Article

Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles for BRAF, PIK3CA, and AKT1

Human Oncology and Pathogenesis Program and Departments of Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Cancer Research (Impact Factor: 9.28). 07/2009; 69(11):4885-93. DOI: 10.1158/0008-5472.CAN-09-0727
Source: PubMed

ABSTRACT Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.

0 Bookmarks
 · 
99 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Advanced thyroid carcinoma is an infrequent tumor entity with limited treatment possibilities until recently. The extraordinary improvement in the comprehension of genetic and molecular alterations involving the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositide 3-kinase/Akt/mammalian target of rapamycin signaling and interacting pathways that are involved in tumor survival, proliferation, differentiation, motility and angiogenesis have been the rationale for the development of new effective targeted therapies. Data coming from phase II clinical trials have confirmed the efficacy of those targeted agents against receptors in cell membrane and cytoplasmic molecules. Moreover, four of those investigational drugs, vandetanib, cabozantinib, sorafenib and lenvatinib, have reached a phase III clinical trial with favorable results in progression-free survival and overall survival in medullary thyroid carcinoma and differentiated thyroid carcinoma. Further analysis for an optimal approach has been conducted according to mutational profile and tumor subtypes. However, consistent results are still awaited and the research for adequate prognostic and predictive biomarkers is ongoing. The following report offers a comprehensive review from the rationale to the basis of targeted agents in the treatment of thyroid carcinoma. In addition, current and future therapeutic developments by the inhibition of further molecular targets are discussed in this setting.
    01/2015; 7(1):22-38. DOI:10.1177/1758834014551936
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thyroid cancer is the most common endocrine malignancy. Despite having a good prognosis in the majority of cases, when the tumor is dedifferentiated it does no longer respond to conventional treatment with radioactive iodine, the prognosis worsens significantly. Treatment options for advanced, dedifferentiated disease are limited and do not cure the disease. Autophagy, a process of self-digestion in which damaged molecules or organelles are degraded and recycled, has emerged as an important player in the pathogenesis of different diseases, including cancer. The role of autophagy in thyroid cancer pathogenesis is not yet elucidated. However, the available data indicate that autophagy is involved in several steps of thyroid tumor initiation and progression as well as in therapy resistance and therefore could be exploited for therapeutic applications. The present review summarizes the most recent data on the role of autophagy in the pathogenesis of thyroid cancer and we will provide a perspective on how this process can be targeted for potential therapeutic approaches and could be further explored in the context of multimodality treatment in cancer and personalized medicine.
    Frontiers in Endocrinology 01/2015; 6:22. DOI:10.3389/fendo.2015.00022
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Distant metastases from thyroid cancer of follicular origin are uncommon. Treatment includes levothyroxine administration at suppressive doses, focal treatment modalities with surgery, external radiation therapy and thermal ablation, and radioiodine in patients with uptake of (131)I in their metastases. Two thirds of distant metastases will become refractory to radioiodine at some point, and when there is a significant tumor burden and documented progression on imaging, a treatment with a kinase inhibitor may provide benefits.
    02/2015; 7. DOI:10.12703/P7-22

Full-text (2 Sources)

Download
19 Downloads
Available from
Aug 13, 2014