RARE TUMORS OF INFANCY. RAJKUMAR VENKATRAMANI, MD, MS Director, Rare Tumors Program, Texas Children s Hospital
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1 RARE TUMORS OF INFANCY RAJKUMAR VENKATRAMANI, MD, MS Director, Rare Tumors Program, Texas Children s Hospital
2 OBJECTIVES Review the epidemiology and clinical presentation of soft tissue sarcomas in infancy. Discuss the classification of soft tissue sarcomas in infants based on molecular diagnostic techniques. Review the management of soft tissue sarcomas in infancy including targeted therapy.
3 OUTLINE Epidemiology Infantile fibrosarcoma Rhabdomyosarcoma Rhabdoid tumor Undifferentiated round cell sarcoma
4 INCIDENCE IN INFANTS, SEER 18, Hepatic tumors Renal tumors Neuroblastoma Soft tissue sarcomas Germ cell tumors 234 cases per million infants/ year Retinoblastoma Leukemia Central nervous system neoplasms
5 INCIDENCE IN INFANTS, SEER 18, Hepatic tumors Renal tumors Neuroblastoma Soft tissue sarcomas Germ cell tumors Retinoblastoma Leukemia Central nervous system neoplasms
6 SOFT TISSUE MASS IN INFANTS: DIFFERENTIAL DIAGNOSIS BENIGN Vascular tumors Infantile hemangioma Kaposiform hemangioendothelioma Epithelioid hemangioendothelioma Fibroblastic tumors Desmoid fibromatosis Infantile myofibromatosis Fibrous hamartoma of infancy MALIGNANT Rhabdomyosarcoma Infantile fibrosarcoma Primitive myxoid mesenchymal tumor of infancy (PMMTI) Malignant Rhabdoid Tumor (MRT) Undifferentiated sarcoma Dermatofibrosarcoma protuberans Hemangiopericytoma
7 SOFT TISSUE MASS DIAGNOSTIC WORK-UP Presentation: History and physical exam Diagnostic imaging: ultrasound, MRI Biopsy (open vs. percutaneous core needle image guided) FNA Pathology: Microscopic, H/E, IHC, molecular staining Metastatic work up: CT chest
8 STS INCIDENCE IN INFANTS Age <30 days Age <1 year RMS IFS RMS IFS MRT NOS MRT NOS Ferrari, Orbach et al. Seminars in fetal and neonatal medicine; 2012.
9 INFANT STS SURVIVAL BY SUBTYPE IFS RMS MRT Survival curves according to histologic subtypes in infants (<1yr) SEER database Figure adapted and modified from Ferrari, Orbach et al. Seminars in fetal and neonatal medicine; 2012.
10 INFANTILE FIBROSARCOMA
11 INFANTILE FIBROSARCOMA Occurs in first 2 years of life 60% diagnosed before 3 months of age Courtesy of Noah Federman MD Coffin CM et al. Pediatr Pathol Jan-Feb;14(1):
12 IFS ETV6-NTRK3 FUSION Knezvich et al. Nature Genetics, 1998., Loxooncology.com
13 IFS: EUROPEAN EXPERIENCE Orbach et al. J Clin Oncol 28:
14 IFS SUGGESTED TREATMENT ALGORITHM Vincristine/Actinomycin/ Cyclophosphamide (VAC) Vincristine, Adriamycin, Cyclophosphamide (VAdriaC) Vincristine/Actinomycin (VA)
15 IFS: NOVEL TARGETED THERAPEUTICS Larotrectinib (Loxo Oncology) Phase 1/2 study of oral TRK inhibitor larotrectinib (LOXO101) for treatment of advanced pediatric solid tumor and primary CNS tumors (Age 1mo-21yo) Entrectinib (Ignyta) Phase 1/1b multicenter dose escalation study of entrectinib in patients with relapsed/refractory solid tumors (Age 2-22yo)
16 LOXO-101 PEDIATRIC PHASE 1 SCOUT TRIAL Rolling-6 dose escalation trial Ages 1-21 years in unselected refractory cancer; As young as 1 month for infantile fibrosarcoma or congenital mesoblastic nephroma Nagasubramanian R et al. Proc ASCO Abstr TPS10583.
