Subbiah Vivek, Westin Shannon N, Wang Kai, Araujo Dejka, Wang Wei-Lien, Miller Vincent A, Ross Jeffrey S, Stephens Phillip J, Palmer Gary A, Ali Siraj M
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.
J Hematol Oncol. 2014 Jan 14;7:8. doi: 10.1186/1756-8722-7-8.
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.
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).
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 A68fs51, SUFU E283fs3, 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.
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.
对分子靶向治疗有极端反应的肿瘤患者为更好地理解反应的生物学基础提供了重要契机，进而为临床决策提供参考。组织学和免疫组化特征不明确的恶性肿瘤在初始诊断检查以及后续治疗中均存在挑战，因为当前的治疗方案是基于形态学诊断。在此，我们报告一例难以明确特征的肉瘤样病变病例，在一项I期临床试验中，通过临床下一代测序（NGS）进行基因组分析确定了联合靶向治疗下病情进展停滞（疾病稳定）的分子基础。
在FoundationOne™平台（美国马萨诸塞州剑桥市Foundation Medicine公司）上进行临床下一代测序的基因组分析。组织病理学和免疫组化研究在MD安德森癌症中心（美国得克萨斯州休斯顿）病理科进行。治疗是在一项I期临床试验（ClinicalTrials.gov标识符：NCT01187199）的背景下进行的。
肿瘤组织学表现为梭形细胞瘤，根据法国国立癌症中心联合会（FNCLCC）标准为2级。免疫组化染色S100和CD34呈阳性。基因组分析确定了以下改变：由串联重复事件导致的KIAA1549 - BRAF基因融合、PTEN纯合缺失以及CDKN2A A68fs51、SUFU E283fs3和MAP3K1 N325fs*3中的移码插入/缺失。在一项I期临床试验中，该患者接受索拉非尼、替西罗莫司和贝伐单抗联合治疗后，肿瘤体积缩小了25%（根据实体瘤疗效评价标准第1.1版[RECIST v1.1]）。
如基于NGS的基因组分析所示，该患者对联合靶向治疗有反应，该联合治疗意外地针对了梭形细胞瘤内的KIAA1549 - BRAF和PTEN缺失。这是首例由KIAA1549 - BRAF融合驱动的肿瘤对基于索拉非尼的联合治疗有反应的报告。
