Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein

Journal of Hematology & Oncology

Siraj M Ali⁵  Gary A Palmer⁵  Phillip J Stephens⁵  Jeffrey S Ross²  Vincent A Miller⁵  Wei-Lien Wang⁶  Dejka Araujo⁴  Kai Wang⁵  Shannon N Westin¹  Vivek Subbiah³ 

[1] Division of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA;Department of Pathology, Albany Medical Center, Albany, NY 12222, USA;Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., FC8.3038, Box 0455, Houston, TX 77030, USA;Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA;Foundation Medicine, Cambridge, Massachusetts, USA;Division of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA

关键词: N = 1 trial;    Next generation sequencing;    Bevacizumab;    mTOR;    Sorafenib;    Targeted therapy;    BRAF;    KIAA1549-BRAF;    Sarcoma;    Spindle cell neoplasm;   

Others  :  802117
DOI  :  10.1186/1756-8722-7-8

 received in 2013-10-04, accepted in 2013-12-31,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Subbiah et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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