Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum
Victoria Parker
(1)
,
Kim Keppler-Noreuil
(2)
,
Laurence Faivre
(3, 4, 5)
,
Maxime Luu
(6)
,
Neal Oden
(7)
,
Leena de Silva
(1)
,
Julie Sapp
(2)
,
Katrina Andrews
(1)
,
Marc Bardou
(6)
,
Kong Chen
(8)
,
Thomas Darling
(9)
,
Elodie Gautier
(4, 3, 5)
,
Barry Goldspiel
(10)
,
Smail Hadj-Rabia
(11, 12, 13)
,
Julie Harris
(1)
,
Georgios Kounidas
(1)
,
Parag Kumar
(10)
,
Marjorie Lindhurst
(2)
,
Romaric Loffroy
(14)
,
Ludovic Martin
(15)
,
Alice Phan
(16)
,
Kristina Rother
(8)
,
Brigitte Widemann
(17)
,
Pamela Wolters
(17)
,
Christine Coubes
(18)
,
Lucile Pinson
(18)
,
Marjolaine Willems
(18)
,
Catherine Vincent-Delorme
(19)
,
- Promise Working Group
,
Pierre Vabres
(3, 4, 5)
,
Robert Semple
(1, 20)
,
Leslie Biesecker
(2)
1
Institute of Metabolic Science-Metabolic Research Laboratories
2 NHGRI - National Human Genome Research Institute
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 Equipe GAD (LNC - U1231)
5 FHU TRANSLAD (CHU de Dijon)
6 CIC-EC - Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques
7 The EMMES Corporation
8 National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda]
9 USUHS - Uniformed Services University of the Health Sciences
10 Pharmacy Department (NIH Clinical Center National, Institutes of Health)
11 MAGEC - Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases
12 UPD5 - Université Paris Descartes - Paris 5
13 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
14 Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon)
15 Département de dermatologie, CHU Angers
16 Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon
17 NIH - National Institutes of Health [Bethesda]
18 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
19 Service de Génétique Médicale [Lille]
20 Queen's Medical Researche Institute
2 NHGRI - National Human Genome Research Institute
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 Equipe GAD (LNC - U1231)
5 FHU TRANSLAD (CHU de Dijon)
6 CIC-EC - Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques
7 The EMMES Corporation
8 National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda]
9 USUHS - Uniformed Services University of the Health Sciences
10 Pharmacy Department (NIH Clinical Center National, Institutes of Health)
11 MAGEC - Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases
12 UPD5 - Université Paris Descartes - Paris 5
13 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
14 Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon)
15 Département de dermatologie, CHU Angers
16 Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon
17 NIH - National Institutes of Health [Bethesda]
18 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
19 Service de Génétique Médicale [Lille]
20 Queen's Medical Researche Institute
Maxime Luu
- Fonction : Auteur
- PersonId : 997729
Marc Bardou
- Fonction : Auteur
- PersonId : 758612
- ORCID : 0000-0003-0028-1837
Romaric Loffroy
- Fonction : Auteur
- PersonId : 868932
- Promise Working Group
- Fonction : Auteur
Robert Semple
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 1042256
Connectez-vous pour contacter l'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