6Tap 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.LBA3Kadoch 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.2013.02.036Kawano 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.0158888Schoffski 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.11057Roberts 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.2018.09.010Italiano 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.0b013e3283442074Chawla 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.2011.35.6329Okuno 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.25928Schwartz 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)70049-4Martin-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/s11523-017-0539-9Trucco 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/s13569-018-0107-9Santoro 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/mds607Escobar C., Munker R., Thomas J.O. et al. Update on desmoid tumors. Ann Oncol 2012;23(3):562–9. DOI: 10.1093/annonc/mdr386Li 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)65614-3Messersmith 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-14-0607Kummar 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.2016.71.1994Penel 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/mdq341Gounder 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-10-3322Gounder 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/NEJMoa1805052Szucs 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.0000000000000474Toulmonde 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)30276-1Miano 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