BRAF addiction of thyroid cancers makes them therapeutically vulnerable

Papillary carcinoma is the most common form of thyroid cancer. Approximately one quarter of these carcinomas have mutations in the BRAF gene. The prevalence of such mutations is even greater in high-grade carcinomas, particularly those that are refractory to standard treatment, which is radioactive iodine (RAI). A team of researchers led by James Fagin, at Memorial Sloan-Kettering Cancer Center, New York, has now identified a way to potentially exploit the expression of BRAF by such cancers for therapeutic purposes.

Despite the prevalence of BRAF mutations in papillary carcinoma it has remained unclear how dependent thyroid cancers are on BRAF expression. Fagin and colleagues first showed that thyroid tumors in mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas were exquisitely dependent on BRAF for viability. Of therapeutic significance, treating thyroid tumor–bearing mice with drugs that inhibited the BRAF signaling pathway rendered the tumor cells susceptible to a therapeutic dose of RAI. Fagin and colleagues therefore suggest that their data provide rationale for clinical trials testing whether such drugs can restore the efficacy of RAI therapy in patients with papillary thyroid carcinomas expressing BRAF mutations.

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TITLE: Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation

Papillary carcinoma is a relatively common well-differentiated thyroid cancer. Papillary/follicular carcinoma must be considered a variant of papillary thyroid carcinoma (mixed form). Despite its well-differentiated characteristics, papillary carcinoma may be overtly or minimally invasive. In fact, these tumors may spread easily to other organs. Papillary tumors have a propensity to invade lymphatics but are less likely to invade blood vessels. Papillary carcinoma appears as an irregular solid or cystic mass in a normal thyroid parenchyma.

Thyroid cancers are more often found in patients with a history of low- or high-dose external irradiation. Papillary tumors of the thyroid are the most common form of thyroid cancer to result from exposure to radiation. The life expectancy of patients with this cancer is related to their age. The prognosis is better for younger patients than for patients who are older than 45 years. Of patients with papillary cancers, about 11% present with metastases outside the neck and mediastinum. Some years ago, lymph node metastases in the cervical area were thought to be aberrant (supernumerary) thyroids because they contained well-differentiated papillary thyroid cancer.

AUTHOR CONTACT:
James A. Fagin
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 646-888-2136; Fax: 646-422-0890; E-mail: faginj@mskcc.org.

Characteristics of Papillary Thyroid Cancer