Serum VEGF-D a Useful Marker in Lymphangioleiomyomatosis

July 22, 2013

By Lorraine L. Janeczko

NEW YORK (Reuters Health) Jul 22 - In lymphangioleiomyomatosis (LAM), vascular endothelial cell growth factor D (VEGF-D) is a useful marker of disease severity and response to treatment, a new paper suggests.

VEGF-D is a known diagnostic biomarker of LAM, but "this is the first clear evidence that VEGF-D is also a biomarker of therapeutic response to sirolimus," Dr. Elizabeth Henske, director of the Center for LAM Research and Clinical Care at Brigham and Women's Hospital in Boston, told Reuters Health by email.

Serum VEGF-D is not routinely monitored in patients with LAM, almost all of whom are women, said Dr. Henske, who was not involved in the study.

Eventually the findings "could change clinical practice by providing a surrogate of lung function, which is currently the standard way to know if LAM is progressing or has stabilized," she added.

The study, online June 20 in The Lancet Respiratory Medicine, is based on data from 87 patients in the MILES trial. In that trial, adults with LAM and forced expiratory volume in 1 second (FEV1) of 70% or less of predicted value were randomly assigned to 12 months of treatment with either sirolimus or placebo.

The researchers measured serum VEGF-D concentrations at baseline and at six and 12 months.

Baseline concentrations varied from 0.34 to 16.7 ng/mL, with higher levels in patients with more severe disease. For example, VEGF-D was higher in patients who needed supplemental oxygen (1.7 vs. 0.84 ng/mL, p<0.0001) and in those with a bronchodilator response (2.01 vs. 1.00 ng/mL, p=0.027).

Median baseline concentrations were similar in both groups. They dropped during the study in the sirolimus group, but remained stable in the placebo group. Between-group differences in concentration were significant at 6 months (p=0.0123) and 12 months (0.0047), the authors reported.

They also found that baseline log(VEGF-D) correlated negatively with the percentage change in FEV1 in individual patients in the placebo group and positively with the percentage change in FEV? in the sirolimus group.

Each one-unit increase in baseline log(VEGF-D) was associated with a 75 mL increase in FEV1 from baseline to 12 months in the sirolimus group and a 59 mL decrease in the placebo group (between-group comparison: p=0.0007). The same pattern was found for forced vital capacity (FVC).

Dr. Francis X. McCormack, who led the study and is a co-inventor on a patent for the use of VEGF-D as a diagnostic test, said serum VEGF-D readings could help doctors weigh the benefits and risks of sirolimus therapy in LAM patients. They might also reduce the number of patients needed for future clinical trials, he told Reuters Health by email.

"Our findings suggest that, when weighing the relative merits of initiating treatment or watchful waiting in a patient with LAM, a high VEGF-D concentration might tip the balance in favor of treatment because it portends an increased likelihood of therapeutic benefit in terms lung function, some measures of quality of life, and functional performance," said Dr. McCormack of the University of Cincinnati School of Medicine in Ohio.

In their paper, he and his colleagues point out: "Whether these results would apply to patients who were excluded from the trial (including those with FEV1 >70% of predicted, those with chylous complications impairing lung function, or those who have undergone lung transplantation) is unknown."

In an editorial, Dr. David Kwiatkowski at Brigham and Women's Hospital in Boston asks whether VEGF-D might be produced directly by LAM cells and could in fact be "a direct contributor to pathogenesis by causing lung parenchymal destruction through MMP (matrix metalloproteinase) enhancement?"

"Although not likely in my view, in this case VEGF-D might become not only a biomarker but also a therapeutic target in lymphangioleiomyomatosis," Dr. Kwiatkowski writes.


Lancet Resp Med 2013.


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