Rapid but nondurable response of a BRAF exon 15 double-mutated spindle cell sarcoma to a combination of BRAF and MEK inhibitors

// Kseniya Sinichenkova 1 , Iliya Sidorov 1 , Nataliya Kriventsova 1 , Dmitriy Konovalov 1 , Ruslan Abasov 1 , Nataliya Usman 1 , Alexander Karachunskiy 1 , Galina Novichkova 1 , Dmitriy Litvinov 1 and Alexander Druy 1 , 2 1 Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian Federation, Moscow, Russia 2 Research Institute of Medical Cell Technologies, Yekaterinburg, Russia Correspondence to: Kseniya Sinichenkova, email: ksinichenkova@gmail.com , ORCID: orcid.org/0000-0002-1661-4205 Keywords: undifferentiated sarcoma; BRAF V600E mutation; low grade spindle cell sarcoma; abdominal cocoon Abbreviations: FDA: Food and Drug Administration; VAF: variant allele frequency Received: April 16, 2024 Accepted: May 17, 2024 Published: July 17, 2024 Copyright: © 2024 Sinichenkova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Introduction: 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. Case presentation: 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. Conclusion: 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.