Redifferentiation of Iodine-Refractory BRAF V600E-Mutant Metastatic Papillary Thyroid Cancer with Dabrafenib—Letter

Recently, Rothenberg and colleagues (1) demonstrated that BRAF-specific inhibition with dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory papillary thyroid cancer. This was previously shown with MEK inhibition (2), and growing evidence exist that anticancer therapy will allow restoring radioiodine uptake in radioiodine-resistant or refractory differentiated thyroid cancers (DTC). Although this phenomenon may generate great hope for patients in this setting with unmet needs, the clinical relevance can be questioned and must be determined to help identifying the optimal multimodal therapeutic strategy.

In radioiodine-resistant metastatic DTC, the standard-approved treatment is currently sorafenib (3) given until disease progression or unacceptable toxicity. Though currently off label, the specific inhibition of BRAF in BRAF-mutated tumors appears as an interesting first-line option. In effect, dabrafenib is an active and well-tolerated treatment that can even lead to long-term responses (up to 22 months; ref. 4) when given until disease progression or unacceptable toxicity. The study by Rothenberg and colleagues (1) shows that dabrafenib can also restore radioiodine uptake. Dabrafenib could therefore be prescribed for its direct antitumor effect or for its ability to restore radioiodine uptake. But even if radioiodine is an active treatment, radioiodine uptake is not per se an objective because it is not constantly associated with clinical efficacy (5). On the other hand, dabrafenib efficacy may not be limited to lesions in which radioiodine uptake is restored. We therefore believe that the protocol selected by Rothenberg and colleagues with a short course of dabrafenib before radioiodine therapy helps understanding the mechanism of efficacy. Indeed in patients with mixed radioiodine uptake after dabrafenib (i.e., patients having new iodine avid lesions or focal uptake enhancement and other lesions with definitely no uptake), the 3- and 6-month CT evaluation should allow to compare response in lesions according to their final uptake capability. If a better response is seen in lesions with significant radioiodine uptake, a prerequisite for substantial dose delivery, this would be in favor of a multimodal approach in this setting. On the other hand in a same patient, posttherapy (5.5 GBq) thyroglobulin levels are likely to be higher in responding patients due to tumor cells radiolysis or redifferentiation, as compared with diagnostic scan values (0.148 GBq). We wonder if, with the longer follow-up now available, the authors could provide this information.

See the Response, p. 5640