BRAF Mutation Predicts Thyroid Ca Recurrence

MINNEAPOLIS — BRAF mutations may offer one answer to the growing need for biomarkers that can accurately predict the risk of thyroid cancer recurrence, said Dr. Stefan K.G. Grebe.

Thyroid cancer, with its rising incidence and low mortality rate, will be the third most common diagnosis in living cancer patients in the next 5–10 years, behind breast and prostate cancers, according to Dr. Grebe. For a newly diagnosed thyroid cancer patient, the lifetime risk of dying from the disease in 10 years—across all ages and stages—is less than 3%.

“We have to bear this in mind when we talk about prognostic markers…. Predictive markers may be more important because hardly anyone ever dies of thyroid cancer,” Dr. Grebe said at the meeting. Depending on the cancer morphotype, 15%–50% of patients will suffer a recurrence in their lifetime. “There really is a need for prolonged—over decades—follow-up of these patients,” which will require sensitive and specific means of detecting recurrences, he stressed.

The BRAF T1799A (V600E) mutation accounts for more than 90% of BRAF mutations in melanoma and papillary thyroid cancer (PTC). Importantly, this mutation is not found in normal tissue. While this mutation occurs in 40%–80% of melanomas and papillary thyroid cancers, it is present in fewer than 10% of other cancers, making it a good candidate biomarker for PTC recurrence, said Dr. Grebe, chair of clinical biochemistry and immunology in the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn.

A good candidate marker also needs a good test. In the case of BRAF V600E this means developing an assay that can detect nucleic acids with this mutation in human blood, plasma, or serum with high sensitivity and specificity. “For residual disease follow-up … you have to have a low sensitivity to detect a low number of mutant copies,” said Dr. Grebe, who has been working on the development of such an assay with his colleagues. They started by evaluating a number of assay techniques to detect BRAF V600E mutations. “Finally we settled on real-time PCR [polymerase chain reaction],” he said.

Once they achieved success with a proof-of-principle study, they prospectively collected blood from all thyroid cancer patients attending a follow-up visit between May 2004 and December 2006 (J. Clin. Endocrinol. Metab. 2009;94:5001–9).

They enrolled 193 patients, of whom 173 had papillary thyroid cancer. Circulating BRAF V600E was detected in 20 of the 173 patients with PTC. It was not detected in the 20 patients with other types of thyroid cancer. Tissue BRAF status correlated with blood BRAF status.

“Overall we found that the BRAF mutation in blood conveyed about a two-and-a-half-fold relative risk of having active or recurrent disease,” said Dr. Grebe. “Potentially this will be an assay of increased value in the future.”

For now, clinicians have to rely on thyroglobulin, which has proved to be a good, but not perfect, tumor marker. Thyroglobulin is highly organ specific but cannot distinguish between benign and cancerous tumor tissue. Its reliability is compromised by residual thyroid tissue.

Perhaps more importantly, thyroglobulin is subject to analytical interferences with uninterpretable results in up to a quarter of patients and measurements. This is largely due to false negatives. “These limitations of thyroglobulin will get worse in the future,” said Dr. Grebe, who predicted that increasing numbers of thyroid cancer patients with even lower mortality will lead to less extensive treatment.

“I don't think in this day and age that you could convince a woman to have a radical mastectomy plus an extensive dissection for a 0.4-cm microcancer of the breast. The same will happen sooner or later with thyroid cancer,” he said. As a result, more patients will have remnant thyroid tissue producing greater background levels of thyroglobulin with greater TSH-related fluctuations.

Disclosures: Dr. Grebe reported that he has no relevant financial relationships.

MINNEAPOLIS — BRAF mutations may offer one answer to the growing need for biomarkers that can accurately predict the risk of thyroid cancer recurrence, said Dr. Stefan K.G. Grebe.

Thyroid cancer, with its rising incidence and low mortality rate, will be the third most common diagnosis in living cancer patients in the next 5–10 years, behind breast and prostate cancers, according to Dr. Grebe. For a newly diagnosed thyroid cancer patient, the lifetime risk of dying from the disease in 10 years—across all ages and stages—is less than 3%.

“We have to bear this in mind when we talk about prognostic markers…. Predictive markers may be more important because hardly anyone ever dies of thyroid cancer,” Dr. Grebe said at the meeting. Depending on the cancer morphotype, 15%–50% of patients will suffer a recurrence in their lifetime. “There really is a need for prolonged—over decades—follow-up of these patients,” which will require sensitive and specific means of detecting recurrences, he stressed.

The BRAF T1799A (V600E) mutation accounts for more than 90% of BRAF mutations in melanoma and papillary thyroid cancer (PTC). Importantly, this mutation is not found in normal tissue. While this mutation occurs in 40%–80% of melanomas and papillary thyroid cancers, it is present in fewer than 10% of other cancers, making it a good candidate biomarker for PTC recurrence, said Dr. Grebe, chair of clinical biochemistry and immunology in the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn.

A good candidate marker also needs a good test. In the case of BRAF V600E this means developing an assay that can detect nucleic acids with this mutation in human blood, plasma, or serum with high sensitivity and specificity. “For residual disease follow-up … you have to have a low sensitivity to detect a low number of mutant copies,” said Dr. Grebe, who has been working on the development of such an assay with his colleagues. They started by evaluating a number of assay techniques to detect BRAF V600E mutations. “Finally we settled on real-time PCR [polymerase chain reaction],” he said.

