Genetic classification helps with precise sirolimus treatment in slow-flow vascular malformations: A prospective cohort study

Background: Targeted therapy of slow-flow vascular malformations (SFVM) needs genetic classification. The efficacy differences between genotypes are still vague.
Objective: To investigate the genomic spectrum of SFVM and sirolimus efficacy differences between various genotypes and phenotypes.
Methods: In a genetic cohort study based on a biobank, participants prospectively received biopsy and genetic sequencing to investigate the genomic spectrum of SFVM. In the sirolimus cohort study, participants of 3 groups based on genetic classifications prospectively received sirolimus for 6 months.
Results: 263 samples from 214 participants were enrolled in the genetic cohort, yielding an overall genetic diagnosis rate of 60.98%. We classified the genetic subtypes as PIK3CA-related vascular malformation (PRVM), TEK-related vascular malformation (TRVM), special types (ST), and non-diagnosed types (ND). 41 participants received a 6-month sirolimus treatment. The total response rate (tRR) and objective response rate (ORR) were 87.80% and 48.78%. ORR of the mutated group (PRVM+TRVM, 64.29%) was significantly higher than ND (15.38%). tRR and ORR of Klippel-Trenaunay syndrome (KTS, 55.56%, 33.33%) were lower than non-KTS SFVM (96.88%, 53.13%).
Limitations: Non-placebo, nonrandomization, small sample size, and single-center design.
Conclusion: Genetic classification may help to indicate targeted therapy. Non-KTS PRVM and TRVM benefit more from sirolimus treatment in lesion regression.

背景：慢流型血管畸形（slow-flow vascular malformations, SFVM）的靶向治疗亟需开展基因分型，目前不同基因型间的疗效差异仍不明确。
研究目的：明确慢流型血管畸形的基因组谱特征，并探讨不同基因型与表型间西罗莫司的疗效差异。
研究方法：本研究包含两项队列研究。其一为基于生物样本库的基因队列研究，入组受试者前瞻性接受活检及基因测序，以明确慢流型血管畸形的基因组谱特征；其二为西罗莫司队列研究，受试者按基因分型分为3组，前瞻性接受为期6个月的西罗莫司治疗。
研究结果：基因队列共纳入214名受试者的263份样本，整体基因诊断率为60.98%。本研究将慢流型血管畸形的基因亚型分为PIK3CA相关血管畸形（PIK3CA-related vascular malformation, PRVM）、TEK相关血管畸形（TEK-related vascular malformation, TRVM）、特殊类型（special types, ST）及未确诊类型（non-diagnosed types, ND）。西罗莫司队列共纳入41名接受6个月治疗的受试者，总缓解率（total response rate, tRR）与客观缓解率（objective response rate, ORR）分别为87.80%与48.78%。突变组（PRVM+TRVM）的客观缓解率为64.29%，显著高于未确诊组（15.38%）。克利佩尔-特伦诺奈综合征（Klippel-Trenaunay syndrome, KTS）患者的总缓解率与客观缓解率分别为55.56%与33.33%，均低于非克利佩尔-特伦诺奈综合征慢流型血管畸形患者（96.88%、53.13%）。
研究局限性：本研究未设置安慰剂对照、未采用随机分组方案、样本量较小且为单中心设计。
研究结论：基因分型有助于指导慢流型血管畸形的靶向治疗；非KTS型PIK3CA相关血管畸形与TEK相关血管畸形患者可从西罗莫司治疗中获得更显著的病灶退缩获益。