title: Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Institutes of Health, US Department of Defense.
authors.forename: Lisa
authors.initials: L
authors.lastname: Young
authors.forename: Hye-Seung
authors.initials: HS
authors.lastname: Lee
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Inoue
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: Lianne G
authors.initials: LG
authors.lastname: Singer
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.forename: Alan F
authors.initials: AF
authors.lastname: Barker
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chapman
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: James M
authors.initials: JM
authors.lastname: Stocks
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Goldberg
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Swigris
authors.forename: Angelo M
authors.initials: AM
authors.lastname: Taveira-DaSilva
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D018192:Lymphangioleiomyomatosis / Q000097:blood / Q000188:drug therapy*; D008875:Middle Aged; D011446:Prospective Studies; D020123:Sirolimus / Q000627:therapeutic use*; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*; D014797:Vital Capacity / Q000187:drug effects; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; D020123:Sirolimus