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Original Article |
1 Department of Surgery, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada
2 Genetic Pathology Evaluation Center at the Prostate Research Center of Vancouver General Hospital, British Columbia Cancer Agency, and University of British Columbia, Vancouver, BC, Canada
3 Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
4 Department of Pathology, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada
Correspondence: Address correspondence and reprint requests to: Sam M. Wiseman; Department of Surgery, St. Paul’s Hospital, University of British Columbia, C303-1081 Burrard Street, Vancouver, BC, Canada V6Z-1Y6; E-mail: smwiseman{at}providencehealth.bc.ca
Background: Anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study. Little is known regarding the expression by anaplastic tumors of molecular targets for new human anticancer agents that have been studied in the preclinical or clinical setting. The objective of this work was to evaluate the expression profile of anaplastic thyroid tumors for molecular targets for treatment.
Methods: Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984–2004), 32 cases (34%) had adequate archival tissue available for evaluation. A tissue microarray was constructed from these anaplastic thyroid tumors and immunohistochemistry was utilized to evaluate expression of 31 molecular markers. The markers evaluated were: epidermal growth factor receptor (EGFR), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, ß-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin.
Results: A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort. The mean age of the anaplastic cohort was 66 years; 16 patients (51%) were females, and the median patient survival was 23 weeks. A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0–100%). The therapeutic targets most frequently and most strongly overexpressed by the anaplastic tumors were: ß-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%).
Conclusions: Anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability. This report is the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supports the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.
Key Words: Anaplastic • Thyroid, Cancer • Targeted therapeutics • EGFR
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