Sinichenkova Kseniya, Sidorov Iliya, Kriventsova Nataliya, Konovalov Dmitriy, Abasov Ruslan, Usman Nataliya, Karachunskiy Alexander, Novichkova Galina, Litvinov Dmitriy, Druy Alexander
Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian Federation, Moscow, Russia.
Research Institute of Medical Cell Technologies, Yekaterinburg, Russia.
Oncotarget. 2024 Jul 17;15:493-500. doi: 10.18632/oncotarget.28606.
BRAF V600E substitution predicts sensitivity of a cancer to BRAF inhibitor therapy. The mutation is rarely found in soft-tissue sarcomas. Here we describe a case of undifferentiated spindle cell sarcoma showing primary insensitivity to standard chemotherapy and pronounced but non-sustained response to BRAF/MEK inhibitors at recurrence.
A 13-year-old girl was diagnosed with low-grade spindle cell sarcoma of pelvic localization, BRAF exon 15 double-mutated: c.1799T>A p.V600E and c.1819T>A p.S607T in cis-position. The tumor showed resistance to CWS-based first-line chemotherapy and was treated surgically by radical resection. Seven months after surgery the patient developed metastatic relapse with abdominal carcinomatosis. Combined targeted therapy with BRAF/MEK inhibitors afforded complete response in 1 month and was continued, though complicated by severe side effects (fever, rash) necessitating 1-2 week toxicity breaks. After 4 months from commencement the disease recurred and anti-BRAF/MEK regimen consolidation was unsuccessful. Intensive salvation chemotherapy was ineffective. Empirical immunotherapy afforded a transient partial response giving way to fatal progression with massive, abdominal cocoon-complicated peritoneal carcinomatosis.
This is the first report of spindle cell sarcoma BRAF V600E/S607T double-mutated, responding to a combination of B-Raf and MEK inhibitors. Despite the low histological grade and radical surgical treatment of the tumor at primary manifestation, the disease had aggressive clinical course and the response to BRAF/MEK targeted therapy at recurrence was complete but nondurable. Empirical use of pembrolizumab provided no unambiguous evidence on the clinical relevance of immunotherapy in protein kinase -rearranged spindle cell tumors.
BRAF V600E替代突变预示癌症对BRAF抑制剂治疗的敏感性。该突变在软组织肉瘤中罕见。在此，我们描述一例未分化梭形细胞肉瘤病例，其对标准化疗原发性不敏感，复发时对BRAF/MEK抑制剂有明显但非持续性反应。
一名13岁女孩被诊断为盆腔低级别梭形细胞肉瘤，BRAF外显子15双突变：顺式位置的c.1799T>A p.V600E和c.1819T>A p.S607T。肿瘤对基于CWS的一线化疗耐药，通过根治性手术治疗。术后7个月，患者出现腹部癌转移复发。BRAF/MEK抑制剂联合靶向治疗在1个月内产生完全缓解并持续进行，尽管出现严重副作用（发热、皮疹），需要停药1 - 2周以缓解毒性。开始治疗4个月后疾病复发，BRAF/MEK方案巩固治疗未成功。强化挽救化疗无效。经验性免疫治疗产生短暂部分缓解，随后进展为致命性进展，伴有大量腹部茧状包裹性腹膜癌。
这是首例关于BRAF V600E/S607T双突变梭形细胞肉瘤对B-Raf和MEK抑制剂联合治疗有反应的报告。尽管肿瘤在初次表现时组织学分级低且接受了根治性手术治疗，但疾病临床病程侵袭性强，复发时对BRAF/MEK靶向治疗的反应完全但不持久。帕博利珠单抗的经验性使用未提供明确证据证明免疫治疗在蛋白激酶重排梭形细胞肿瘤中的临床相关性。
