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Abstract：
PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders.
PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations, and PIK3CA-related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA-related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA-related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA-related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib).
Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.
PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations, and PIK3CA-related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA-related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA-related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA-related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib).
Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.
摘要：
PIK3CA相关疾病包括由合子后引起的血管畸形和各种组织的过度生长，编码磷脂酰肌醇3激酶（PI3K）催化亚基α的基因中的体细胞变体。这些突变导致PI3K/AKT/mTOR信号传导途径的激活。这篇综述的目的是提供关于这组罕见疾病的潜在机制的教育，并总结在理解方面的最新进展，以及PIK3CA相关疾病的当前和新兴治疗选择。
PIK3CA相关疾病包括PIK3CA相关的过度生长谱（PROS），PIK3CA相关血管畸形,和PIK3CA相关的非血管病变。体细胞激活突变（主要在PIK3CA的螺旋和激酶结构域的热点，但在其他领域也是如此)，导致PI3K信号通路过度激活，导致异常的组织生长。与PIK3CA相关疾病相关的表型的变异性和重叠使诊断变得复杂，应由具有所需专业知识的临床医生以及多学科团队的协调护理进行诊断。尽管组织镶嵌对确认PIK3CA突变提出了挑战，下一代测序和组织选择改善了检测.临床改善,放射学响应，和患者报告的结果通常用于评估PIK3CA相关疾病患者的临床研究中的治疗反应，但是使用影像学很难客观评估治疗反应（由于这些疾病的异质性，叠加在患者的生长和发育上)。尽管有其局限性,患者报告的结果工具可能最适合衡量患者的改善情况.需要新的治疗选择以提供诸如手术和硬化疗法的标准方法的替代或补充。目前,这些疾病没有获得监管部门批准的全身性药物，但mTOR抑制剂西罗莫司已经在临床试验中使用了数年,并且在标签外用于治疗症状.还有其他药物正在研究PIK3CA相关疾病，这些药物可作为抑制剂靶向PI3K信号通路的不同成分，包括AKT（miransertib）和PI3Kα（alpelisib）。
PIK3CA相关疾病患者的治疗需要多学科方法。来自靶向PI3K途径的药物的正在进行的临床研究的进一步结果是高度预期的。
PIK3CA相关疾病包括PIK3CA相关的过度生长谱（PROS），PIK3CA相关血管畸形,和PIK3CA相关的非血管病变。体细胞激活突变（主要在PIK3CA的螺旋和激酶结构域的热点，但在其他领域也是如此)，导致PI3K信号通路过度激活，导致异常的组织生长。与PIK3CA相关疾病相关的表型的变异性和重叠使诊断变得复杂，应由具有所需专业知识的临床医生以及多学科团队的协调护理进行诊断。尽管组织镶嵌对确认PIK3CA突变提出了挑战，下一代测序和组织选择改善了检测.临床改善,放射学响应，和患者报告的结果通常用于评估PIK3CA相关疾病患者的临床研究中的治疗反应，但是使用影像学很难客观评估治疗反应（由于这些疾病的异质性，叠加在患者的生长和发育上)。尽管有其局限性,患者报告的结果工具可能最适合衡量患者的改善情况.需要新的治疗选择以提供诸如手术和硬化疗法的标准方法的替代或补充。目前,这些疾病没有获得监管部门批准的全身性药物，但mTOR抑制剂西罗莫司已经在临床试验中使用了数年,并且在标签外用于治疗症状.还有其他药物正在研究PIK3CA相关疾病，这些药物可作为抑制剂靶向PI3K信号通路的不同成分，包括AKT（miransertib）和PI3Kα（alpelisib）。
PIK3CA相关疾病患者的治疗需要多学科方法。来自靶向PI3K途径的药物的正在进行的临床研究的进一步结果是高度预期的。
