Journal
GENETICS IN MEDICINE
Volume 21, Issue 5, Pages 1189-1198Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41436-018-0297-9
Keywords
overgrowth; mosaicism; PIK3CA; sirolimus
Categories
Funding
- Pfizer [WI189842]
- National Institute for Health Research (NIHR) through the Rare Disease Translational Research Collaboration
- Cambridge Biomedical Research Centre
- Wellcome Trust [WT098498]
- Cambridge Clinical Trials Unit (CCTU)
- National Human Genome Research Institute [HG200388-03]
- National Institute of Diabetes and Digestive and Kidney Diseases [Z01 DK07013]
- Societe Francaise de Dermatologie
- Dijon University Hospital
- Regional council of Burgundy (Plan d'Actions Regionales pour l'Innovation PARI 2015)
- European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs
- FEDER 2016
- NATIONAL CANCER INSTITUTE [ZIABC010801] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIAHG200388] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZICDK071013] Funding Source: NIH RePORTER
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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 p110 alpha 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= 1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.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.
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