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Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2018-10-01 , DOI: 10.1038/s41436-018-0297-9
Victoria E R Parker 1 , Kim M Keppler-Noreuil 2 , Laurence Faivre 3 , Maxime Luu 4 , Neal L Oden 5 , Leena De Silva 1 , Julie C Sapp 2 , Katrina Andrews 1 , Marc Bardou 4 , Kong Y Chen 6 , Thomas N Darling 7 , Elodie Gautier 3 , Barry R Goldspiel 8 , Smail Hadj-Rabia 9 , Julie Harris 1 , Georgios Kounidas 1 , Parag Kumar 8 , Marjorie J Lindhurst 2 , Romaric Loffroy 10 , Ludovic Martin 11 , Alice Phan 12 , Kristina I Rother 6 , Brigitte C Widemann 13 , Pamela L Wolters 13 , Christine Coubes 14 , Lucile Pinson 14 , Marjolaine Willems 14 , Catherine Vincent-Delorme 15 , , Pierre Vabres 3 , Robert K Semple 1, 16 , Leslie G Biesecker 2
Affiliation  

PURPOSE PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. METHODS Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. RESULTS Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. CONCLUSION This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

中文翻译:

低剂量西罗莫司在 PIK3CA 相关过度生长谱中的安全性和有效性。

目的 PIK3CA 相关过度生长谱 (PROS) 包括一系列由镶嵌激活 PIK3CA 变体引起的不对称过度生长所定义的衰弱条件。PIK3CA 编码磷脂酰肌醇-3-激酶 (PI3K) 的 p110α 催化亚基,PI3K 是生长因子信号传导的关键转导。由于 mTOR 介导 PI3K 的生长促进作用,我们假设 mTOR 抑制剂西罗莫司会减缓病理性过度生长。方法 39 名患有 PROS 和进行性过度生长的参与者被纳入三个中心的开放标签研究,并汇总结果。对于主要结果,在未经治疗的 26 周磨合期和 26 周的西罗莫司治疗期间,通过双能 X 射线吸收法测量受累和未受累部位的组织体积。结果 30 名参与者完成了研究。西罗莫司导致受影响部位的平均总组织体积百分比变化为 -7.2%(标准差 16.0,p = 0.04),但未受影响的部位没有变化(+1.7%,标准差 11.5,p = 0.48)(n = 23 可评估) . 39 名参与者中有 28 名 (72%) 出现 ≥1 次与西罗莫司相关的不良事件,其中 37% 的严重程度为 3 级或 4 级,7/39 (18%) 的参与者因此退出。结论 本研究表明,低剂量西罗莫司可适度减少过度生长,但警告副作用显着,需要对 PROS 中的西罗莫司治疗进行个体化风险效益评估。39 名参与者中有 28 名 (72%) 出现 ≥1 次与西罗莫司相关的不良事件,其中 37% 的严重程度为 3 级或 4 级,7/39 (18%) 的参与者因此退出。结论 本研究表明,低剂量西罗莫司可适度减少过度生长,但警告副作用显着,需要对 PROS 中的西罗莫司治疗进行个体化风险效益评估。39 名参与者中有 28 名 (72%) 出现 ≥1 次与西罗莫司相关的不良事件,其中 37% 的严重程度为 3 级或 4 级,7/39 (18%) 的参与者因此退出。结论 本研究表明,低剂量西罗莫司可适度减少过度生长,但警告副作用显着,需要对 PROS 中的西罗莫司治疗进行个体化风险效益评估。
更新日期:2018-10-01
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