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Diagnosis, Prognosis, and Treatment of Alveolar Soft-Part SarcomaA Review

Educational Objective:
To learn current approaches to the diagnosis and treatment of alveolar soft-part sarcomas.
1 Credit CME

Importance  Alveolar soft-part sarcoma (ASPS) is a rare, translocation-driven sarcoma of the soft tissues. Alveolar soft-part sarcoma often affects young adults and is characterized by indolent behavior but early evidence of metastatic spread. After recognition of ASPS as a specific entity in 1952, retrospective data indicated prolonged survival in patients with metastases, despite inherent resistance to conventional doxorubicin-based chemotherapy. Tyrosine kinase inhibitors and immune checkpoint inhibitors have provided unexpected new treatment strategies for ASPS.

Observations  This review includes articles published between 1952 and March 1, 2018. With the introduction of new molecular diagnostic tools and therapies, the distinctive features of ASPS have become more evident. The identification and better understanding of molecular pathways activated by the characteristic t(X;17)(p11;q25) translocation and its correspondent chimeric ASPSCR1-transcription factor E3 (TFE3) fusion protein open new paths to drug development. The associations of TFE3 and facilitation of an immunosuppressive microenvironment provide a rationale for exploring treatments that affect the balance between T-effector cells and T-regulatory cells. Tyrosine kinase inhibitors, such as sunitinib, cediranib, and pazopanib, show activity with either tumor responses or disease stabilization in more than 50% of the cases. Given the association of new agents with patient outcomes, it is too early to say whether metastatic ASPS should still be considered incurable in all patients.

Conclusions and Relevance  The biologic outcomes of the canonical genomic event in ASPS remain under investigation; a better understanding of the tumor microenvironment and the multiple pathways activated in this sarcoma, including unusual bioenergetics, MET signaling, and angiogenesis, should lead to more rational therapy. Basket trials and related prospective studies focusing on the intersection of specific signaling pathways and diseases with unique genomic features, such as ASPS, will provide an understanding of new options for care.

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Article Information

Accepted for Publication: July 5, 2018.

Corresponding Author: Luca Paoluzzi, MD, Department of Medicine, New York University Langone Medical Center, 160 E 34th St, 10th Flr, Room 1011, New York, NY 10016 (luca.paoluzzi@nyumc.org).

Published Online: October 18, 2018. doi:10.1001/jamaoncol.2018.4490

Author Contributions: Drs Paoluzzi and Maki had full access to all the data in the study and take responsibility of the integrity of the data and the accuracy of the data analysis.

Concept and design: Both authors.

Acquisition, analysis, or interpretation of data: Both authors.

Drafting of the manuscript: Both authors.

Critical revision of the manuscript for important intellectual content: Both authors.

Administrative, technical, or material support: Paoluzzi.

Conflict of Interest Disclosures: Dr Maki is a board member and member of the medical oncology examination committee for American Board of Internal Medicine; receives consultant fees from Aadi Bioscience, Karyopharm Therapeutics, Deciphera data and safety monitoring board, Arcus, Bayer, Eisai, Immune Design, Janssen, Pharma Mar, Presage, Tracon, and Sarcoma Alliance for Research Through Collaboration (SARC); and research support to New York University from Immune Design, Immunocore, Lilly, Presage, Tracon, SARC, Regeneron, and Genentech. No other conflicts were reported.

