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Fibulin-3 biomarker may detect early-stage pleural mesothelioma
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Levels of fibulin-3 in plasma and effusions may determine the prognosis and diagnosis of pleural mesothelioma, according to results from a study.
New biomarkers and treatment strategies are needed to detect early-stage pleural mesothelioma, according to background information in the study.
For the study, researchers investigated whether fibulin-3 in plasma and pleural effusions could meet the sensitivity and specificity criteria for a robust biomarker.
Harvey I. Pass, MD, Stephen E. Banner professor of thoracic oncology at New York University Langone Medical Center, and researchers prospectively measured fibulin-3 levels at Wayne State University from 1998 to 2005 (Detroit cohort) and at New York University from 2005 to 2011 (New York cohort).
The Detroit cohort consisted of patients with mesothelioma (n=78), patients exposed to asbestos (n=41) and patients with effusions not due to mesothelioma (n=53).
The New York cohort consisted of patients with mesothelioma (n=64), patients exposed to asbestos (n=95) and patients with effusions not due to mesothelioma (n=40).
Researchers also evaluated 43 healthy controls.
Results from the trial found that plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure or degree of radiographic changes.
“The results of our study suggest that levels of fibulin-3 in plasma and effusions may aid in determining the diagnosis and prognosis of pleural mesothelioma,” Pass and colleagues wrote in the study.
Data results from the study indicated significantly higher plasma fibulin-3 levels in patients with pleural mesothelioma (105 ± 7 ng/mL) compared with asbestos-exposed patients without mesothelioma (14 ± 1 ng/mL) for the Detroit cohort. Results from the study indicated significantly higher plasma fibulin-3 levels in patients with pleural mesothelioma (113 ± 8 ng/mL) compared with asbestos-exposed patients without mesothelioma (24 ± 1 ng/mL; P<.001) for the New York cohort as well.
Data results from the study indicated significantly higher effusion fibulin-3 levels in patients with pleural mesothelioma (694 ± 37 ng/mL) compared with patients with effusions not due to mesothelioma (212 ± 25 ng/mL) for the Detroit cohort. For the New York cohort, results from the study indicated significantly higher effusion fibulin-3 levels in patients with pleural mesothelioma (636 ± 92 ng/mL) compared with patients with effusions not due to mesothelioma (151 ± 23 ng/mL; P<.001).
The receiver operating characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3/mL in an overall comparison of patients with and those without mesothelioma.
In a comparison of patients with early-stage mesothelioma with asbestos exposure, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46 ng of fibulin-3/mL, according to data results from the study.
“The specificity and sensitivity of fibulin-3 in discriminating between asbestos-exposed persons, as well as patients with effusions not due to mesothelioma and patients with mesothelioma are superior to those of other published markers and fibulin-3 levels are not influenced by the duration of asbestos exposure,” Pass and colleagues wrote in the study. “In addition, high levels of fibulin-3 in effusions have a high positive predictive value for the presence of mesothelioma and appear to reflect this prognosis.”
According to Pass and colleagues, future studies should explore why fibulin-3 is selectively elevated in mesothelioma compared with other cancers.
Disclosure: Pass is a board member, consultant and lecturer for and holds stock options with Champions Oncology, the International Association for the Study of Lung Cancer, Pinpoint Genomics, Rosetta Genomics, SomaLogic and others.
Perspective
Back to TopJames P. Stevenson, MD
This study is important in that it describes the first highly-sensitive and specific plasma and pleural effusion biomarker for pleural mesothelioma. Studies of other markers including soluble mesothelin-related protein (SMRP) and osteopontin did not show enough sensitivity/specificity to be considered “robust” biomarkers for mesothelioma. The authors do caution that while promising, these results need to be validated prospectively in future studies.
Does this mean we now have a screening test for mesothelioma, given the finding that fibulin-3 levels were not elevated in asbestos-exposed individuals who did not have mesothelioma? No. To have an effective screening test you must able to apply the test to a well-defined at-risk population. There are multiple, varied workplaces and occupations that were associated with asbestos use and exposure, and mesothelioma can develop in people who had both short and prolonged exposures (as well as family members who had indirect exposure through clothing, etc.). Also, the lag time between asbestos exposure and the development of mesothelioma is typically 20-50 years, raising the question of when to screen.
Another key to an effective screening test is that it must reduce deaths due to the condition in the population being studied, not just find it at an earlier stage or point in time. Pleural mesothelioma is rarely cured with aggressive surgical resection, even at earlier stages. Therefore, earlier diagnosis may not decrease mesothelioma-related mortality, and may only lead to lead-time bias, overdiagnosis, and overtreatment – all pitfalls to be avoided in screening. Even screening studies once considered to be “effective” in reducing cancer mortality – mammograms and PSA levels are now being questioned. A recent publication suggests that the reduction in breast cancer mortality since the 1970’s is the result of improved treatments, not screening mammography. Establishing fibulin-3 as an effective screening test for mesothelioma in an unselected group of asbestos-exposed individuals seems unlikely.
Despite this, the fibulin-3 test could be effective in helping to establish a diagnosis of mesothelioma in patients with pleural effusions – mesothelioma cells are often not detected in effusion samples from patients, and the diagnosis can be missed despite multiple thoracenteses. Even invasive pleural biopsies are not 100% sensitive in making the diagnosis as there can be discontinuous areas of disease. Discriminating mesothelioma from other tumor types such as non-small cell lung cancer is also frequently difficult, even in the hands of experienced pathologists – the finding that fibulin-3 levels were higher in mesothelioma patients compared to those with other cancers also suggests that it could be an adjunct in confirming a diagnosis of mesothelioma, which impacts not only treatment planning, but also the ability of a patient/family to recover legal compensation.
Fibulin-3 may also have promise as a biomarker to measure disease activity when patients are monitored after surgery/off treatment or in determining the effectiveness of treatments such as chemotherapy – measuring improvement or disease progression on imaging studies such as CT scans is uniquely difficult in pleural mesothelioma due to disease location and inability to reproducibly apply tumor measurements such as RECIST. SMRP has shown some promise here however it is not routinely used even at large mesothelioma treatment centers. Lastly, but perhaps most importantly, gaining more insight into the function of fibulin-3 and its role in the growth and progression of mesothelioma may lead to targets for drug development and ultimately more effective therapies for this disease, which are desperately needed.
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