Abstract A46: Identification of NTRK fusions in pediatric tumors via comprehensive genomic profiling
Authors: Pavlick Dean , Ali Siraj Mahamed , Elvin Julia A. , Stephens Phil J. , Miller Vincent A. , Ross Jeffrey S. , Suh James H. , Vergilio Jo-Anne , Chmielecki Juliann , Brennan Tim , Crawford John R. , Malicki Denise M. , Ahn Hyunah , Wong Victor N. 
Published: May 2016

Purpose: NTRK1-3 fusions are oncogenic drivers in lung and other carcinomas in adults, suggest benefit from targeted therapy. We examined a large series of pediatric/adolescent advanced cancer cases to identify those with NTRK fusions.

Background: The NTRK, neurotrophic tyrosine kinase receptor, genes encode proteins essential for normal neuronal growth and development. Fusions of NTRK family members have recently been linked to oncogenesis as well as identified as potential targets of therapy. In this study, a hybrid capture based comprehensive genomic profiling (CGP) assay was used to study a large series of pediatric solid tumors to search for NTRK gene fusions.

Methods: CGP using hybridization capture of at least 3,320 exons from 182 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer (previous version of the test) was applied to ≥ 50ng of DNA extracted from 1351 pediatric/adolescent/young adult tumors (&lt;22).

Results:, From 1351 pediatric/adolescent young adult advanced cancer patients, 7 (0.52%) harbored NTRK family member fusions. Of these, 5 were pediatric (&lt;18 years) (0.51% from 986 total cases). Ages of the patients ranged from &lt;1 to 22 years, with 4 cases being &lt;5 years and included 5 males and 2 females. Histologic diagnoses of these neoplasms were 2 soft tissue fibrosarcomas, soft tissue sarcoma NOS, soft tissue solitary fibrous tumor, soft tissue hemangioma, soft tissue schwanoma and a soft tissue dendritic cell neoplasm. The fusions identified were LMNA-NTRK1 (twice) and SQSTM1-NTRK1, TPM3-NTRK1, TPR-NTRK1, TFG-NTRK3, and ETV6-NTRK3. Four (57%) of 7 of these patients also harbored a CDKN2A/B homozygous deletion. Other genomic alterations in these cases included in one case each: PTRPO R231H, EP300 E628fs*7, MAP3K14 R218fs*731 and KDM4C amplification. One case was that of a 1.5 year old boy initially diagnosed with infantile fibrosarcoma (IFS) on a morphologic basis. CGP demonstrated his tumor harbored LMNA-NTRK1 and CDNK2A/B loss, and the patient then received crizotinib for pulmonary and skeletal metastases. He achieved an ongoing complete response exceeding 8 months.

Conclusions: 0.5% pediatric/adolescent/young advanced cancers harbor NTRK1 and NTRK3 fusions, and all such tumors are mesenchymal in origin. Of these, an index case benefitted from crizotinib treatment, suggesting pathways to clinical benefit for such cases.

Citation Format: Dean Pavlick, Siraj Mahamed Ali, Julia A. Elvin, Phil J. Stephens, Vincent A. Miller, Jeffrey S. Ross, James H. Suh, Jo-Anne Vergilio, Juliann Chmielecki, Tim Brennan, John R. Crawford, Denise M. Malicki, Hyunah Ahn, Victor N. Wong. Identification of NTRK fusions in pediatric tumors via comprehensive genomic profiling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A46.