Dr. Antonescu Research Lab Update

Angiosarcoma Research Update 

May 2022

Cancer that forms in the inner lining of lymph and blood vessels, called angiosarcoma, is rare, aggressive, and challenging to treat. Angiosarcoma affects people of all ages, occurs throughout the body, and often metastasizes or recurs even when initial treatment is successful.   

Memorial Sloan Kettering (MSK) investigators are reporting early successes with new angiosarcoma treatments rooted in emerging insights into the disease itself and the factors that may influence treatment outcomes.   

A Role for Immunotherapy 

Immunotherapy, which uses a person’s own immune system to attack cancer cells, has been successful across a range of cancers, but data on outcomes when used for angiosarcoma are limited. Recent studies led by MSK’s William Tap, MD, Chief of the Sarcoma Medical Oncology Service, and Cristina Antonescu, MD, Director of Bone and Soft Tissue Pathology, along with medical oncologists Evan Rosenbaum, MD, and Sandra D’Angelo, MD, are expanding the knowledge base and reporting clinical trial results that affirm angiosarcomas can respond to immunotherapy.

A study of a small group of patients treated with immune checkpoint blockade, a type of immunotherapy, revealed that a significant number of people with angiosarcoma saw no further progression of disease for at least four months.

Importantly, the research team noted that factors like tumor location and certain genetic mutations increased or decreased the likelihood of response to immunotherapy.     

These insights are the direct result of philanthropic support that has allowed MSK to expand existing immunotherapy clinical trials and enroll people with angiosarcoma who would not be included otherwise. This advances the field and creates opportunities for people with angiosarcoma to receive potentially beneficial treatments. Analyses of blood and tissue samples collected during these trials yield valuable information about the composition and function of immune cells within angiosarcoma tumors. Researchers hope to use these details to identify predictive biomarkers, which are features that help indicate the tumors best suited to treatment with immunotherapy.    

Linking Genomics and Prognosis

Some angiosarcomas develop following radiation therapy for other cancers. Most commonly, radiation-associated angiosarcoma (RT-AS) occurs after treatment for breast cancer. Patients with these rare tumors have a poor prognosis, and in a recent paper, Dr. Antonescu and collaborators describe one possible explanation. Most RT-AS tumors carry a genetic hallmark: excess copies of a gene known as MYC, which helps regulate cell proliferation and cell death. However, a small percentage of tumors lack this trait. The researchers assessed a large group of RT-AS tumors without excess MYC and confirmed that those patients had a better prognosis. More research is needed to determine whether this finding can help guide treatment. Studies using a new laboratory model of RT-AS developed at MSK are beginning to shed light on this area, as well as help researchers understand how these tumors develop and screen potential therapeutics. 

The Work Ahead   

The treatment landscape for angiosarcoma is shifting, with multiple novel therapies under investigation. But significant work remains. MSK has the largest known collection of genomic and clinical data on angiosarcoma, and with continued support, our researchers and clinicians will probe deeper than ever to improve outcomes.   

Relevant Publications  

Antonescu CR, Yoshida A, Guo T, Chang NE, Zhang L, Agaram NP, Qin LX, Brennan MF, Singer S, Maki RG. KDR Activating Mutations in Human Angiosarcomas Are Sensitive to Specific Kinase Inhibitors. Cancer Res 2009; 69:7175-9.

Guo T, Zhang L, Chang N, Singer S, Maki RG, Antonescu CR. Consistent MYC and FLT4 Gene Amplification in Radiation-Induced Angiosarcoma but not in other Radiation-Associated Atypical Vascular Lesions. Genes Chromosomes Cancer, 2011; 50: 25-33.   

Errani C, Zhang L, Sung YS, Hajdu M, Singer S, Maki RG, Healey JH, Antonescu CR. A novel WWTR1CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendo-thelioma of different anatomic sites. Genes Chromosomes Cancer 2011; 50: 644-53.   

Errani C, Zhang L, Panicek DM, Healey JH, Antonescu CR. Epithelioid Hemangioma of Bone and Soft Tissue: A Reappraisal of a Controversial Entity. Clin Orthop Relat Res. 2012; 470: 1498-506.  

Italiano A, Cioffi A, Penel N, Levra MG, Delcambre C, Kalbacher E, Chevreau C, Bertucci F, Isambert N, Blay JY, Bui B, Antonescu CR, D'Adamo DR, Maki RG, Keohan ML. Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas. Cancer. 2012; 118:3330-6.  

Italiano A, Thomas R, Breen M, Zhang L, Crago AM, Singer S, Khanin R, Maki RG, Mihailovic A, Hafner M, Tuschl T, Antonescu CR. The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification. Genes Chromosomes Cancer. 2012; 51:569-78   

Cioffi A, Reichert S, Antonescu CR, Maki RG. Angiosarcomas and other sarcomas of endothelial origin. Hematol Oncol Clin North Am. 2013; 27:975-88 2013. Review.  

Errani C, Sung YS, Zhang L, Healey JH, Antonescu CR. Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1-CAMTA1 breakpoints. Cancer Genet. 2012; 205:12-7.  

