Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein
Authors: Vivek Subbiah, Shannon N Westin, Kai Wang, Dejka Araujo, Wei-Lien Wang, Vincent A Miller, Jeffrey S Ross, Phillip J Stephens, Gary A Palmer, Siraj M Ali
Journal: J Hematol Oncol (2014)
MeSH terms: Antineoplastic Combined Chemotherapy Protocols / therapeutic use, Molecular Targeted Therapy / methods, Oncogene Proteins, Fusion / antagonists & inhibitors, Proto-Oncogene Proteins B-raf / antagonists & inhibitors, Sarcoma / drug therapy, TOR Serine-Threonine Kinases / antagonists & inhibitors, Case Reports, Clinical Trial, Phase I, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Antibodies, Monoclonal, Humanized / administration & dosage, Antigens, CD34 / metabolism, Bevacizumab, Female, Humans, Immunohistochemistry, Middle Aged, Niacinamide / administration & dosage, Niacinamide / analogs & derivatives, Oncogene Proteins, Fusion / genetics, Phenylurea Compounds / administration & dosage, Proto-Oncogene Proteins B-raf / metabolism, S100 Proteins / metabolism, Sarcoma / genetics, Sarcoma / metabolism, Sequence Analysis, DNA, Sirolimus / administration & dosage, Sirolimus / analogs & derivatives, Sorafenib, TOR Serine-Threonine Kinases / metabolism, Treatment Outcome, Antibodies, Monoclonal, Humanized, Antigens, CD34, BRAF-KIAA1549 fusion protein, human, Oncogene Proteins, Fusion, Phenylurea Compounds, S100 Proteins, Niacinamide, Bevacizumab, temsirolimus, Sorafenib, MTOR protein, human, Proto-Oncogene Proteins B-raf, TOR Serine-Threonine Kinases, Sirolimus

Background:
Oncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial.
Methods:
Genomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199).
Results:
The histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial.
Conclusions:
The patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.