Fletcher  CDM, Bridge  JA, Hogendoorn  PCW, Mertens  F.  World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone. Pathology and Genetics. Lyon, France: IARC Press; 2013:218-220.
Siegel  RL, Miller  KD, Jemal  A.  Cancer statistics, 2018.  CA Cancer J Clin. 2018;68(1):7-30. doi:10.3322/caac.21442PubMedGoogle ScholarCrossref
Am  KM, Am  R, Sumrein  N, Foltz  C, Abraham  J, Mallick  AB. Epidemiology, incidence and survival of alveolar soft-part sarcoma: SEER database analysis [abstract 013]. Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting. November 8-11, 2017; Maui, Hawaii.
Christopherson  WM, Foote  FW  Jr, Stewart  FW.  Alveolar soft-part sarcomas; structurally characteristic tumors of uncertain histogenesis.  Cancer. 1952;5(1):100-111. doi:10.1002/1097-0142(195201)5:1<100::AID-CNCR2820050112>3.0.CO;2-KPubMedGoogle ScholarCrossref
Ladanyi  M, Lui  MY, Antonescu  CR,  et al.  The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25.  Oncogene. 2001;20(1):48-57. doi:10.1038/sj.onc.1204074PubMedGoogle ScholarCrossref
Williams  A, Bartle  G, Sumathi  VP,  et al.  Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, paraffin-embedded tissue in a series of 18 cases of alveolar soft part sarcoma: useful diagnostic tools in cases with unusual histological features.  Virchows Arch. 2011;458(3):291-300. doi:10.1007/s00428-010-1039-9PubMedGoogle ScholarCrossref
Conley  AP, Trinh  VA, Zobniw  CM,  et al. Positive tumor response to combined checkpoint inhibitors in a patient with refractory alveolar soft part sarcoma: a case report. J Global Oncol. http://ascopubs.org/doi/full/10.1200/JGO.2017.009993. Published 2017. Accessed April 19, 2018.
Wilky  BA, Wieder  E, Kolonias  D,  et al. Antitumor activity of axitinib plus pembrolizumab in a phase II trial for patients with advanced alveolar soft part sarcoma (ASPS) and other soft tissue sarcoma [abstract 009]. Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting. November 8-11, 2017; Maui, Hawaii.
Flores  RJ, Harrison  DJ, Federman  NC,  et al.  Alveolar soft part sarcoma in children and young adults: A report of 69 cases.  Pediatr Blood Cancer. 2018;65(5):e26953. doi:10.1002/pbc.26953PubMedGoogle ScholarCrossref
Portera  CA  Jr, Ho  V, Patel  SR,  et al.  Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution.  Cancer. 2001;91(3):585-591. doi:10.1002/1097-0142(20010201)91:3<585::AID-CNCR1038>3.0.CO;2-0PubMedGoogle ScholarCrossref
Ju  X, Sun  K, Liu  R,  et al.  Exploring the histogenesis and diagnostic strategy using immunoassay and RT-PCR in alveolar soft part sarcoma.  Pathol Oncol Res. 2018;24(3):593-600. doi:10.1007/s12253-017-0280-9PubMedGoogle ScholarCrossref
Folpe  AL, Deyrup  AT.  Alveolar soft-part sarcoma: a review and update.  J Clin Pathol. 2006;59(11):1127-1132. doi:10.1136/jcp.2005.031120PubMedGoogle ScholarCrossref
Argani  P, Antonescu  CR, Illei  PB,  et al.  Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents.  Am J Pathol. 2001;159(1):179-192. doi:10.1016/S0002-9440(10)61684-7PubMedGoogle ScholarCrossref
Stockwin  LH, Vistica  DT, Kenney  S,  et al.  Gene expression profiling of alveolar soft-part sarcoma (ASPS).  BMC Cancer. 2009;9:22. doi:10.1186/1471-2407-9-22PubMedGoogle ScholarCrossref
Lazar  AJ, Das  P, Tuvin  D,  et al.  Angiogenesis-promoting gene patterns in alveolar soft part sarcoma.  Clin Cancer Res. 2007;13(24):7314-7321. doi:10.1158/1078-0432.CCR-07-0174PubMedGoogle ScholarCrossref
Ishiguro  N, Yoshida  H.  ASPL-TFE3 oncoprotein regulates cell cycle progression and induces cellular senescence by up-regulating p21.  Neoplasia. 2016;18(10):626-635. doi:10.1016/j.neo.2016.08.001PubMedGoogle ScholarCrossref