Italiano A, Chen CL, Thomas R, Breen M, Bonnet F, Sevenet N, Longy M, Maki RG, Coindre JM, Antonescu CR. Alterations of p53 and PIK3CA/AKT/mTOR pathways in angiosarcomas: A pattern distinct from other sarcomas with complex genomics. Cancer 2012, 118:5878-87.  

D'Angelo SP, Antonescu CR, Kuk D, Qin L, Moraco N, Carvajal RC, Chi P, Dickson MA, Gounder M, Keohan ML, Singer S, Schwartz GK, Tap WD. High-risk features in radiation-associated breast angiosarcomas. Br J Cancer. 2013;109:2340-6  

Palmerini E, Maki RG, Staals EL, Alberghini M, Antonescu CR, Ferrari C, Ruggieri P, Mavrogenis A, Bertoni F, Cesari M, Paioli A, Marchesi E, Picci P, Ferrari S. Primary angiosarcoma of bone: a retrospective analysis of 60 patients from 2 institutions. Am J Clin Oncol. 2014; 37:528-34.   

Antonescu CR. Malignant vascular tumors--an update. Mod Pathol. 2014 Jan;27 Suppl 1:S30  

D'Angelo SP, Munhoz RR, Kuk D, Landa J, Hartley EW, Bonafede M, Dickson

MA, Gounder M, Keohan ML, Crago AM, Antonescu CR, Tap WD. Outcomes of Systemic Therapy for Patients with Metastatic Angiosarcoma. Oncology. 2015;89:205-14.   

D'Angelo SP, Mahoney MR, Van Tine BA, Adkins DR, Perdekamp MT, Condy MM, Luke JJ, Hartley EW, Antonescu

CR, Tap WD, Schwartz GK. Alliance A091103 a phase II study of the angiopoietin 1 and 2 peptibody trebananib for the treatment of angiosarcoma. Cancer Chemother Pharmacol. 2015; 75:629-38.  

Anderson T, Zhang L, Hameed M, Rusch V, Travis WD, Antonescu CR. Thoracic epithelioid malignant vascular tumors: a clinicopathologic study of 52 cases with emphasis on pathologic grading and molecular studies of WWTR1-CAMTA1 fusions. Am J Surg Pathol. 2015; 39:132-9.  

Verbeke SL, de Jong D, Bertoni F, Sciot R, Antonescu CR, Szuhai K, Bovée JV. Array CGH analysis identifies two distinct subgroups of primary angiosarcoma of bone. Genes Chromosomes Cancer. 2015; 54:72-81.  

Huang SC, Zhang L, Sung YS, Chen CL, Kao YC, Agaram NP, Singer S, Tap WD, D'Angelo S, Antonescu CR. Recurrent CIC gene abnormalities in angiosarcomas: A molecular study of 120 cases with concurrent investigation of PLCG1, KDR, MYC, and FLT4 gene alterations. Am J Surg Pathol. 2016; 40:645-55.  

Sebastiano C, Gennaro L, Brogi E, Morris E, Bowser ZL, Antonescu CR, Pareja F, Brennan S, Murray MP. Benign vascular lesions of the breast diagnosed by core needle biopsy do not require excision. Histopathology. 2017; 71:795-804  

Rosenbaum E, Jadeja B, Xu B, Zhang L, Agaram NP, Travis W, Singer S, Tap WD, Antonescu CR. Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets. Mod Pathol. 2020; 33:591-602  

Suurmeijer AJH, Dickson BC, Swanson D, Sung YS, Zhang L, Antonescu CR. Variant WWTR1 gene fusions in epithelioid hemangioendothelioma-A genetic subset associated with cardiac involvement. Genes Chromosomes Cancer. 2020; 59:389-395.  

Kelly CM, Antonescu CR, Bowler T, Munhoz R, Chi P, Dickson MA, Gounder MM, Keohan ML, Movva S, Dholakia R, Ahmad H, Biniakewitz M, Condy M, Phelan H, Callahan M, Wong P, Singer S, Ariyan C, Bartlett EK, Crago A,

Yoon S, Hwang S, Erinjeri JP, Qin LX, Tap WD, D'Angelo SP. Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab: A Phase 2 Clinical Trial. JAMA Oncol. 2020; 6:402-408.  

Antonescu CR, Dickson BC, Sung YS, Zhang L, Suurmeijer AJH, Stenzinger A, Mechtersheimer G, Fletcher CDM. Recurrent YAP1 and MAML2 Gene Rearrangements in Retiform and Composite Hemangioendothelioma. Am J Surg Pathol. 2020; 44:1677-1684.  

Tsuda Y, Suurmeijer AJH, Sung YS, Zhang L, Healey JH, Antonescu CR. Epithelioid hemangioma of bone harboring FOS and FOSB gene rearrangements: A clinicopathologic and molecular study. Genes Chromosomes Cancer. 2021; 60:17-25.  

M Gabriela Kuba, Bin Xu, Sandra P D’Angelo, Evan Rosenbaum, George Plitas, Dara S Ross, Edi Brogi, Antonescu CR. The impact of MYC amplification on clinicopathologic features and prognosis of radiation-associated angiosarcomas of the breast. Histopathology, Accepted/in press 2021.