Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum

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had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.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.

Keywords: PIK3CA; mosaicism; overgrowth; sirolimus.

Conflict of interest statement

V.E.R.P. is an employee of MedImmune Ltd and has stock holdings in AstraZeneca. L.G.B. and M.J.L. receive royalties from Genentech Corporation and L.G.B. is an advisor to the Illumina Corp. The other authors declare no conflicts of interest.

Figures

Fig. 1

CONSORT flow-chart and schematic of nonrandomized open-label pilot study.a Schematic of number of participants assessed for eligibility and excluded or allocated to the study, treated, followed, and analyzed. Of the 39 subjects enrolled, 30 completed 26 weeks of sirolimus therapy, and 23/30 had anatomy that permitted analysis of the primary outcome measure. Safety and tolerability were evaluated in all treated participants. b Overview of study design including schedule of procedures. AE/SAEs adverse events/serious adverse events, CXR chest X-ray, DXA/MRI dual energy X-ray absorptiometry/magnetic resonance imaging, QOL quality of life.

Fig. 2

Clinical heterogeneity of study participants with PIK3CA-related overgrowth spectrum.a 15-year-old girl with fibroadipose hyperplasia of left arm; unaffected right arm (patient 1). b 39-year-old man with fibroadipose and bony hyperplasia of left lower leg, foot s/p multiple amputations, and lipectomies; unaffected right leg, foot (patient 17). c 48-year-old woman with tongue fibromas, fibroadipose hyperplasia masses of trunk, back, paraspinal s/p (status post) excision, and scoliosis s/p surgical bracing (patient 30). d 5-year-old boy with fibroadipose hyperplasia of the left leg, buttock visualized on magnetic resonance image (MRI) scan (patient 4). e 17-year-old boy with right fibroadipose hemihyperplasia (patient 2). f 19-year-old woman with right fibroadipose hemihyperplasia and capillary malformation, MCAP (Megalencephaly-capillary malformation syndrome) phenotype (patient 3). g 6-year-old girl with vascular malformations/overgrowth of left leg, foot; unaffected right leg, foot (patient 19). h 26-year-old man with vascular malformations/overgrowth of right leg; unaffected left leg (patient 12). i 23-year-old man with vascular malformations of the left arm and hand (patient 13). j 3-year-old boy with fibroadipose hyperplasia of the right arm, hand, fingers, and trunk and left partial chest/axilla (patient 16). k 44-year-old man with fibroadipose hyperplasia and vascular malformations of his back and bilateral legs (patient 10). l 8-year-old girl with fibroadipose hyperplasia masses of her trunk, back, paraspinal s/p excision, muscular hyperplasia of her legs and feet (left > right), regional lipohypoplasia of her bilateral arms (patient 27). m 6-year-old boy with facial infiltrating lipomatosis affecting left cheek visualized on MRI scan (patient 9). n 31-year-old man with vascular malformations and fibroadipose hyperplasia of the lower trunk, leg (patient 5). o 13-year-old boy with epidermal nevus of right face, neck; right facial, tongue, trunk, bilateral legs, feet (right > left) fibroadipose hyperplasia s/p multiple amputations/debulking surgeries of feet and toes; lymphovascular malformations of bilateral arms (right > left), trunk (patient 29). Written informed consent was obtained for use of all identifiable images.

Fig. 3

Dual energy X-ray absorptiometry (DXA)-estimated changes in tissue volume during study period.a Change in absolute volumes in ml at affected and unaffected sites at the beginning of the run-in period (week 0), after the 26-week run-in period (week 26), and after the 26-week sirolimus treatment period (week 52). Note major differences in the magnitude and variability of volume measurements between affected and unaffected sites. b Change in percent tissue volume at affected and unaffected sites during the run-in period at week 26 and during the sirolimus treatment phase at week 52. Individual values plotted, bars denote mean values and error bars standard deviation. c Post hoc subanalysis of progressive growth during the run-in period. Linear regression analysis of % volume change during run-in period, i.e., whether or not subjects had progressive overgrowth versus difference in % volume change between the run-in and treatment phase at affected sites. The result was significant implying the largest effect sizes were obtained in subjects with progressive overgrowth during the run-in period.