Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Genetics in Medicine Année : 2019

Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum

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Neal Oden
  • Fonction : Auteur
Ludovic Martin
  • Fonction : Auteur
  • PersonId : 992606
- Promise Working Group
  • Fonction : Auteur

Résumé

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had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.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

Dates et versions

hal-02000984 , version 1 (31-01-2019)

Identifiants

Citer

Victoria Parker, Kim Keppler-Noreuil, Laurence Faivre, Maxime Luu, Neal Oden, et al.. Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. Genetics in Medicine, In press, ⟨10.1038/s41436-018-0297-9⟩. ⟨hal-02000984⟩
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