Goodwin  ML, Jin  H, Straessler  K,  et al.  Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment.  Cancer Cell. 2014;26(6):851-862. doi:10.1016/j.ccell.2014.10.003PubMedGoogle ScholarCrossref
Chang  W, Brohl  AS, Patidar  R,  et al.  Multidimensional clinomics for precision therapy of children and adolescent young adults with relapsed and refractory cancer: a report from the Center for Cancer Research.  Clin Cancer Res. 2016;22(15):3810-3820. doi:10.1158/1078-0432.CCR-15-2717PubMedGoogle ScholarCrossref
Cancer Genome Atlas Research Network.  Comprehensive and integrated genomic characterization of adult soft tissue sarcomas.  Cell. 2017;171(4):950-965.e28. doi:10.1016/j.cell.2017.10.014PubMedGoogle ScholarCrossref
Cui  JF, Chen  HS, Hao  DP, Liu  JH, Hou  F, Xu  WJ; Cancer Genome Atlas Research Network.  Magnetic resonance features and characteristic vascular pattern of alveolar soft-part sarcoma.  Oncol Res Treat. 2017;40(10):580-585. doi:10.1159/000477443PubMedGoogle ScholarCrossref
Lieberman  PH, Brennan  MF, Kimmel  M, Erlandson  RA, Garin-Chesa  P, Flehinger  BY.  Alveolar soft-part sarcoma: a clinico-pathologic study of half a century.  Cancer. 1989;63(1):1-13. doi:10.1002/1097-0142(19890101)63:1<1::AID-CNCR2820630102>3.0.CO;2-EPubMedGoogle ScholarCrossref
Penel  N, Coindre  JM, Giraud  A,  et al.  Presentation and outcome of frequent and rare sarcoma histologic subtypes: a study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers.  Cancer. 2018;124(6):1179-1187. doi:10.1002/cncr.31176PubMedGoogle ScholarCrossref
Brennan  B, Zanetti  I, Orbach  D,  et al.  Alveolar soft part sarcoma in children and adolescents: the European Paediatric Soft Tissue Sarcoma study group prospective trial (EpSSG NRSTS 2005).  Pediatr Blood Cancer. 2018;65(4). doi:10.1002/pbc.26942PubMedGoogle Scholar
Reichardt  P, Lindner  T, Pink  D, Thuss-Patience  PC, Kretzschmar  A, Dörken  B.  Chemotherapy in alveolar soft part sarcomas: what do we know?  Eur J Cancer. 2003;39(11):1511-1516. doi:10.1016/S0959-8049(03)00264-8PubMedGoogle ScholarCrossref
Orbach  D, Brennan  B, Casanova  M,  et al.  Paediatric and adolescent alveolar soft part sarcoma: a joint series from European cooperative groups.  Pediatr Blood Cancer. 2013;60(11):1826-1832. doi:10.1002/pbc.24683PubMedGoogle ScholarCrossref
Billingsley  KG, Burt  ME, Jara  E,  et al.  Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival.  Ann Surg. 1999;229(5):602-610. doi:10.1097/00000658-199905000-00002PubMedGoogle ScholarCrossref
Stacchiotti  S, Negri  T, Zaffaroni  N,  et al.  Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect.  Ann Oncol. 2011;22(7):1682-1690. doi:10.1093/annonc/mdq644PubMedGoogle ScholarCrossref
Li  T, Wang  L, Wang  H,  et al.  A retrospective analysis of 14 consecutive Chinese patients with unresectable or metastatic alveolar soft part sarcoma treated with sunitinib.  Invest New Drugs. 2016;34(6):701-706. doi:10.1007/s10637-016-0390-3PubMedGoogle ScholarCrossref
Jagodzińska-Mucha  P, Świtaj  T, Kozak  K,  et al.  Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma.  Tumori. 2017;103(3):231-235. doi:10.5301/tj.5000617PubMedGoogle ScholarCrossref
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(23):5894-5902. doi:10.1002/cncr.27582PubMedGoogle ScholarCrossref
Kummar  S, Allen  D, Monks  A,  et al.  Cediranib for metastatic alveolar soft part sarcoma.  J Clin Oncol. 2013;31(18):2296-2302. doi:10.1200/JCO.2012.47.4288PubMedGoogle ScholarCrossref
Judson  I, Scurr  M, Gardner  K,  et al.  Phase II study of cediranib in patients with advanced gastrointestinal stromal tumors or soft-tissue sarcoma.  Clin Cancer Res. 2014;20(13):3603-3612. doi:10.1158/1078-0432.CCR-13-1881PubMedGoogle ScholarCrossref
