Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum

Victoria E R Parker, Kim M. Keppler-Noreuil, Laurence Faivre, Maxime Luu, Neal L. Oden, Leena De Silva, Julie C Sapp, Katrina Andrews, Marc Bardou, Kong Y Chen, Thomas Darling, Elodie Gautier, Barry R Goldspiel, Smail Hadj-Rabia, Julie Harris, Georgios Kounidas, Parag Kumar, Marjorie J Lindhurst, Romaric Loffroy, Ludovic MartinAlice Phan, Kristina I Rother, Brigitte C Widemann, Pamela L Wolters, Christine Coubes, Lucile Pinson, Marjolaine Willems, Catherine Vincent-Delorme, PROMISE Working Group, Pierre Vabres, Robert K. Semple, Leslie G Biesecker

Research output: Contribution to journalArticlepeer-review

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had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.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.
Original languageEnglish
JournalGenetics in Medicine
Early online date1 Oct 2018
DOIs
Publication statusE-pub ahead of print - 1 Oct 2018

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