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Yeon-Sook Choi, Hyemi Kwon, Mi-Hyeon You, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Min Ji Jeon, and Won Gu Kim

Dabrafenib is a BRAF kinase inhibitor approved for treatment of BRAF-mutated anaplastic thyroid carcinoma (ATC) in combination with trametinib. Erlotinib is a tyrosine kinase inhibitor of EGF receptor (EGFR). We evaluated effects of dabrafenib and erlotinib combination treatment on ATC cells in vitro and in vivo. Cell proliferation, colony formation, apoptosis, and migration of ATC cells harboring a BRAF mutation (BHT101, 8505C, and SW1736) were evaluated after treatment with dabrafenib in combination with erlotinib or trametinib. The changes in activation of mitogen extracellular kinase (MEK) and extracellular signal-related kinase (ERK) signaling were also evaluated by Western blot analysis. Effects of these combinations were also evaluated using an in vivo xenograft model. First, we detected EGFR activation in dabrafenib-resistant SW1736 cells using a phospho-receptor tyrosine kinase array. A dabrafenib and erlotinib combination synergistically inhibited cell proliferation, colony formation, and migration, with an induction of apoptotic cell death in all three ATC cells, compared with dabrafenib or erlotinib alone. This synergistic effect was comparable with a dabrafenib and trametinib combination. The dabrafenib and erlotinib combination effectively inhibited phosphorylated (p)-MEK, p-ERK, and p-EGFR expressions compared with dabrafenib or erlotinib alone, while the dabrafenib and trametinib combination only inhibited p-MEK and p-ERK expressions. The dabrafenib with erlotinib or trametinib combinations also significantly suppressed tumor growth and induced apoptosis in a BHT101 xenograft model. The dabrafenib and erlotinib combination could be a potential novel treatment regimen to overcome drug resistance to dabrafenib alone in patients with BRAF-mutated ATC.

Free access

Eyun Song, Dong Eun Song, Jonghwa Ahn, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Min Ji Jeon, and Won Gu Kim

Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 from distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit–related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, respectively. When the mutational status was analyzed in 15 matched pairs of thyroid tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor–metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance.

Open access

Francis Worden, Martin Fassnacht, Yuankai Shi, Tatiana Hadjieva, Françoise Bonichon, Ming Gao, Laura Fugazzola, Yuichi Ando, Yasuhisa Hasegawa, Do Joon Park, Young Kee Shong, Johannes W A Smit, John Chung, Christian Kappeler, Gerold Meinhardt, Martin Schlumberger, and Marcia S Brose

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive iodine-refractory, differentiated thyroid carcinoma. Four hundred and seventeen adult patients were randomized (1:1) to receive oral sorafenib (400 mg, twice daily) or placebo, until progression, unacceptable toxicity, noncompliance, or withdrawal. Progression-free survival, the primary endpoint of DECISION, was reported previously. To elucidate the patterns and management of AEs in sorafenib-treated patients in the DECISION trial, this report describes detailed, by-treatment-cycle analyses of the incidence, prevalence, and severity of hand–foot skin reaction (HFSR), rash/desquamation, hypertension, diarrhea, fatigue, weight loss, increased serum thyroid stimulating hormone, and hypocalcemia, as well as the interventions used to manage these AEs. By-cycle incidence of the above-selected AEs with sorafenib was generally highest in cycle 1 or 2 then decreased. AE prevalence generally increased over cycles 2–6 then stabilized or declined. Among these AEs, only weight loss tended to increase in severity (from grade 1 to 2) over time; severity of HFSR and rash/desquamation declined over time. AEs were mostly grade 1 or 2, and were generally managed with dose interruptions/reductions, and concomitant medications (e.g. antidiarrheals, antihypertensives, dermatologic preparations). Most dose interruptions/reductions occurred in early cycles. In conclusion, AEs with sorafenib in DECISION were typically grade 1 or 2, occurred early during the treatment course, and were manageable over time.

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Hye In Kim, Meihua Jin, Nak Gyeong Ko, Young Lyun Oh, Jung Hee Shin, Jung-Han Kim, Jee Soo Kim, Min Ji Jeon, Tae Yong Kim, Sun Wook Kim, Won Bae Kim, Jae Hoon Chung, Young Kee Shong, Won Gu Kim, and Tae Hyuk Kim

We previously reported that high thyroid-stimulating hormone (TSH) levels are associated with papillary thyroid microcarcinoma (PTMC) progression during active surveillance. However, validation with multicenter, long-term data, and identification of appropriate age or TSH levels are needed. This multicenter retrospective study enrolled PTMC patients under active surveillance with TSH measurements and ultrasonography. The primary outcome was PTMC progression (volume increase ≥50%, size increase ≥3 mm, or new lymph node (LN) metastasis). PTMC progression according to time-weighted average of TSH (TW-TSH) groups was compared using survival analyses in overall patients and each age subgroups (<40, 40–49, 50–59, and ≥60 years). The identification of TW-TSH cutoff point for PTMC progression and trend analysis of PTMC progression rate according to LT4 treatment were also performed. During 1061 person-years of follow-up, 93 of 234 patients (39.7%) showed PTMC progression (90, 17, and 5 patients for volume increase ≥50%, size increase ≥3 mm, and new LN metastasis, respectively). The highest TW-TSH group was the risk factor most strongly associated with PTMC progression (hazard ratio 2.13 (1.24–3.65); P = 0.006), but the impact was significant only in patients aged <40 or 40–49 years (hazard ratio 30.79 (2.90–326.49; P = 0.004), 2.55 (1.00–6.47; P = 0.049)). For patients aged <50 years, TW-TSH cutoff for PTMC progression was 1.74 mU/L, and PTMC progression rates successively increased in the order of effective, no, and ineffective LT4 treatment group (P for trend = 0.034). In young PTMC patients (<50 years), sustained low-normal TSH levels during active surveillance might be helpful to prevent progression.