Judson  I, Morden  JP, Leahy  MG,  et al. Activity of cediranib in alveolar soft part sarcoma (ASPS) confirmed by CASPS (cediranib in ASPS), an international, randomized phase II trial [abstract 11004]. Proc ASCO. 2017; 35(15).
Judson  I, Morden  J, Leahy  M,  et al. CASPS (cediranib in alveolar soft part sarcoma), an international randomized phase II trial. Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting [abstract 031]. November 8-11, 2017; Maui, Hawaii.
Schuetze  SM, Bolejack  V, Choy  E,  et al.  Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor.  Cancer. 2017;123(1):90-97. doi:10.1002/cncr.30379PubMedGoogle ScholarCrossref
Schöffski  P, Wozniak  A, Kasper  B,  et al.  Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase 2 trial 90101 “CREATE”.  Ann Oncol. 2018;29(3):758-765.Google Scholar
Stacchiotti  S, Mir  O, Le Cesne  A,  et al.  Activity of pazopanib and trabectedin in advanced alveolar soft part sarcoma.  Oncologist. 2018;23(1):62-70. doi:10.1634/theoncologist.2017-0161PubMedGoogle ScholarCrossref
Stacchiotti  S, Tamborini  E, Marrari  A,  et al.  Response to sunitinib malate in advanced alveolar soft part sarcoma.  Clin Cancer Res. 2009;15(3):1096-1104. doi:10.1158/1078-0432.CCR-08-2050PubMedGoogle ScholarCrossref
Fox  E, Aplenc  R, Bagatell  R,  et al.  A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors.  J Clin Oncol. 2010;28(35):5174-5181. doi:10.1200/JCO.2010.30.9674PubMedGoogle ScholarCrossref
Kuo  DJ, Menell  JS, Glade Bender  JL.  Treatment of metastatic, refractory alveolar soft part sarcoma: case reports and literature review of treatment options in the era of targeted therapy.  J Pediatr Hematol Oncol. 2016;38(5):e169-e172. doi:10.1097/MPH.0000000000000571PubMedGoogle ScholarCrossref
Glade Bender  JL, Lee  A, Reid  JM,  et al.  Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children’s oncology group phase I consortium report.  J Clin Oncol. 2013;31(24):3034-3043. doi:10.1200/JCO.2012.47.0914PubMedGoogle ScholarCrossref
Read  WL, Williams  F.  Metastatic alveolar soft part sarcoma responsive to pazopanib after progression through sunitinib and bevacizumab: two cases.  Case Rep Oncol. 2016;9(3):639-643. doi:10.1159/000450545PubMedGoogle ScholarCrossref
Funakoshi  Y, Okada  M, Kawata  S, Ito  N, Abe  K, Moriuchi  H.  The significant effects of pazopanib on multiple pulmonary metastatic lesions of alveolar soft part sarcoma: a case report.  J Pediatr Hematol Oncol. 2017;39(3):238-239. doi:10.1097/MPH.0000000000000736PubMedGoogle ScholarCrossref
Zhou  Y, Tang  F, Wang  Y,  et al.  Advanced alveolar soft part sarcoma responds to apatinib.  Oncotarget. 2017;8(30):50314-50322. doi:10.18632/oncotarget.18599PubMedGoogle Scholar
Goldberg  JM, Gavcovich  T, Saigal  G, Goldman  JW, Rosen  LS.  Extended progression-free survival in two patients with alveolar soft part sarcoma exposed to tivantinib.  J Clin Oncol. 2014;32(34):e114-e116. doi:10.1200/JCO.2013.48.7462PubMedGoogle ScholarCrossref
Chen  A, O’Sullivan Coyne  G, Meehan  R,  et al. A phase 2 trial of cabozantinib (XL184) in metastatic refractory soft tissue sarcoma [abstract 013]. Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting. November 8-11, 2017; Maui, Hawaii.
Takahashi  M, Takahashi  S, Araki  N,  et al.  Efficacy of trabectedin in patients with advanced translocation-related sarcomas: pooled analysis of two phase II studies.  Oncologist. 2017;22(8):979-988. doi:10.1634/theoncologist.2016-0064PubMedGoogle ScholarCrossref
