PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
CONCLUSIONS: 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.
METHODS: 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.
CONCLUSIONS: 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.
摘要：
背景：BRAFV600E替代预测癌症对BRAF抑制剂治疗的敏感性。这种突变在软组织肉瘤中很少见。在这里，我们描述了一个未分化的梭形细胞肉瘤，显示对标准化疗的原发性不敏感，并且在复发时对BRAF/MEK抑制剂有明显但非持续的反应。
方法：一名13岁女孩被诊断为盆腔定位的低级梭形细胞肉瘤，BRAF外显子15双突变：c.1799T>Ap.V600E和c.1819T>Ap.S607T在顺位。该肿瘤对基于CWS的一线化疗表现出耐药性，并通过根治性切除术进行了手术治疗。手术后七个月，患者出现转移性复发，伴有腹部癌。BRAF/MEK抑制剂联合靶向治疗可在1个月内完全缓解，并继续治疗。虽然并发严重的副作用(发烧，皮疹)需要1-2周的毒性中断。开始4个月后，疾病复发，抗BRAF/MEK方案巩固不成功。强化抢救化疗无效。经验性免疫疗法提供了短暂的部分反应，导致致命的进展，腹茧并发腹膜癌。
结论：这是首例梭形细胞肉瘤BRAFV600E/S607T双突变，响应B-Raf和MEK抑制剂的组合。尽管肿瘤的主要表现是低组织学分级和根治性手术治疗，该疾病具有侵袭性的临床病程,复发时对BRAF/MEK靶向治疗的反应是完全的,但不持久.经验使用pembrolizumab没有提供明确的证据表明免疫疗法在蛋白激酶重排的梭形细胞肿瘤中的临床相关性。
方法：一名13岁女孩被诊断为盆腔定位的低级梭形细胞肉瘤，BRAF外显子15双突变：c.1799T>Ap.V600E和c.1819T>Ap.S607T在顺位。该肿瘤对基于CWS的一线化疗表现出耐药性，并通过根治性切除术进行了手术治疗。手术后七个月，患者出现转移性复发，伴有腹部癌。BRAF/MEK抑制剂联合靶向治疗可在1个月内完全缓解，并继续治疗。虽然并发严重的副作用(发烧，皮疹)需要1-2周的毒性中断。开始4个月后，疾病复发，抗BRAF/MEK方案巩固不成功。强化抢救化疗无效。经验性免疫疗法提供了短暂的部分反应，导致致命的进展，腹茧并发腹膜癌。
结论：这是首例梭形细胞肉瘤BRAFV600E/S607T双突变，响应B-Raf和MEK抑制剂的组合。尽管肿瘤的主要表现是低组织学分级和根治性手术治疗，该疾病具有侵袭性的临床病程,复发时对BRAF/MEK靶向治疗的反应是完全的,但不持久.经验使用pembrolizumab没有提供明确的证据表明免疫疗法在蛋白激酶重排的梭形细胞肿瘤中的临床相关性。