17 LOXO-101 PEDIATRIC PHASE 1 SCOUT TRIAL Laetsch et al, J Clin Oncol 35, 2017 (suppl; abstr 10510).
18 IFS: PLANNED COG PHASE 2 STUDY ADVL1821: Larotrectinib for Newly Diagnosed TRK Fusion Positive Solid Tumors and TRK Fusion Positive Relapsed Acute Leukemias
19 RHABDOMYOSARCOMA
20 RHABDOMYOSARCOMA 4% of RMS occurs in infants 76 infants enrolled in IRS-IV, D9602 and D9803 Median age 7.4 months (17% < 3 months) 57% embryonal, 21% alveolar, 22% other Lower proportion of parameningeal Higher proportion of trunk/abdomen Malempati et al. Cancer 2011;117:
21 RHABDOMYOSARCOMA 5-YEAR SURVIVAL 87% 81% 75 % 68% 57% 76% Malempati et al. Cancer 2011;117:
22 RHABDOMYOSARCOMA SURVIVAL BY IRS GROUP 89% 69% 39% Malempati et al. Cancer 2011;117:
23 RHABDOMYOSARCOMA GROUP III BY XRT 63% 47 % 58% 32 % The rate of local failure for infants with Group III tumors was 42% vs 17% for all Group III patients Malempati et al. Cancer 2011;117:
24 SPINDLE CELL RHABDOMYOSARCOMA t(8;11) NCOA2-TEAD1 FUSION
25 SPINDLE CELL RHABDOMYOSARCOMA < 1 year old (n=11) VGLL2 rearrangements in 7 (VGLL2-CITED2, VGLL2-NCOA2) NCOA2 gene fusions in 3 All localized tumors > 1 year old (n=15) MYOD1L122R mutations in 10 Sclerosing variants had coexisting PIK3CA mutations Fatal outcome in all Long term survivors Alaggio et al. Am J Surg Pathol 2016;40:
26 NEONATAL ALVEOLAR RHABDOMYOSARCOMA Neonatal period Alveolar histology Multiple skin and subcutaneous metastases Early development of brain metastases Poor outcome Rodriguez-Galindo et al. Cancer, 92:
27 RHABDOID TUMOR
28 RHABDOID TUMOR Sites: kidney, non-renal soft tissue, CNS Bi-allelic deletion of SMARCB1/INI1 gene Treatment: surgical resection, chemotherapy and radiation NWTS 1-5 age distribution Tomlinson et al. J Clin Oncol 23:
29 RHABDOID TUMOR SURVIVAL: EpSSG NRSTS % 40.1% 8.7% 13% VDCy alternating with CyCE x 10 cycles Brennan et al. European Journal of Cancer 60 (2016) 69e82
30 RHABDOID TUMOR: HIGH DOSE CHEMOTHERAPY Study of 58 patients with rhabdoid tumor of kidney 31 patients without events at 90 days No difference in prognosis between those who got high dose chemo and those who did not. Futwangler et al. Pediatr Blood Cancer. 2017;e26746
31 RHABDOID TUMOR: LOWER SURVIVAL IN INFANTS Tomlinson et al. J Clin Oncol 23: van den Heuvel-Eibrink. Pediatr Blood Cancer, 56:
32 RHABODID TUMOR OUTCOMES Stage NWTS 1-3 (number of pts.) NWTS 1-5 (number of pts.) NWTS-5 (number of pts.) AREN0321 (number of pts.) I 50% (6) 33.3% (15) 50.0% (2) 100%(2) II 44% (9) 46.9% (25) 33.3% (3) 100%(5) III 22% (37) 21.8% (58) 33.3% (9) 26.1%(23) IV 0% (18) 8.4% (41) 21.4% (14) 11.1%(9)
33 TAZEMETOSTAT (EPZ-6438): EZH2 INHIBITOR Novel Structure, Potent Target Inhibition Selective for EZH2 Ki <2.5 nm Selectivity >20,000-fold (100-fold for EZH1) PRMTs PKMTs Antitumor Activity in Xenograft Model of INI1-negative MRT (G401) Knutson 2013
34 % change from baseline TAZEMETOSTAT RESPONSE IN ADULT PHASE I STUDY 75% * 50% * 25% * 0% -25% -50% -75% INI1-negative SMARCA4-negative Other solid tumor** * Patients censored at time of progression ** Four additional other solid tumor patients with pending disease evaluation 34
35 UNDIFFERENTIATED ROUND CELL SARCOMA
36 URCS IN INFANTS 5 months female 4 months female 2 months male CCSK PMMTI URCS
37 R. Furtwangler et al. / European Journal of Cancer 49 (2013) URCS- CCSK Median age of diagnosis between 2-3 years Approximately 4% of all kidney tumors in children May metastasize to bone, lungs and brain Addition of doxorubicin and XRT has improved outcomes
38 URCS- CCSK AREN0321 OUTCOMES Stage Treatment n 4-year EFS % 4-year OS% I DD4A, no XRT II Regimen I III Regimen I IV Regimen UH1 3 1/3 with relapse/death Preliminary data. Slide courtesy of Jeff Dome
39 URCS- CCSK t(10;17)(q22;p13) YWHAE-NUTM2B BCOR ITD O Meara et al. J Pathol May;227(1): Roy et al. Nat Commun Nov 17;6:8891 Ueno-Yokohata et al. Nat Genet Aug;47(8):861-3.
40 URCS- PMMTI Initially classified as infantile fibrosarcomas Locally aggressive Local recurrence 16 cases reported in literature Sites: trunk, extremities, head and neck Treatment: surgery Poor response to chemotherapy Alaggio et al. Am J Surg Pathol 2006 Foster et al. Pediatric developmetal pathology 2016
41 URCS- PMMTI BCOR ITD testing by PCR and RNA sequencing 6/7 positive Kao et al. Am J Surg Pathol 2016
42 URCS BCOR MUTATED SARCOMA YWHAE-NUTM2B in 2 (9%) BCOR ITD in 9 (41%) Clinical features and treatment not well defined Kao et al. Am J Surg Pathol 2016
43 URCS BCOR MUTATED SARCOMA TREATMENT Complete surgical resection Ifosfamide/doxorubicin VDC/IE Ewings regimen?ccsk regimen J Natl Compr Canc Netw 2017;15(7):
44 BCOR-MUTATED SARCOMA REGISTRY
45 STS IN INFANTS Infantile fibrosarcoma, rhabdomyosarcoma and malignant rhabdoid tumor are the most common soft tissue sarcomas in infants. In general, infants with STS have worse outcomes when compared to older children. Molecular studies have resulted in accurate diagnosis and classification. Newer targeted therapies are likely to improve the prognosis of infants with STS in the near future.
46 THANK YOU
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