Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas.
Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas.
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DOI：
10.18632/oncotarget.16845
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发表时间：
2017-06-13
期刊：
影响因子：
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通讯作者：
Subbiah V
中科院分区：
文献类型：
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作者：
Groisberg R;Hong DS;Holla V;Janku F;Piha-Paul S;Ravi V;Benjamin R;Kumar Patel S;Somaiah N;Conley A;Ali SM;Schrock AB;Ross JS;Stephens PJ;Miller VA;Sen S;Herzog C;Meric-Bernstam F;Subbiah V
目前，除了胃肠道间质瘤外，美国食品和药物管理局还没有批准用于肉瘤的分子匹配疗法。复杂的是这些肿瘤的极端多样性，异质性和罕见性。复发性和难治性肉瘤的治疗选择很少。在临床实践中，许多肿瘤学家推荐患者进行基因组分析，希望在标准治疗后获得治疗选择的指导。然而，尚未完成对可采取行动的突变的系统分析。我们分析了MD安德森癌症中心晚期肉瘤患者的基因组谱结果，以阐明该人群中潜在可操作的基因组改变的频率。我们回顾了晚期肉瘤患者的图表，这些患者被转诊到研究性癌症治疗部门，并在至少50 ng DNA中具有CLIA认证的236或315个癌症基因的综合基因组图谱（CGP）。可操作的改变被定义为在市场上、注册的临床试验中或药物-基因相互作用数据库中识别抗癌药物的那些改变。在分析的102例患者中，中位年龄为45.5岁（范围8-76岁），男性：女性比例为48：54。我们研究中最常见的亚型是平滑肌肉瘤（18.6%）、去分化脂肪肉瘤（11%）、骨肉瘤（11%）、高分化脂肪肉瘤（7%）、癌肉瘤（6%）和横纹肌肉瘤（6%）。102例患者中有95例（93%）至少有一个基因组变异，平均每例患者有6个突变。在95个具有可识别的基因组改变的活检样本中，最常见的受影响基因是TP 53（31.4%）、CDK 4（23.5%）、MDM 2（21.6%）、RB 1（18.6%）和CDKN 2A/B（13.7%）。值得注意的共分离扩增包括MDM 2-CDK 4和FRS 2-FGF。16%的患者接受了基于CGP的靶向治疗，其中50%至少病情稳定。将CGP应用于肉瘤治疗可以更精确地诊断和分类这种多样化和罕见的疾病，以及患者与靶向治疗的个性化匹配，例如篮子临床试验中可用的那些。
There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas. In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy. However, a systematic analysis of actionable mutations has yet to be completed. We analyzed genomic profiling results in patients referred to MD Anderson Cancer Center with advanced sarcomas to elucidate the frequency of potentially actionable genomic alterations in this population. We reviewed charts of patients with advanced sarcoma who were referred to investigational cancer therapeutics department and had CLIA certified comprehensive genomic profiling (CGP) of 236 or 315 cancer genes in at least 50ng of DNA. Actionable alterations were defined as those identifying anti-cancer drugs on the market, in registered clinical trials, or in the Drug-Gene Interaction Database. Among the 102 patients analyzed median age was 45.5 years (range 8-76), M: F ratio 48:54. The most common subtypes seen in our study were leiomyosarcoma (18.6%), dedifferentiated liposarcoma (11%), osteosarcoma (11%), well-differentiated liposarcoma (7%), carcinosarcoma (6%), and rhabdomyosarcoma (6%). Ninety-five out of 102 patients (93%) had at least one genomic alteration identified with a mean of six mutations per patient. Of the 95 biopsy samples with identifiable genomic alterations, the most commonly affected genes were TP53 (31.4%), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), and CDKN2A/B (13.7%). Notable co-segregating amplifications included MDM2-CDK4 and FRS2-FGF. Sixteen percent of patients received targeted therapy based on CGP of which 50% had at least stable disease. Incorporating CGP into sarcoma management may allow for more precise diagnosis and sub-classification of this diverse and rare disease, as well as personalized matching of patients to targeted therapies such as those available in basket clinical trials.