TY - JOUR
T1 - Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response
T2 - A prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial
AU - Young, Lisa R.
AU - Lee, Hye Seung
AU - Inoue, Yoshikazu
AU - Moss, Joel
AU - Singer, Lianne G.
AU - Strange, Charlie
AU - Nakata, Koh
AU - Barker, Alan F.
AU - Chapman, Jeffrey T.
AU - Brantly, Mark L.
AU - Stocks, James M.
AU - Brown, Kevin K.
AU - Lynch, Joseph P.
AU - Goldberg, Hilary J.
AU - Downey, Gregory P.
AU - Swigris, Jeffrey J.
AU - Taveira-DaSilva, Angelo M.
AU - Krischer, Jeffrey P.
AU - Trapnell, Bruce C.
AU - McCormack, Francis X.
N1 - Funding Information:
LRY and FXM are coinventors on a patent for the use of VEGF-D as a diagnostic test (all potential personal royalties were waived before issuance of the patent) and members of the advisory board of the LAM Foundation. LGS received a peer-reviewed research grant from Pfizer (cosponsored with the Ontario Lung Association) for studies unrelated to this Article. All other authors declare that they have no conflicts of interest.
Funding Information:
Funding for the VEGF-D testing, validation, and analysis was provided by the National Institutes of Health Institutional Clinical and Translational Science Award (1UL1RR02631401) at Cincinnati Children's Hospital Medical Center (to LRY and FXM), and Department of Defense (W81XWH-10-1-0885; to LRY and FXM). Funding for the MILES trial was as previously reported. 18 We thank Leslie Korbee, Peter Gulleman, and Elke Grassman for assistance with analysis of VEGF-D samples.
PY - 2013/8
Y1 - 2013/8
N2 - Background: VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. Methods: In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. Findings: We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99-3·36] vs 0·84 ng/mL [0·52-1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99-2·86] vs 1·00 ng/mL [0·61-2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Interpretation: Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk-benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. Funding: National Institutes of Health, US Department of Defense.
AB - Background: VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. Methods: In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. Findings: We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99-3·36] vs 0·84 ng/mL [0·52-1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99-2·86] vs 1·00 ng/mL [0·61-2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). Interpretation: Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk-benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. Funding: National Institutes of Health, US Department of Defense.
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U2 - 10.1016/S2213-2600(13)70090-0
DO - 10.1016/S2213-2600(13)70090-0
M3 - Article
C2 - 24159565
AN - SCOPUS:84881343915
SN - 2213-2600
VL - 1
SP - 445
EP - 452
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 6
ER -