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Rapid but nondurable response of a BRAF exon 15 double-mutated spindle cell sarcoma to a combination of BRAF and MEK inhibitors
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  • Sinichenkova KYu,
  • * Sidorov,
  • Kriventsova NA,
  • Konovalov DM,
  • Abasov RH,
  • Usman Yu N,
  • Alexander Karachunskii,
  • Novichkova GA,
  • Dmitry Litvinov,
  • Druy AE
Sinichenkova KYu
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva

Corresponding Author:[email protected]

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* Sidorov
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Kriventsova NA
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Konovalov DM
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Abasov RH
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Usman Yu N
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Alexander Karachunskii
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Novichkova GA
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Dmitry Litvinov
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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Druy AE
FGBU Nacional'nyj medicinskij issledovatel'skij centr detskoj gematologii onkologii i immunologii imeni Dmitria Rogaceva
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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.