Asbestos-related cancers like mesothelioma are especially deadly: after diagnosis, patients usually only live 8 to 18 months, as fibrotic plaques cover their lungs and invade their chest cavity. In almost all cases, patients with mesothelioma can trace the origins of their cancer to occupational exposures such as manufacturing or installing insulation, shipbuilding, or other occupations where they handled asbestos-rich materials on a routine basis. Since fewer than 5% of mesothelioma cases are detected early, clinicians in “hot spots” where mesothelioma clusters have grown around industrial and shipbuilding centers have long hoped for a way to target patients in the earliest stages, when therapy might be beneficial and ease the suffering of this cancer. Years of research have indicated that a protein called osteopontin—a glycoprotein secreted by many cell types including osteoblasts and activated T cells—might be a promising biomarker for early detection. Strategies examines recent osteopontin research profiled in the New England Journal of Medicine, and what’s next for early detection of mesothelioma.
For over 15 years, Harvey Pass, MD, Chief of the Division of Thoracic Surgery and Thoracic Oncology at the New York University School of Medicine has been researching mesothelioma and storing away mesothelioma samples. As his research began to include more of a genomic angle, he began to search for a biomarker for mesothelioma. His recent research, published in the Oct. 13th issue of the New England Journal of Medicine, suggests that the protein osteopontin might be an early indicator of this type of cancer, which is typically found in clusters such as around Boston, Mass.; Baltimore, Md.; and Hampton Roads, Va., where shipbuilding was formerly a major industry and employment source. More recently, Pass has been working with researchers at the Center for Asbestos Related Disease (CARD) in Libby, Montana, where a vermiculate mine operated from the 1920s to 1991.
“This vermiculite ore is contaminated with asbestos,” explained Pass. “When you process this, the asbestos gets released, which is a problem.” Over the past 30 or 40 years, Libby has had 24 cases of mesothelioma in a community whose population is currently 7,500. The usual occurrence for mesothelioma is 1 in 150,000.
“Mesothelioma is a very deadly cancer, few people survive it,” explained Brad Black, MD, one of CARD’s directors. It’s almost uniformly fatal. Usually we don’t diagnose it until it’s in an advanced stage where the tumor mass is large, but by the time that hits, there’s very little effective therapy. Like most cancers we find, if we have early detection and early treatment, we have a much better chance for an effective cure.”
Good Discriminatory Potential
In this recent study, Pass compared specimens in his serum bank from 193 patients: 69 who had asbestos-related non-malignant diseases, 45 who were current or former smokers who had no previous exposure to asbestos, and 79 patients who were in various stages of mesothelioma and were undergoing surgery. “These were patients who I operated on, so I knew exactly what their stages were,” said Pass. “We did some receiver operating curves (ROC) and found that the ROC for all of the diagnosed patients compared to the 69 controls was about .89, which is a terrific area under the curve. This tells us that this is a pretty good discriminatory marker.”
Pass and his colleagues also compared the osteopontin levels in relation to the duration of asbestos exposure, and found that the higher the duration, the higher the osteopontin level, and these levels also rose as X-rays showed more radiographic changes. “There was also a real jump, say from a level of 60 to 130, once you look at the worst X-ray picture and then the Stage I mesothelioma image,” explained Pass. “I think what this is saying is that osteopontin is percolating in the pathogenesis pathways as its brewing. Then it gets excreted and can be measured, so there’s the potential to take high-risk people who are characterized by their asbestos exposure and their scan characteristics, and concentrate on them for your screenings, so you can do it in an economically feasible and robust manner and hopefully predict which ones are the patients who are brewing mesothelioma.”
While osteopontin certainly shows promise for a diagnostic test, Pass believes that the marker needs to be validated, and the range levels in high risk populations need to be defined. Through a grant from the National Cancer Institute’s Early Detection Research Network, Pass will be working with Black and other CARD researchers to determine these range values and further validate this prospective marker by analyzing specimens from Libby patients.
Osteopontin is also being evaluated by Fujirebio Diagnostics (Malvern, Pa.), who licensed a research assay based on Pass’ research when he was at Wayne State University (Detroit, Mich.). In March 2006, Fujirebio will begin a multicenter prospective trail looking at how a research form of an osteopontin assay performs in differential diagnosis of lung cancer and mesothelioma, explained Vice President and Chief Scientific Officer Jeff Allard, PhD., who added that the company has not yet committed to developing a commercial assay.
“If we could validate this marker, that would give us some hope and help us find out if it’s accurate in predicting mesothelioma,” said CARD’s Black. “It certainly has the appearance that it does, but it’s only been studied in a smaller population. By expanding it to our 1,000 participants, we think we could gather enough information about the marker to make it a valuable tool.”
Julie McDowell is the Editor of Strategies. She can be reached by email.