BRAF Mutation Status May Change Papillary Thyroid Cancer Management

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.