PDF(Pubmed)
Abstract：
Anaplastic thyroid carcinoma, BRAF non-V600, NRAS, combination immunotherapy and targeted therapy, case report. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with a mortality rate near 100%. BRAF V600 and NRAS mutations are the most common drivers of ATC. While patients with BRAF V600-mutated ATC can be treated with BRAF-targeted therapy, there is no effective treatment for ATC driven by NRAS or non-V600 BRAF mutations. For patients with untargetable driver mutations, immunotherapy provides an alternative treatment option. Here, we present a metastatic ATC patient with PD-L1 positive (tumor proportion score of 60%) tumor and NRAS Q61R/BRAF D594N mutations, who progressed on PD-1 antibody sintilimab plus angiogenesis inhibitor anlotinib. The class 3 BRAF mutant D594N is sensitive to the inhibition of MEK inhibitor trametinib, and its oncogenic activity also depends on CRAF, which can be inhibited by BRAF inhibitor dabrafenib. For these reasons, the patient received a salvage treatment regime of dabrafenib, trametinib, and sintilimab, which resulted in a complete pathological response. To our best knowledge, this is the first report of successful treatment of ATC patients with concurrent NRAS/BRAF non-V600 mutations with the combination of immunotherapy and targeted therapy. Further investigation is required to decipher the mechanism by which the combination of dabrafenib/trametinib with PD-1 antibody overcomes initial immunotherapy resistance likely mediated by concurrent BRAF and NRAS mutations.
摘要：
间变性甲状腺癌，BRAF非V600,NRAS,联合免疫疗法和靶向治疗，病例报告。间变性甲状腺癌（ATC）是一种罕见的甲状腺癌，死亡率接近100％。BRAFV600和NRAS突变是ATC最常见的驱动因素。虽然BRAFV600突变的ATC患者可以接受BRAF靶向治疗，对于由NRAS或非V600BRAF突变驱动的ATC,目前尚无有效的治疗方法.对于具有不可靶向驱动突变的患者，免疫疗法提供了另一种治疗选择.这里,我们提出了一个转移性ATC患者PD-L1阳性（肿瘤比例评分为60％）肿瘤和NRASQ61R/BRAFD594N突变，他在PD-1抗体sintilimab加血管生成抑制剂安洛替尼方面取得了进展。3类BRAF突变体D594N对MEK抑制剂曲美替尼的抑制作用敏感，其致癌活性也取决于CRAF，可以被BRAF抑制剂dabrafenib抑制。由于这些原因,患者接受了达拉非尼的抢救治疗方案，曲美替尼,还有Sintilimab,导致完全的病理反应。据我们所知，这是首次报道联合免疫治疗和靶向治疗成功治疗并发NRAS/BRAF非V600突变的ATC患者.需要进一步的研究来破译dabrafenib/trametinib与PD-1抗体的组合克服可能由同时的BRAF和NRAS突变介导的初始免疫疗法抗性的机制。
