Department of Medicine, New York University Langone Medical Center, New York.
Northwell Cancer Institute, Zucker School of Medicine at Hofstra/Northwell, Cold Spring Harbor Laboratory, Long Island, New York.
JAMA Oncol. 2019 Feb 1;5(2):254-260. doi: 10.1001/jamaoncol.2018.4490.
Alveolar soft-part sarcoma (ASPS) is a rare, translocation-driven sarcoma of the soft tissues. Alveolar soft-part sarcoma often affects young adults and is characterized by indolent behavior but early evidence of metastatic spread. After recognition of ASPS as a specific entity in 1952, retrospective data indicated prolonged survival in patients with metastases, despite inherent resistance to conventional doxorubicin-based chemotherapy. Tyrosine kinase inhibitors and immune checkpoint inhibitors have provided unexpected new treatment strategies for ASPS.
This review includes articles published between 1952 and March 1, 2018. With the introduction of new molecular diagnostic tools and therapies, the distinctive features of ASPS have become more evident. The identification and better understanding of molecular pathways activated by the characteristic t(X;17)(p11;q25) translocation and its correspondent chimeric ASPSCR1-transcription factor E3 (TFE3) fusion protein open new paths to drug development. The associations of TFE3 and facilitation of an immunosuppressive microenvironment provide a rationale for exploring treatments that affect the balance between T-effector cells and T-regulatory cells. Tyrosine kinase inhibitors, such as sunitinib, cediranib, and pazopanib, show activity with either tumor responses or disease stabilization in more than 50% of the cases. Given the association of new agents with patient outcomes, it is too early to say whether metastatic ASPS should still be considered incurable in all patients.
The biologic outcomes of the canonical genomic event in ASPS remain under investigation; a better understanding of the tumor microenvironment and the multiple pathways activated in this sarcoma, including unusual bioenergetics, MET signaling, and angiogenesis, should lead to more rational therapy. Basket trials and related prospective studies focusing on the intersection of specific signaling pathways and diseases with unique genomic features, such as ASPS, will provide an understanding of new options for care.
腺泡状软组织肉瘤（ASPS）是一种罕见的、由易位驱动的软组织肉瘤。ASPS 常影响年轻成年人，其特征为惰性行为，但有早期转移扩散的证据。1952 年 ASPS 被确认为一种特定实体后，回顾性数据表明，即使对传统阿霉素为基础的化疗存在固有耐药性，转移患者的生存率仍有所延长。酪氨酸激酶抑制剂和免疫检查点抑制剂为 ASPS 提供了意想不到的新治疗策略。
本综述包括 1952 年至 2018 年 3 月 1 日期间发表的文章。随着新的分子诊断工具和治疗方法的引入，ASPS 的独特特征变得更加明显。特征性 X;17(p11;q25)易位及其相应的嵌合 ASPSCR1-转录因子 E3（TFE3）融合蛋白激活的分子途径的鉴定和更好的理解为药物开发开辟了新的途径。TFE3 的关联和免疫抑制微环境的促进为探索影响 T 效应细胞和 T 调节细胞之间平衡的治疗方法提供了依据。酪氨酸激酶抑制剂，如舒尼替尼、西地尼布和帕唑帕尼，在超过 50%的病例中显示出肿瘤反应或疾病稳定的活性。鉴于新药物与患者结局的关联，现在说转移性 ASPS 是否仍应被认为对所有患者均不可治愈还为时过早。
ASPS 中典型基因组事件的生物学结局仍在研究中；对肿瘤微环境和在这种肉瘤中激活的多种途径（包括不寻常的生物能量学、MET 信号和血管生成）的更好理解，应导致更合理的治疗。针对特定信号通路和具有独特基因组特征的疾病（如 ASPS）的杂交试验和相关前瞻性研究将提供对新护理选择的理解。
