RARE TUMORS OF INFANCY
RAJKUMAR VENKATRAMANI, MD, MS Director, Rare Tumors Program, Texas Children’s Hospital 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. OUTLINE
• Epidemiology • Infantile fibrosarcoma • Rhabdomyosarcoma • Rhabdoid tumor • Undifferentiated round cell sarcoma INCIDENCE IN INFANTS, SEER 18, 2010-2014 Hepatic tumors Renal tumors Neuroblastoma
Soft tissue sarcomas
234 cases per million Germ cell tumors infants/ year
Leukemia Retinoblastoma
Central nervous system neoplasms INCIDENCE IN INFANTS, SEER 18, 2010-2014 Hepatic tumors Renal tumors Neuroblastoma
Soft tissue sarcomas
Germ cell tumors
Leukemia Retinoblastoma
Central nervous system neoplasms SOFT TISSUE MASS IN INFANTS: DIFFERENTIAL DIAGNOSIS
BENIGN MALIGNANT
Vascular tumors Rhabdomyosarcoma Infantile hemangioma Infantile fibrosarcoma Kaposiform hemangioendothelioma Primitive myxoid mesenchymal tumor of Epithelioid hemangioendothelioma infancy (PMMTI) Malignant Rhabdoid Tumor (MRT) Fibroblastic tumors Undifferentiated sarcoma Desmoid fibromatosis Dermatofibrosarcoma protuberans Infantile myofibromatosis Hemangiopericytoma Fibrous hamartoma of infancy 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 STS INCIDENCE IN INFANTS
Age <30 days Age <1 year
RMS IFS RMS IFS
MRT MRT NOS NOS
Ferrari, Orbach et al. Seminars in fetal and neonatal medicine; 2012. INFANT STS SURVIVAL BY SUBTYPE
IFS
RMS
MRT
Survival curves according to histologic subtypes in infants (<1yr) SEER database 1973-2007 Figure adapted and modified from Ferrari, Orbach et al. Seminars in fetal and neonatal medicine; 2012. INFANTILE FIBROSARCOMA 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. 1994 Jan-Feb;14(1):133-50. IFS ETV6-NTRK3 FUSION
Knezvich et al. Nature Genetics, 1998., Loxooncology.com IFS: EUROPEAN EXPERIENCE
Orbach et al. J Clin Oncol 28:318-323. IFS SUGGESTED TREATMENT ALGORITHM
Vincristine/Actinomycin/ Cyclophosphamide (VAC) Vincristine, Adriamycin, Cyclophosphamide (VAdriaC) Vincristine/Actinomycin (VA) 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) 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 2016. Abstr TPS10583. LOXO-101 PEDIATRIC PHASE 1 SCOUT TRIAL
Laetsch et al, J Clin Oncol 35, 2017 (suppl; abstr 10510). IFS: PLANNED COG PHASE 2 STUDY
ADVL1821: Larotrectinib for Newly Diagnosed TRK Fusion Positive Solid Tumors and TRK Fusion Positive Relapsed Acute Leukemias RHABDOMYOSARCOMA 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;117:3493–501. RHABDOMYOSARCOMA 5-YEAR SURVIVAL
87% 81% 75 %
68% 76% 57%
Malempati et al. Cancer 2011;117:3493–501. RHABDOMYOSARCOMA SURVIVAL BY IRS GROUP
89%
69%
39%
Malempati et al. Cancer 2011;117:3493–501. 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;117:3493–501. SPINDLE CELL RHABDOMYOSARCOMA
t(8;11) NCOA2-TEAD1 FUSION SPINDLE CELL RHABDOMYOSARCOMA
< 1 year old (n=11) > 1 year old (n=15) • VGLL2 rearrangements in 7 • MYOD1L122R mutations in 10 (VGLL2-CITED2, VGLL2-NCOA2) • Sclerosing variants had coexisting • NCOA2 gene fusions in 3 PIK3CA mutations
• All localized tumors • Fatal outcome in all
• Long term survivors
Alaggio et al. Am J Surg Pathol 2016;40:224–235 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: 1613–1620. RHABDOID TUMOR 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 23:7641-7645. RHABDOID TUMOR SURVIVAL: EpSSG NRSTS 2005
40.1% 39.3%
13% 8.7%
VDCy alternating with CyCE x 10 cycles
Brennan et al. European Journal of Cancer 60 (2016) 69e82 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 RHABDOID TUMOR: LOWER SURVIVAL IN INFANTS
Tomlinson et al. J Clin Oncol 23:7641-7645. van den Heuvel-Eibrink. Pediatr Blood Cancer, 56: 733–737. RHABODID TUMOR OUTCOMES
Stage NWTS 1-3 NWTS 1-5 NWTS-5 AREN0321 (number (number of (number of (number of of pts.) pts.) pts.) 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) TAZEMETOSTAT (EPZ-6438): EZH2 INHIBITOR
Novel Structure, Potent Target Inhibition Selective for EZH2
Ki <2.5 nM PRMTs Selectivity >20,000-fold (100-fold for EZH1) PKMTs
Antitumor Activity in Xenograft Model of INI1-negative MRT (G401)
Knutson 2013 TAZEMETOSTAT RESPONSE IN ADULT PHASE I STUDY
75% *
50%
*
25% *
0%
-25% % change from from baseline change %
-50% INI1-negative SMARCA4-negative
-75% Other solid tumor** * Patients censored at time of progression 34 ** Four additional other solid tumor patients with pending disease evaluation UNDIFFERENTIATED ROUND CELL SARCOMA URCS IN INFANTS
5 months female 4 months female 2 months male
CCSK PMMTI URCS 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
R. Furtwangler et al. / European Journal of Cancer 49 (2013) 3497–3506 URCS- CCSK AREN0321 OUTCOMES
Stage Treatment n 4-year EFS % 4-year OS%
I DD4A, no XRT 8 80 100
II Regimen I 28 87 96
III Regimen I 43 77 95
IV Regimen UH1 3 1/3 with relapse/death
Preliminary data. Slide courtesy of Jeff Dome URCS- CCSK t(10;17)(q22;p13) YWHAE-NUTM2B BCOR ITD
O’Meara et al. J Pathol. 2012 May;227(1):72-80. Roy et al. Nat Commun. 2015 Nov 17;6:8891 Ueno-Yokohata et al. Nat Genet. 2015 Aug;47(8):861-3. URCS- PMMTI
Initially classified as infantile fibrosarcomas 16 cases reported in literature Locally aggressive Sites: trunk, extremities, head and neck Local recurrence Treatment: surgery Poor response to chemotherapy
Alaggio et al. Am J Surg Pathol 2006 Foster et al. Pediatric developmetal pathology 2016 URCS- PMMTI
• BCOR ITD testing by PCR and RNA sequencing • 6/7 positive
Kao et al. Am J Surg Pathol 2016 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 URCS BCOR MUTATED SARCOMA TREATMENT
• Complete surgical resection • Ifosfamide/doxorubicin • VDC/IE Ewings regimen • ?CCSK regimen
J Natl Compr Canc Netw 2017;15(7):868–871 BCOR-MUTATED SARCOMA REGISTRY
[email protected] 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. THANK YOU