Gene Marker Useful in Thyroid Cancer Patients

Paul W. Mamula, PhD

May 19, 2010

May 19, 2010 (Minneapolis, Minnesota) — A genetic mutation provides a prognostic marker for assessing risk stratification and treatment decisions in patients with papillary thyroid cancer (PTC), according to a presentation here at the American Thyroid Association Spring 2010 Meeting.

Mingzhao Xing, MD, PhD, associate professor of medicine, oncology and cellular and molecular medicine; associate director of the Thyroid Tumor Center; and chief of the laboratory for cellular and molecular research at Johns Hopkins University School of Medicine in Baltimore, Maryland, said that the BRAF genetic marker has the potential to direct treatment decisions in patients with PTC.

"This is the most common genetic alteration with a fundamental role in thyroid cancer," said Dr. Xing. "This mutation is a unique prognostic marker that is useful in helping physicians with risk stratification and treatment decision-making for patients with thyroid cancer."

The BRAF protein lies in the middle of the kinase pathway, which mediates the cellular response to extracellular signals that control proliferation, differentiation, and apoptosis. Dr. Xing stated that the most common mutation is designated T1799A and results from a single base change in exon 15 of the gene. The mutation changes an amino acid in the protein. The BRAF mutation is a common mutation that occurs in PTC and anaplastic thyroid cancer, but not in follicular or medullary thyroid cancer or benign thyroid tumors.

Dr. Xing reported that, according to work recently published in Molecular and Cellular Endocrinology (2010;321:86-93), in PTC, "the BRAF mutation is closely associated with extrathyroidal extension, lymph node metastasis, advanced tumor stages, disease recurrence, and even patient mortality."

"Many of the responsible molecular derangements promoted by or associated with BRAF mutation have been identified, including overexpression of tumor-promoting genes, suppression of tumor-suppressor genes, and silencing of thyroid iodide-handling genes, resulting in impairment or loss of radioiodine avidity and, hence, the failure of radioiodine treatment of PTC," Dr. Xing said.

Dr. Xing pointed out that a major challenge that commonly occurs is the initial surgery decision. Among the options for patients with PTC are total thyroidectomy, lobectomy, neck dissection, and no neck dissection.

Then the question is which therapy is best for a particular patient and which serves to prevent and reduce PTC recurrence, according to Dr. Xing.

Dr. Xing noted that BRAF-positive patients have more aggressive cancer and poor outcomes. He showed that, in data from 6 studies, the overall odds ratio for recurrence of PTC was about 2.7.

The combined study data reveal that the presence of a BRAF mutation has a positive predictive value of about 28% and a negative predictive value of 87%. The value of these tests for patients who have an indeterminate-type thyroid nodule are important, according to Dr. Xing. These nodules have about a 15% to 20% chance of malignancy. Thyroidectomy is almost always recommended for these patients.

Dr. James Fagin, MD, chief of endocrine service at Memorial Sloan-Kettering Cancer Center in New York City, said that molecular methods and markers have become fairly common and can refine the ability to do preoperative diagnosis and decide treatment.

Even though the test has value, Dr. Xing said in his presentation that there are still many uncertainties. He noted that even though the mutation has a high predictive power, it still does not answer all questions.

All of the reviews presented at this meeting will appear in the July 2010 issue of Thyroid.

Dr. Xing reports receiving royalties as the coholder of a licensed patent for BRAF mutation in thyroid cancer. Dr. Fagin has disclosed no relevant financial relationships.

American Thyroid Association (ATA) Spring 2010 Meeting. Presented May 14, 2010.

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