In Reply I disagree with Dr Ciarrocchi and colleagues that BRAF V600E has no role in the aggressiveness of PTC because of its dependence on tumor behaviors, including local and distant metastases and invasion. It is clear that PTC would not cause patient death without aggressive tumor behaviors.
Our study demonstrated a strong synergism between BRAF V600E and aggressive clinicopathological behaviors, as reflected by the strong synergy indices and the fact that the association of mortality with BRAF V600E or clinicopathological behavior alone was only moderate but increased when the 2 were considered jointly. Thus, BRAF V600E does have a significant association with mortality, which likely occurs through promoting aggressive tumor behaviors and would be misleadingly lost using conventional multivariable models. Further efforts are needed to define how to specifically use the prognostic value of BRAF V600E clinically.
Some studies have not shown an association of BRAF V600E with aggressive behaviors of PTC. However, most have, as shown in large meta-analyses.1,2 Many factors could bias the conclusion about the prognostic value of BRAF V600E. For example, in a large study of 631 patients with PTC that failed to show an association of aggressiveness of PTC with BRAF V600E,3 many patients (41.5%) had only partial thyroidectomy, making thorough pathological characterization difficult. In addition, the majority of the patients in this study did not receive radioiodine ablation, potentially masking an effect of BRAF V600E on clinical outcomes given that BRAF mutation-negative PTC is more sensitive to radioiodine ablation.1,2
Ciarrocchi and colleagues' statement that a previous study4 showing no aggressive role of BRAF V600E in PTC confirms our study is incorrect. However, the 2 studies are not comparable; the former was a single institution study focused on a small number of highly selected cases and the latter was a large multicenter study of consecutive cases.
The study by Sancisi et al4 selected patients with distant metastases who only had well-differentiated primary cancer; cases of PTC with distant metastases and high-grade disease or poorly differentiated or undifferentiated components were excluded. This biased case selection misrepresents the real metastatic behaviors of PTC, in which cases with high-grade disease or aggressive pathological components tend to metastasize distantly. This exclusion criterion is problematic, particularly when the role of BRAF V600E is studied because the BRAF mutation promotes dedifferentiation of PTC.5
It is also unclear whether the control patients were matched with respect to factors that may potentially affect BRAF V600E. For example, only the mean age of patients and the mean and range of the follow-up time were provided, without detailed informationonpatientagedistributionandthechronologicaltime of recruitment. This is an important issue because BRAF V600E displays a lower prevalence in younger vs older patients and in patients treated earlier compared with more recently.6
This is a commentary on article Ciarrocchi A, Cavuto S, Piana S. BRAF V600E mutation and papillary thyroid cancer.. JAMA. 2013;310(5):534.
Footnotes
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grant R01CA134225 from the National Institutes of Health; and receiving royalties as a co-holder of a licensed US patent related to BRAF V600E mutation in thyroid cancer.
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