Redifferentiation of Iodine-Refractory BRAF V600E-Mutant Metastatic Papillary Thyroid Cancer with Dabrafenib—Response
Authors: S. Michael Rothenberg, Gilbert H. Daniels, Lori J. Wirth
Journal: Clinical Cancer Research (2015)

Thank you for the opportunity to discuss the letter from Hullard and colleagues concerning our recent article, “Redifferentiation of Iodine-Refractory BRAF V600E-Mutant Metastatic Papillary Thyroid Cancer with Dabrafenib” (1).We agree with these authors that radioiodine uptake per se is not a measure of treatment efficacy. In our study, we used diagnostic whole-body radioactive iodine scanning to assess the ability of dabrafenib to induce new radioiodine uptake in patients with iodine-refractory disease. In patients whose tumors demonstrated new uptake, dabrafenib treatment was followed by treatment with radioactive iodine, which we believe is the primary cause of the tumor responses we observed. Although we cannot completely rule out a contribution to efficacy from treatment with dabrafenib (e.g., in the absence of radioiodine), this seems less likely, because, as we discuss in the article, no patient without new radioactive iodine underwent treatment with radioiodine or demonstrated a tumor response, although each was treated with dabrafenib for 4 weeks.Although there are preliminary data describing tumor responses in patients treated with dabrafenib continuously, until progression, the study that was quoted examined a subset of 14 BRAF V600E thyroid cancer patients from a larger phase I study (2, 3). Notably, the partial response rate was 29% (4/14 patients), and there were five treatment-related adverse events ≥ grade 3. Therefore, treatment with BRAF inhibitors, either continuously until progression, or short-term as part of a redifferentiation strategy, should both be considered investigational.Unfortunately, as we discuss in our article, traditional whole-body radioactive iodine scanning does not permit sufficient anatomic resolution or allow lesional dosimetry, both of which would be required to determine whether the degree of response in individual tumors is correlated with the amount of radioiodine uptake (we summarize estimated percent uptake in different regions in the same patient in Supplementary Fig. S1). Iodine-124 PET-CT, utilized in the selumetinib redifferentiation study, allows sufficient anatomic localization and lesional dosimetry to permit quantification of uptake in individual lesions (4). In that study, a treatment dose radioiodine was administered when I-124 PET-CT predicted a minimal deliverable dose of 2,000 cGy. However, this type of imaging is not widely used (nor approved for regular clinical use) and not available at most centers.Regarding the two patients with partial responses whose serum thyroglobulin levels appeared to rise shortly after completing therapy, we note the following:Patient 4 demonstrated progressive disease on imaging 20.5 months after the initial posttreatment scans that showed complete response.Patient 8 maintained her tumor response for 18 months on serial imaging after her 3-month posttreatment scan showed partial response, at which time imaging demonstrated enlargement of several pulmonary nodules consistent with progression.Serum thyroglobulin concentrations at later time points were only available for patient 8 and are shown in Table 1.Values remained moderately elevated until documentation of tumor progression, and then has slowly risen.See the original Letter to the Editor, p. 5639S.M. Rothenberg is Senior Scientist at Loxo Oncology. L.J. Wirth is a consultant/advisory board member for Ashion, Eisai, and Loxo. No potential conflicts of interest were disclosed by the other author.This work was supported in part by GlaxoSmithKline and a grant from the Ellison Foundation (to G.H. Daniels). S.M. Rothenberg was supported by K08DE020139.