Uncertain Prognostic Value of BRAF Mutation in Papillary Thyroid Cancer

Thyroid

Across several studies, theBRAF^V600Emutation 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 inJAMA Otolaryngology — Head & Neck Surgeryhave prolonged a definitive conclusion on the prognostic role of the gene.

According to the study, theBRAF^V600Emutation in patients with PTC did not demonstrate a consistent association with negative prognosis.¹This analysis, the largest U.S. study to date, shows thatBRAFstatus 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 theBRAFmutation and 26.8% (n = 115) were negative. There was no significant association ofBRAFmutation with patient age (P= .91) or gender (P= .07). On multivariate analysis, it was determined that male sex was a predictor of positiveBRAFstatus (odds ratio [OR], 3.2; 95% CI, 1.4-7.2). There was no correlation betweenBRAFmutation and tumor size (P= .15).

Patients in theBRAFmutation-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 withBRAFstatus in multivariate models. Lymph node metastasis, another negative prognostic feature, was significantly associated withBRAFmutation (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 andBRAFstatus.

The authors of this study concluded that there “remains no definitive correlation betweenBRAF^V600Emutation and the clinicopathologic features of PTC.” However, these results contradict the belief thatBRAFmutations 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 inBRAF^V600Emutation-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 theBRAFmutation 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 ofBRAFmutations, researchers from the Seoul National University, Seoul, South Korea, reported that theBRAF^V600Emutation in PTC was related to both high-risk clinicopathological features and poor clinical outcome.³In 26 of the 27 studies in this meta-analysis, PTC patients with theBRAF^V600Emutation 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 theBRAF^V600Emutation 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 heterozygousBRAFWT/V600E-PTC. In this study, the efficacy of vemurafenib, a selective small-molecule inhibitor of BRAF^V600E, was examined in a preclinical model ofBRAF^V600E-positive nonmetastatic or metastatic human PTC.⁴

"Patients withBRAF^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 ofBRAFstatus for PTC prognosis unanswered. Prospective studies are needed beforeBRAFmutation 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).