STUMP un“stumped”: anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion

Journal of Hematology & Oncology

Siraj M. Ali⁴  Jeffrey S. Ross⁴  Philip J. Stephens⁴  Vincent A. Miller⁴  John Mayfield⁴  Zachary R. Chalmers⁴  Juliann Chmielecki⁴  Tim Brennan⁴  Jenny Berry¹  Charles F. Levenback⁵  Deepa Anand²  Dhakshina Moorthy Ganeshan²  Chimela Ohaji¹  Ishwaria M. Subbiah¹  Julia A. Elvin⁴  Elvio G Silva³  Ralph Zinner¹  Shreyaskumar Patel⁶  Caitlin McMahon⁴  Vivek Subbiah¹ 

[1] Division of Cancer Medicine, Department of Investigational Cancer Therapeutic (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, FC8.3038, Houston 77030, TX, USA;Division of Diagnostic Imaging and Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA;Division of Diagnostic Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA;Foundation Medicine, Inc, Cambridge 02141, MA, USA;Division of Surgery, Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Division of Cancer Medicine, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston 77030, TX, USA

关键词: Smooth muscle tumor of uncertain malignant potential (STUMP);    Uterine myxoid tumors;    ALK fusions;    Pazopanib;    Crizotinib;    Targeted therapy;    Inflammatory myofibroblastic tumor;    Sarcoma;    ALK;   

Others  :  1217370
DOI  :  10.1186/s13045-015-0160-2

 received in 2015-04-10, accepted in 2015-05-25,  发布年份 2015

【 摘 要 】

Background

Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein.

Methods

Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01548144 webcite).

Results

Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria.

Conclusions

For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

【 授权许可】

   
2015 Subbiah et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Zulfiqar MI, Sheikh UN, Montgomery EA. Myxoid neoplasms. Surg Pathol Clin. 2011; 4:843-64.
• [2]Frampton GM, Fitchtenholtz A, Otto GA, Wang K, Downing SR, He J et al.. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013; 31:1023-31.
• [3]Zinner R. Pazopanib or pemetrexed and crizotinib in advanced cancer. (M.D. Anderson Cancer Center). at https://clinicaltrials.gov/ct2/show/NCT01548144.
• [4]Marino-Enriquez A, Dal CP. ALK as a paradigm of oncogenic promiscuity: different mechanisms of activation and different fusion partners drive tumors of different lineages. Cancer Genet. 2013; 206:357-73.
• [5]Wang X, Krishnan C, Nguyen EP, Meyer KJ, Oliverira JL, Yang P et al.. Fusion of dynactin 1 to anaplastic lymphoma kinase in inflammatory myofibroblastic tumor. Hum Pathol. 2012; 43:2047-52.
• [6]Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I et al.. Kinase fusions are frequent in Spitz tumors and spitzoid melanomas. Nat Commun. 2014; 5:3116.
• [7]Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL et al.. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994; 263:1281-4.
• [8]Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8.
• [9]Allen PW. Myxoid tumors of soft tissues. Pathol Annu. 1980; 15:133-92.
• [10]Mackenzie DH. The myxoid tumors of somatic soft tissues. Am J Surg Pathol. 1981; 5:443-58.
• [11]Graadt van Roggen JF, Hogendoorn PC, Fletcher CD. Myxoid tumours of soft tissue. Histopathology. 1999;35:291–312.
• [12]Coffin CM, Patel A, Perkins S, Elenitoba-Johnson KS, Perlman E, Griffin CA. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol. 2001; 14:569-76.
• [13]Lovly CM, Gupta A, Lipson D, Otto G, Brennan T, Chung CT et al.. Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov. 2014; 4:889-95.
• [14]Fraggetta F, Doglioni C, Scollo P, Pecciarini L, Ippolito M, Amico P, et al. Uterine inflammatory myofibroblastic tumor in a 10-year-old girl presenting as polypoid mass. J Clin Oncol. 2015;33.
• [15]Gleason BC, Hornick JL. Inflammatory myofibroblastic tumours: where are we now? J Clin Pathol. 2008; 61:428-37.
• [16]Cook JR, Dehner LP, Collins MH, Ma Z, Morris SW, Coffin CM et al.. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol. 2001; 25:1364-71.
• [17]Kushnir CL, Gerardi M, Banet N, Shih I-M, Diaz-Montes T. Extrauterine inflammatory myofibroblastic tumor: a case report. Gynecol Oncol Case Rep. 2013;6.
• [18]Parra-Herran C, Quick CM, Howitt BE, Dal Cin P, Quade BJ, Nucci MR. Inflammatory myofibroblastic tumor of the uterus: clinical and pathologic review of 10 cases including a subset with aggressive clinical course. Am J Surg Pathol. 2015; 39:157-68.
• [19]Fuehrer NE, Keeney GL, Ketterling RP, Knudson RA, Bell DA. ALK-1 protein expression and ALK gene rearrangements aid in the diagnosis of inflammatory myofibroblastic tumors of the female genital tract. Arch Pathol Lab Med. 2012; 136:623-6.
• [20]Melloni G, Carretta A, Ciriaco P, Arrigoni G, Fieschi S, Rizzo N et al.. Inflammatory pseudotumor of the lung in adults. Ann Thorac Surg. 2005; 79:426-32.
• [21]Mosse YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J et al.. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013; 14:472-80.
• [22]Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG et al.. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010; 363:1693-703.
• [23]Ou SH, Kwak EL, Siawak-Tapp C, Dy J, Bergethon K, Clark JW et al.. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011; 6:942-6.
• [24]Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT et al.. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012; 30:863-70.
• [25]Butrynski JE, D’Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, Jhanwar SC et al.. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010; 363:1727-33.
• [26]Lorenzi L, Cigognetti M, Medicina D, Pellegrini V, Balzarini P, Cestari R et al.. ALK-positive inflammatory myofibroblastic tumor of the abdomen with widespread microscopic multifocality. Int J Surg Pathol. 2014; 22:640-4.
• [27]Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D et al.. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015; 372:30-9.
• [28]Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ et al.. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013; 368:2385-94.
• [29]Stinchcombe, T. E. Recent advances in the treatment of non-small cell and small cell lung cancer. F1000Prime Rep. 2014;6:117.
• [30]Van Geel RM, Beijnen JH, Schellens JH. Concise drug review: pazopanib and axitinib. Oncologist. 2012; 17:1081-9.