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Therapy Options for Pediatric Cancer Patients with NTRK Fusions

Pediatric cancer is devastating for patients and families, particularly when the diagnosis and appropriate course of therapy are difficult to determine. This was the case for a one-month-old with a recurrent sarcoma, eventually diagnosed as ETV6-NTRK3 negative congenital infantile fibrosarcoma (CIFS), whose disease progressed despite treatment with multiple chemotherapies. Spindle cell sarcoma and ex-dermatofibrosarcoma protuberans (DFSP) were also initially considered as diagnoses; however, FISH diagnostic testing for the DFSP-PDGFRB fusion was negative. Ultimately, comprehensive genomic profiling with FoundationOne Heme® led to the identification of an LMNA-NTRK1 gene fusion, and confirmation of the CIFS diagnosis. The patient began crizotinib monotherapy, and experienced tumor regression after six weeks of treatment. Currently, the patient has achieved an ongoing complete response exceeding eight months with no adverse effects from ongoing crizotinib therapy.

This clinical case, as well as additional data, were presented in a poster at the Second American Association for Cancer Research (AACR) Special Conference on Pediatric Cancer on November 10th by Dean Pavlick, Clinical Bioinformatics Analyst, abstract A46. Fusions of neurotrophic tyrosine kinase receptor (NTRK) family members have recently been linked to oncogenesis as well as identified as potential targets of therapy, particularly in adults with lung and other carcinomas. In this study, Foundation Medicine and its collaborators at Rady Children’s Hospital in San Diego conducted comprehensive genomic profiling with Foundation One on tumor samples from 1,351 pediatric, adolescent and young adult cancer patients to search for NTRK gene fusions. Results showed that 7 (0.52%) patients harbored NTRK family member fusions, five of which were pediatric cancer patients (less than 18 years of age). Four of the seven 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.

A recent report suggests the promise of NTRK inhibitors in clinical development, but until these therapies are approved, the findings here suggest crizotinib as a possible therapeutic option for these patients based on the aforementioned case study. Additionally, currently available multi-kinase inhibitors with NTRK activity could be considered in situations where therapeutics options have otherwise been exhausted. Importantly, these results demonstrate that comprehensive genomic profiling can identify clinically relevant genomic alterations that suggest potentially effective targeted therapeutic options in pediatric cancers, which is a critical step forward for these patients and their families.