Demetri  GD, Chawla  SP, von Mehren  M,  et al.  Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules.  J Clin Oncol. 2009;27(25):4188-4196. doi:10.1200/JCO.2008.21.0088PubMedGoogle ScholarCrossref
Groisberg  R, Hong  DS, Behrang  A,  et al.  Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials.  J Immunother Cancer. 2017;5(1):100. doi:10.1186/s40425-017-0301-yPubMedGoogle ScholarCrossref
Broto  JM, Hindi  N, Redondo  A,  et al.  IMMUNOSARC: a collaborative Spanish (GEIS) and Italian (ISG) Sarcoma Groups phase I/II trial of sunitinib plus nivolumab in selected bone and soft tissue sarcoma subtypes—results of the phase I part  [abstract 11515].  J Clin Oncol. 2018;36:36. suppl.Google Scholar
Jiang  W, Liu  P, Li  X, Wang  P.  Identification of target genes of cediranib in alveolar soft part sarcoma using a gene microarray.  Oncol Lett. 2017;13(4):2623-2630. doi:10.3892/ol.2017.5779PubMedGoogle ScholarCrossref
Mukaihara  K, Tanabe  Y, Kubota  D,  et al.  Cabozantinib and dastinib exert anti-tumor activity in alveolar soft part sarcoma.  PLoS One. 2017;12(9):e0185321. doi:10.1371/journal.pone.0185321PubMedGoogle ScholarCrossref
Gherardi  E, Birchmeier  W, Birchmeier  C, Vande Woude  G.  Targeting MET in cancer: rationale and progress.  Nat Rev Cancer. 2012;12(2):89-103. doi:10.1038/nrc3205PubMedGoogle ScholarCrossref
Tawbi  HA, Burgess  M, Bolejack  V,  et al.  Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial.  Lancet Oncol. 2017;18(11):1493-1501. doi:10.1016/S1470-2045(17)30624-1PubMedGoogle ScholarCrossref
D’Angelo  SP, Mahoney  MR, Van Tine  BA,  et al.  Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials.  Lancet Oncol. 2018;19(3):416-426. doi:10.1016/S1470-2045(18)30006-8PubMedGoogle ScholarCrossref
Panda  A, De Cubas  A, Beckermann  K,  et al. Expression of endogenous retroviruses and response to immune checkpoint therapy in renal cell cancer [abstract 104]. ASCO-SITC Clinical Immuno-Oncology Symposium. January 25-27, 2018; San Francisco, CA.
Worley  BS, van den Broeke  LT, Goletz  TJ,  et al.  Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations.  Cancer Res. 2001;61(18):6868-6875.PubMedGoogle Scholar
Huan  C, Kelly  ML, Steele  R, Shapira  I, Gottesman  SR, Roman  CA.  Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity.  Nat Immunol. 2006;7(10):1082-1091. doi:10.1038/ni1378PubMedGoogle ScholarCrossref
Hua  X, Miller  ZA, Benchabane  H, Wrana  JL, Lodish  HF.  Synergism between transcription factors TFE3 and Smad3 in transforming growth factor-beta–induced transcription of the Smad7 gene.  J Biol Chem. 2000;275(43):33205-33208. doi:10.1074/jbc.C000568200PubMedGoogle ScholarCrossref
Travis  MA, Sheppard  D.  TGF-β activation and function in immunity.  Annu Rev Immunol. 2014;32:51-82. doi:10.1146/annurev-immunol-032713-120257PubMedGoogle ScholarCrossref
BaniHani  MN, Al Manasra  AR.  Spontaneous regression in alveolar soft part sarcoma: case report and literature review.  World J Surg Oncol. 2009;7:53. doi:10.1186/1477-7819-7-53PubMedGoogle ScholarCrossref
A phase III trial of anlotinib in metastatic or advanced alveolar soft part sarcoma, leiomyosarcoma and synovial sarcoma (APROMISS). https://clinicaltrials.gov/ct2/show/NCT03016819. Accessed April 19, 2018.
Atezolizumab in treating patients with newly diagnosed and metastatic alveolar soft part sarcoma that cannot be removed by surgery. NCT03141684. https://clinicaltrials.gov/ct2/show/NCT03141684. Accessed April 19, 2018.
Multi-arm study to test the efficacy of immunotherapeutic agents in multiple sarcoma subtypes. https://clinicaltrials.gov/ct2/show/NCT02815995. Accessed April 19, 2018.
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