BACKGROUND: Infantile myofibromatosis belongs to a family of soft tissue tumors. The majority of these tumors have benign behavior but resistant and malignant courses are known, namely in tumors with visceral involvement. The standard of care is surgical resection. Observations suggest that low dose chemotherapy is beneficial. The treatment of resistant or relapsed patients with multifocal disease remains challenging. Patients that harbor an actionable mutation in the kinase domain are potential subjects for targeted tyrosine kinase inhibitor therapy. CASE PRESENTATION: An infant boy with inborn generalized infantile myofibromatosis that included bone, intracranial, soft tissue and visceral involvement was treated according to recent recommendations with low dose chemotherapy. The presence of a partial but temporary response led to a second line of treatment with six cycles of chemotherapy, which achieved a partial response again but was followed by severe toxicity. The generalized progression of the disease was observed later. Genetic analyses were performed and revealed a PDGFRB gene c.1681C>A missense heterozygous germline mutation, high PDGFRβ phosphokinase activity within the tumor and the heterozygous germline Slavic Nijmegen breakage syndrome 657del5 mutation in the NBN gene. Targeted treatment with sunitinib, the PDGFRβ inhibitor, plus low dose vinblastine led to an unexpected and durable response without toxicities or limitations to daily life activities. The presence of the Slavic NBN gene mutation limited standard chemotherapy dosing due to severe toxicities. Sister of the patient suffred from skull base tumor with same genotype and histology. The same targeted therapy led to similar quick and durable response. CONCLUSION: Progressive and resistant incurable infantile myofibromatosis can be successfully treated with the new approach described herein. Detailed insights into the biology of the patient's tumor and genome are necessary to understand the mechanisms of activity of less toxic and effective drugs except for up to date population-based chemotherapy regimens.

Central European Institute of Technology Masaryk University Kamenice 753 5 Brno 625 00 Czech Republic

Department of Pathology University Hospital Brno and School of Medicine Masaryk University Cernopolni 9 Brno 613 00 Czech Republic

Department of Pediatric Oncology University Hospital Brno and School of Medicine Masaryk University Cernopolni 9 Brno 613 00 Czech Republic

Department of Pediatric Radiology University Hospital Brno and School of Medicine Masaryk University Cernopolni 9 Brno 613 00 Czech Republic

Division of Medical Genetics Department of Biology University Hospital Brno and School of Medicine Masaryk University Cernopolni 9 Brno 613 00 Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Pekarska 53 Brno 656 91 Czech Republic

Laboratory of Tumor Biology Department of Experimental Biology School of Science Masaryk University Kotlarska 2 Brno 611 37 Czech Republic

See more in PubMed

Levine E, Fréneaux P, Schleiermacher G, Brisse H, Pannier S, Teissier N, et al. Risk-adapted therapy for infantile myofibromatosis in children. Pediatr Blood Cancer. 2012;59:115–120. doi: 10.1002/pbc.23387. PubMed DOI

Johnson K, Notrica DM, Carpentieri D, Jaroszewski D, Henry MM. Successful treatment of recurrent pediatric inflammatory myofibroblastic tumor in a single patient with a novel chemotherapeutic regimen containing celecoxib. J Pediatr Hematol Oncol. 2013;35:414–416. doi: 10.1097/MPH.0b013e3182915cef. PubMed DOI

Auriti C, Kieran MW, Deb G, Devito R, Pasquini L, Danhaive O. Remission of infantile generalized myofibromatosis after interferon alpha therapy. J Pediatr Hematol Oncol. 2008;30:179–181. doi: 10.1097/MPH.0b013e31815e62bb. PubMed DOI

Ferrari A, Alaggio R, Meazza C, Chiaravalli S, de Pava MV, Casanova M, et al. Fibroblastic tumors of intermediate malignancy in childhood. Expert Rev Anticancer Ther. 2013;13:225–236. doi: 10.1586/era.12.180. PubMed DOI

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;363:1727–1733. doi: 10.1056/NEJMoa1007056. PubMed DOI PMC

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;4:889–895. doi: 10.1158/2159-8290.CD-14-0377. PubMed DOI PMC

