Questions Remain Regarding Prognostic Value of BRAF Mutation in Papillary Thyroid Cancer

Scrape cytology illustrating features of papillary carcinoma of the thyroid.

Across several studies, the BRAF^V600E mutation has been reported to be associated with several negative prognostic clinicopathologic features as well as an increase in overall mortality in patients with papillary thyroid carcinoma (PTC). Inconsistent study results and a recent study published in JAMA Otolaryngology — Head & Neck Surgery have prolonged a definitive conclusion on the prognostic role of the gene.

According to the study, the BRAF^V600E mutation in patients with PTC did not demonstrate a consistent association with negative prognosis.¹ This analysis, the largest U.S. study to date, shows that BRAF status was not significantly related to most features of aggressive disease.

In the study, 429 patients with PTC were analyzed: 73.2% (n = 314) were positive for the BRAF mutation and 26.8% (n = 115) were negative. There was no significant association of BRAF mutation with patient age (P = .91) or gender (P = .07). On multivariate analysis, it was determined that male sex was a predictor of positive BRAF status (odds ratio [OR], 3.2; 95% CI, 1.4-7.2). There was no correlation between BRAF mutation and tumor size (P = .15).

Patients in the BRAF mutation-positive arm demonstrated a significant association with tumor margin positivity (P = .03) and a trend toward increased extrathyroidal extension (P = .06), though there was no significant association for these factors with BRAF status in multivariate models. Lymph node metastasis, another negative prognostic feature, was significantly associated with BRAF mutation (P = .002), though the association was not significant in multivariate analysis (OR, 1.4; 95% CI, 0.7-2.6). Additionally, there was no significant association with extranodal extension, distant metastasis, or advanced-stage disease and BRAF status.

The authors of this study concluded that there “remains no definitive correlation between BRAF^V600E mutation and the clinicopathologic features of PTC.” However, these results contradict the belief that BRAF mutations play an important role in determining the aggressiveness of disease for patients with PTC. To date, this topic has been the focus of several meta-analyses.

In a literature review of 14 published studies performed by a team at Johns Hopkins Medical Institution the risk ratios in BRAF^V600E mutation-positive patients were 1.93 for PTC recurrence (95% CI, 1.61—2.32; Z = 7.01; P < .00001), 1.32 for lymph node metastasis (95% CI, 1.20—1.45; Z = 5.73; P < .00001), 1.71 for extrathyroidal extension (95% CI, 1.50—1.94; Z = 8.09; P < .00001), 0.95 for distant metastasis (95% CI, 0.63—1.44; Z = 0.23; P = 0.82), and 1.70 for advanced stage AJCC III/IV (95% CI, 1.45—1.99; Z = 6.46; P < 0.00001).²

Researchers reported that the BRAF mutation in PTC was significantly associated with all examined factors, excluding distant metastasis. These patients, the authors wrote, seem to be likely to demonstrate factors related to an increased risk for disease recurrence.

Further collaborating the prognostic value of BRAF mutations, researchers from the Seoul National University, Seoul, South Korea, reported that the BRAF^V600E mutation in PTC was related to both high-risk clinicopathological features and poor clinical outcome.³ In 26 of the 27 studies in this meta-analysis, PTC patients with the BRAF^V600E mutation had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI, 1.68-2.73), lymph node metastasis (OR, 1.54; 95% CI, 1.21-1.97), and advanced TNM stage (OR, 2.00; 95% CI, 1.61-2.49). In 8 studies in the analysis, patients with the BRAF^V600E mutation had 2.14-fold increased risk of recurrent and persistent disease (95% CI, 1.67-2.74).

In a study published in conjunction with the 2013 ASCO Annual Meeting, researchers from Beth Israel Deaconess, a major teaching hospital of Harvard Medical School, established the first translational therapeutic model of heterozygous BRAF WT/V600E-PTC. In this study, the efficacy of vemurafenib, a selective small-molecule inhibitor of BRAF^V600E, was examined in a preclinical model of BRAF^V600E -positive nonmetastatic or metastatic human PTC.⁴

"Patients with BRAF^V600E -positive human PTC have poorer prognosis, higher rates of metastases and mortality, and resistance to radioiodine treatment," the authors of the study wrote.

These inconsistent findings leave the question of the utility of BRAF status for PTC prognosis unanswered. Prospective studies are needed before BRAF mutation can be considered as a reliable factor to guide the treatment of PTC.

References

1. Gouveia C, Can N, Bostrom A, Grenert JP, van Zante A, Orloff LA. Lack of Association of BRAF Mutation With Negative Prognostic Indicators in Papillary Thyroid Carcinoma: The University of California, San Francisco, Experience. JAMA Otolaryngol Head Neck Surg. 2013;():-. doi:10.1001/jamaoto.2013.4501.
2. Tufano RP, Teixeira GV, Bishop J, Carson KA, Xing M. BRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. Medicine (Baltimore). 2012;91(5):274-286.
3. Kim TH, Park YJ, Lim JA, et al. The association of the BRAF (V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer. 2012;118(7):1764-1773.
4. Duquette M, Sadow PM, Priolo C, et al. Investigating an orally available small-molecule inhibitor (vemurafenib) of BRAFV600E in a novel preclinical model of human papillary thyroid cancer. J Clin Oncol. 31, 2013 (suppl; abstr e17014).