Clinical Responses to Vemurafenib in Patients with Metastatic Papillary Thyroid Cancer Harboring BRAF^V600EMutation

Abstract

Background: Clinical benefit from cytotoxic chemotherapy for metastatic papillary thyroid carcinoma (PTC) is disappointing, and effective therapeutic approaches for these patients are urgently needed. Because kinaseactivating mutations in the BRAF proto-oncogene commonly occur in advanced PTC, and inhibition of BRAF V600E has shown promising clinical activity in melanoma, BRAF inhibitor therapy may be an effective strategy to treat metastatic PTC. Methods: The dose escalation portion of a first-in-human, phase I study of vemurafenib, a selective RAF inhibitor, included three patients with metastatic PTC harboring the BRAF V600E mutation. Vemurafenib was initially dosed at 240-360 mg twice a day, later escalated to 720 mg twice a day. Response evaluation was performed every 8 weeks per Response Evaluation Criteria in Solid Tumors (RECIST). Results: Among the three patients, one had a confirmed partial response with reduction of pulmonary target lesions by 31%, and the duration of response was 7.6 months before the disease progressed in the lungs and the bones. The time to progression was 11.7 months. The other two patients had stable disease, and the time to progression was 13.2 and 11.4 months, respectively. Conclusions: Vemurafenib appears to have a promising clinical activity in patients with metastatic PTC, and our data suggest that the BRAF V600E mutant kinase is a relevant target for therapy in this patient population. Further investigation of inhibitors of mutated BRAF kinase in patients with PTC in a phase II study is warranted.

Identification of a novel HRAS variant and its association with papillary thyroid carcinoma

“…The BRAF V600E mutation has been demonstrated to be the most common genetic alteration in PTC (8). BRAF is a member of the RAF family and is involved in the MAPK pathway (28).…”

“…In recent years, B-raf proto-oncogene (BRAF) mutation has been demonstrated to be the most common genetic alteration in PTC (8). It is a molecular marker associated with aggressive tumor behaviors, including size, extra-thyroidal extension, multifocality, lymph node metastasis, tumor recurrence and advanced disease stage (9,10).…”

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…The presence of a BRAF mutation has been associated with a more aggressive phenotype, with a higher tumor stage and likelihood of lymph node involvement at diagnosis (59). While inhibition of BRAF with small molecule inhibitors have demonstrated anti-tumor activity in various other BRAFmutated malignancies and have become a standardized treatment in BRAF-mutated melanoma, its therapeutic relevance in IHCC is unknown, but represents an intriguing therapeutic option for this disease (60)(61)(62)(63)(64)(65)(66). Ongoing early clinical trials are investigating the role of BRAF mutations as a potential targetable mutation in BC ( Table 3).…”

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

“…[7][8][9] Similarly, these targeted therapies might also have antitumor activity in various other BRAF-mutated neoplasias. [10][11][12][13][14] Accurate and rapid detection of BRAF mutations in metastatic melanoma is therefore essential for optimal patient care and may possibly be also required in other tumor entities in the near future.…”