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Clin Cancer Res. 2018 Feb 15;24(4):753-765. doi: 10.1158/1078-0432.CCR-17-2101. Epub 2017 Nov 29.

Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib.

Author information

1
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
2
Department of Pediatrics, New York University Langone Medical Center, New York, New York.
3
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
4
Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland.
5
Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
6
Developmental Endocrine Oncology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland.
7
Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Clinical Research, Harris IT Services, Sterling, Virginia.
9
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
10
Translational Surgical Pathology Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
11
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. John.Glod@nih.gov.
#
Contributed equally

Abstract

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years-undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1-undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753-65. ©2017 AACR.

PMID:
29187393
PMCID:
PMC5815946
DOI:
10.1158/1078-0432.CCR-17-2101
[Indexed for MEDLINE]
Free PMC Article

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