학술논문
Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum
Document Type
Original Paper
Author
Parker, Victoria E. R.; Keppler-Noreuil, Kim M.; Faivre, Laurence; Luu, Maxime; Oden, Neal L.; De Silva, Leena; Sapp, Julie C.; Andrews, Katrina; Bardou, Marc; Chen, Kong Y.; Darling, Thomas N.; Gautier, Elodie; Goldspiel, Barry R.; Hadj-Rabia, Smail; Harris, Julie; Kounidas, Georgios; Kumar, Parag; Lindhurst, Marjorie J.; Loffroy, Romaric; Martin, Ludovic; Phan, Alice; Rother, Kristina I.; Widemann, Brigitte C.; Wolters, Pamela L.; Coubes, Christine; Pinson, Lucile; Willems, Marjolaine; Vincent-Delorme, Catherine; PROMISE Working Group; Vabres, Pierre; Semple, Robert K.; Biesecker, Leslie G.
Source
Genetics in Medicine: Official journal of the American College of Medical Genetics and Genomics. 21(5):1189-1198
Subject
Language
English
ISSN
1098-3600
1530-0366
1530-0366
Abstract
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had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.Conclusion: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant,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.