Martignetti JA, Tian L, Li D, Ramirez MCM, Camacho-Vanegas O, Camacho SC, et al. Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet. 2013;92:1001–1007. doi: 10.1016/j.ajhg.2013.04.024. PubMed DOI PMC

Jo J-C, Hong YS, Kim K-P, Lee J-L, Lee J, Park YS, et al. A prospective multicenter phase II study of sunitinib in patients with advanced aggressive fibromatosis. Invest New Drugs. 2014;32:369–376. doi: 10.1007/s10637-013-0059-0. PubMed DOI

Skubitz KM, Manivel JC, Clohisy DR, Frolich JW. Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors. Cancer Chemother Pharmacol. 2009;64:635–640. doi: 10.1007/s00280-009-1010-0. PubMed DOI

Skoda J, Neradil J, Zitterbart K, Sterba J, Veselska R. EGFR signaling in the HGG-02 glioblastoma cell line with an unusual loss of EGFR gene copy. Oncol Rep. 2014;31:480–487. PubMed

Dewaele B, Floris G, Finalet-Ferreiro J, Fletcher CD, Coindre J-M, Guillou L, et al. Coactivated platelet-derived growth factor receptor and epidermal growth factor receptor are potential therapeutic targets in intimal sarcoma. Cancer Res. 2010;70:7304–7314. doi: 10.1158/0008-5472.CAN-10-1543. PubMed DOI

Ströbel P, Bargou R, Wolff A, Spitzer D, Manegold C, Dimitrakopoulou-Strauss A, et al. Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience. Br J Cancer. 2010;103:196–200. doi: 10.1038/sj.bjc.6605740. PubMed DOI PMC

Zhang Y-X, van Oosterwijk JG, Sicinska E, Moss S, Remillard SP, van Wezel T, et al. Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. Clin Cancer Res. 2013;19:3796–3807. doi: 10.1158/1078-0432.CCR-12-3647. PubMed DOI

Arts FA, Chand D, Pecquet C, Velghe AI, Constantinescu S, Hallberg B, et al. PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. Oncogene. 2015 PubMed

Cheung YH, Gayden T, Campeau PM, LeDuc CA, Russo D, Nguyen V-H, et al. A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am J Hum Genet. 2013;92:996–1000. doi: 10.1016/j.ajhg.2013.04.026. PubMed DOI PMC

Davies KD, Doebele RC. Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res. 2013;19:4040–4045. doi: 10.1158/1078-0432.CCR-12-2851. PubMed DOI PMC

Jin S, Hansson EM, Tikka S, Lanner F, Sahlgren C, Farnebo F, et al. Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ Res. 2008;102:1483–1491. doi: 10.1161/CIRCRESAHA.107.167965. PubMed DOI

Reynolds AR. Potential relevance of bell-shaped and u-shaped dose-responses for the therapeutic targeting of angiogenesis in cancer. Dose-response Publ Int Hormesis Soc. 2009;8:253–284. PubMed PMC

Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 2009;15:392–400. doi: 10.1038/nm.1941. PubMed DOI

Chrzanowska K. Nijmegen Breakage Syndrome Treatment & Management. 2016. http://emedicine.medscape.com/article/1116869-treatment. Accessed 09 Jan 2016

Andre N, Cointe S, Barlogis V, Arnaud L, Lacroix R, Pasquier E, et al. Maintenance chemotherapy in children with ALL exerts metronomic-like thrombospondin-1 associated anti-endothelial effect. Oncotarget. 2015;6:23008–23014. doi: 10.18632/oncotarget.3984. PubMed DOI PMC

Thiosemicarbazones and selected tyrosine kinase inhibitors synergize in pediatric solid tumors: NDRG1 upregulation and impaired prosurvival signaling in neuroblastoma cells

Phospho-Protein Arrays as Effective Tools for Screening Possible Targets for Kinase Inhibitors and Their Use in Precision Pediatric Oncology

Individualization of Treatment Improves the Survival of Children With High-Risk Solid Tumors: Comparative Patient Series Analysis in a Real-Life Scenario

Effects of Sunitinib and Other Kinase Inhibitors on Cells Harboring a PDGFRB Mutation Associated with Infantile Myofibromatosis