To the Editor Our recent multicenter study1 reported an association between BRAF V600E and PTC-related patient mortality. However, this association was not independent of tumor behaviors and the prognostic value of BRAF V600E was debated in an accompanying Editorial.2 This issue warrants further discussion in several aspects.
First, the synergistic interaction between BRAF V600E and tumor behaviors demonstrated in our study1 suggests that BRAF V600E promotes aggressive tumor behaviors to exert its effect on mortality. Thus, multivariable analyses adjusting for tumor behaviors would artificially nullify the association between BRAF V600E and mortality, underestimating its prognostic value.
Second, the strong synergism between BRAF V600E and patient age in affecting PTC mortality demonstrated in our study1 not only represents a unique mechanism of BRAF V600E in affecting mortality, as the Editorial2 pointed out, but is also a reason for the attenuation of the significance of BRAF V600E when the multivariable model included patient age. Adjusting for patient age underestimates the incremental prognostic value of BRAF V600E when its status can in fact distinguish patients of similar age into higher- and lower-risk groups.
Third, contrary to the statement in the Editorial,2 our study supports the position that prognostic BRAF V600E testing should be performed in conventionally low-risk patients with PTC. Our study1 demonstrated that in the BRAF mutation-negative and conventionally low-risk patients, particularly in patients with conventional PTC, mortality was virtually zero, whereas a few deaths did occur in the BRAF mutation-positive patients. This high negative predictive value of BRAF V600E for mortality is consistent with the high negative predictive value of BRAF V600E for PTC recurrence,3,4 particularly in conventionally low-risk patients.4
How to manage low-risk PTC has been debated and over-treatment of these patients is common. With this high negative predictive value, testing for BRAF V600E would help identify many mutation-negative patients who could be considered for conservative management.
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.
References
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