Once they achieved success with a proof-of-principle study, they prospectively collected blood from all thyroid cancer patients attending a follow-up visit between May 2004 and December 2006 (J. Clin. Endocrinol. Metab. 2009;94:5001–9).

They enrolled 193 patients, of whom 173 had papillary thyroid cancer. Circulating BRAF V600E was detected in 20 of the 173 patients with PTC. It was not detected in the 20 patients with other types of thyroid cancer. Tissue BRAF status correlated with blood BRAF status.

“Overall we found that the BRAF mutation in blood conveyed about a two-and-a-half-fold relative risk of having active or recurrent disease,” said Dr. Grebe. “Potentially this will be an assay of increased value in the future.”

For now, clinicians have to rely on thyroglobulin, which has proved to be a good, but not perfect, tumor marker. Thyroglobulin is highly organ specific but cannot distinguish between benign and cancerous tumor tissue. Its reliability is compromised by residual thyroid tissue.

Perhaps more importantly, thyroglobulin is subject to analytical interferences with uninterpretable results in up to a quarter of patients and measurements. This is largely due to false negatives. “These limitations of thyroglobulin will get worse in the future,” said Dr. Grebe, who predicted that increasing numbers of thyroid cancer patients with even lower mortality will lead to less extensive treatment.

“I don't think in this day and age that you could convince a woman to have a radical mastectomy plus an extensive dissection for a 0.4-cm microcancer of the breast. The same will happen sooner or later with thyroid cancer,” he said. As a result, more patients will have remnant thyroid tissue producing greater background levels of thyroglobulin with greater TSH-related fluctuations.

Disclosures: Dr. Grebe reported that he has no relevant financial relationships.

MINNEAPOLIS — BRAF mutations may offer one answer to the growing need for biomarkers that can accurately predict the risk of thyroid cancer recurrence, said Dr. Stefan K.G. Grebe.

Thyroid cancer, with its rising incidence and low mortality rate, will be the third most common diagnosis in living cancer patients in the next 5–10 years, behind breast and prostate cancers, according to Dr. Grebe. For a newly diagnosed thyroid cancer patient, the lifetime risk of dying from the disease in 10 years—across all ages and stages—is less than 3%.

“We have to bear this in mind when we talk about prognostic markers…. Predictive markers may be more important because hardly anyone ever dies of thyroid cancer,” Dr. Grebe said at the meeting. Depending on the cancer morphotype, 15%–50% of patients will suffer a recurrence in their lifetime. “There really is a need for prolonged—over decades—follow-up of these patients,” which will require sensitive and specific means of detecting recurrences, he stressed.

The BRAF T1799A (V600E) mutation accounts for more than 90% of BRAF mutations in melanoma and papillary thyroid cancer (PTC). Importantly, this mutation is not found in normal tissue. While this mutation occurs in 40%–80% of melanomas and papillary thyroid cancers, it is present in fewer than 10% of other cancers, making it a good candidate biomarker for PTC recurrence, said Dr. Grebe, chair of clinical biochemistry and immunology in the department of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn.

A good candidate marker also needs a good test. In the case of BRAF V600E this means developing an assay that can detect nucleic acids with this mutation in human blood, plasma, or serum with high sensitivity and specificity. “For residual disease follow-up … you have to have a low sensitivity to detect a low number of mutant copies,” said Dr. Grebe, who has been working on the development of such an assay with his colleagues. They started by evaluating a number of assay techniques to detect BRAF V600E mutations. “Finally we settled on real-time PCR [polymerase chain reaction],” he said.

Once they achieved success with a proof-of-principle study, they prospectively collected blood from all thyroid cancer patients attending a follow-up visit between May 2004 and December 2006 (J. Clin. Endocrinol. Metab. 2009;94:5001–9).

They enrolled 193 patients, of whom 173 had papillary thyroid cancer. Circulating BRAF V600E was detected in 20 of the 173 patients with PTC. It was not detected in the 20 patients with other types of thyroid cancer. Tissue BRAF status correlated with blood BRAF status.

“Overall we found that the BRAF mutation in blood conveyed about a two-and-a-half-fold relative risk of having active or recurrent disease,” said Dr. Grebe. “Potentially this will be an assay of increased value in the future.”

For now, clinicians have to rely on thyroglobulin, which has proved to be a good, but not perfect, tumor marker. Thyroglobulin is highly organ specific but cannot distinguish between benign and cancerous tumor tissue. Its reliability is compromised by residual thyroid tissue.

Perhaps more importantly, thyroglobulin is subject to analytical interferences with uninterpretable results in up to a quarter of patients and measurements. This is largely due to false negatives. “These limitations of thyroglobulin will get worse in the future,” said Dr. Grebe, who predicted that increasing numbers of thyroid cancer patients with even lower mortality will lead to less extensive treatment.

“I don't think in this day and age that you could convince a woman to have a radical mastectomy plus an extensive dissection for a 0.4-cm microcancer of the breast. The same will happen sooner or later with thyroid cancer,” he said. As a result, more patients will have remnant thyroid tissue producing greater background levels of thyroglobulin with greater TSH-related fluctuations.

Disclosures: Dr. Grebe reported that he has no relevant financial relationships.