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 Martin; Alice 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

doi:10.1038/s41436-018-0297-9

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 journal › Article › peer-review

Abstract / Description of output

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 language	English
Journal	Genetics in Medicine
Early online date	1 Oct 2018
DOIs	https://doi.org/10.1038/s41436-018-0297-9
Publication status	E-pub ahead of print - 1 Oct 2018

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s41436-018-0297-9Final published version, 1.28 MB

Causes and Consequences of Pathological Adipose Remodelling
Semple, R.
UK-based charities
1/06/18 → 31/05/23
Project: Research

Robert Semple
- Deanery of Clinical Sciences - Chair of Translational Molecular Medicine
- Centre for Cardiovascular Science
Person: Academic: Research Active

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Parker, V. E. R., Keppler-Noreuil, K. M., Faivre, L., Luu, M., Oden, N. L., De Silva, L., Sapp, J. C., Andrews, K., Bardou, M., Chen, K. Y., Darling, T., Gautier, E., Goldspiel, B. R., Hadj-Rabia, S., Harris, J., Kounidas, G., Kumar, P., Lindhurst, M. J., Loffroy, R., ... Biesecker, L. G. (2018). Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum. Genetics in Medicine. Advance online publication. https://doi.org/10.1038/s41436-018-0297-9

@article{1faa797620e343e9ace957afcddeec98,

title = "Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum",

abstract = "PurposePIK3CA-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.MethodsThirty-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.ResultsThirty 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.ConclusionThis 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.",

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

year = "2018",

month = oct,

day = "1",

doi = "10.1038/s41436-018-0297-9",

language = "English",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

}

Parker, VER, Keppler-Noreuil, KM, Faivre, L, Luu, M, Oden, NL, De Silva, L, Sapp, JC, Andrews, K, Bardou, M, Chen, KY, Darling, T, Gautier, E, Goldspiel, BR, Hadj-Rabia, S, Harris, J, Kounidas, G, Kumar, P, Lindhurst, MJ, Loffroy, R, Martin, L, Phan, A, Rother, KI, Widemann, BC, Wolters, PL, Coubes, C, Pinson, L, Willems, M, Vincent-Delorme, C, Working Group, PROMISE, Vabres, P, Semple, RK & Biesecker, LG 2018, 'Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum', Genetics in Medicine. https://doi.org/10.1038/s41436-018-0297-9

TY - JOUR

T1 - Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum

AU - Parker, Victoria E R

AU - Keppler-Noreuil, Kim M.

AU - Faivre, Laurence

AU - Luu, Maxime

AU - Oden, Neal L.

AU - De Silva, Leena

AU - Sapp, Julie C

AU - Andrews, Katrina

AU - Bardou, Marc

AU - Chen, Kong Y

AU - Darling, Thomas

AU - Gautier, Elodie

AU - Goldspiel, Barry R

AU - Hadj-Rabia, Smail

AU - Harris, Julie

AU - Kounidas, Georgios

AU - Kumar, Parag

AU - Lindhurst, Marjorie J

AU - Loffroy, Romaric

AU - Martin, Ludovic

AU - Phan, Alice

AU - Rother, Kristina I

AU - Widemann, Brigitte C

AU - Wolters, Pamela L

AU - Coubes, Christine

AU - Pinson, Lucile

AU - Willems, Marjolaine

AU - Vincent-Delorme, Catherine

AU - Working Group, PROMISE

AU - Vabres, Pierre

AU - Semple, Robert K.

AU - Biesecker, Leslie G

PY - 2018/10/1

Y1 - 2018/10/1

N2 - PurposePIK3CA-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.MethodsThirty-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.ResultsThirty 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.ConclusionThis 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.

AB - PurposePIK3CA-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.MethodsThirty-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.ResultsThirty 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.ConclusionThis 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.

U2 - 10.1038/s41436-018-0297-9

DO - 10.1038/s41436-018-0297-9

M3 - Article

SN - 1098-3600

JO - Genetics in Medicine

JF - Genetics in Medicine

ER -

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

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Causes and Consequences of Pathological Adipose Remodelling

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Robert Semple

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