Lung Cancer Biomarker May Increase Sensitivity of Bronchoscopy

Allison Gandey

March 07, 2007

March 7, 2007 — Researchers have identified an 80-gene biomarker to help in the early detection of lung cancer. Prolonging bronchoscopy by only about 5 minutes, the new biomarker is designed to help evaluate smokers suspected of having cancer. But the group, in a study published online March 4 in Nature Medicine, says it hopes the biomarker will one day prove to be an effective stand-alone screening tool.

During an interview with Medscape, lead author Avrum Spira, MD, from Boston University Medical Center, in Massachusetts, predicted that the test, coupled with bronchoscopy, is about 1 or 2 years from the clinic and, as an independent screening method, perhaps about 10 years away.

"In our current study, we piggybacked our test on top of the standard clinical procedure, but ideally, moving forward, we want to move to a less-invasive site such as the nose or throat. That's the direction we are going with this," he said. "Just like in colon cancer, we know that screening is effective, but people don't like the colonoscopy and often are not examined as regularly as they should be. In lung cancer, we hope to develop a method that will be less invasive than the current standard bronchoscopy."

The investigators recruited more than 200 current and former smokers undergoing flexible bronchoscopy. Participants were from 4 institutions, including Boston University Medical Center, the Boston Veterans Administration, the Lahey Clinic, and St. James’s Hospital.

The researchers explain in their paper that cigarette smoke creates a field of injury in all airway epithelial cells exposed to it. Previous studies have shown that noncancerous large-airway epithelial cells of smokers with and without lung cancer exhibit allelic loss, p53 mutations, changes in promoter methylation, and increased telomerase activity. Using DNA microarrays, Dr. Spira and colleagues recently reported on smoking-induced changes in the gene expression of large-airway epithelial cells obtained during bronchoscopy from nonsmokers and from current and former smokers without lung cancer.

"These studies led us to question whether profiles of gene expression in large-airway epithelial cells could provide insights into how individual smokers differ in their responses to cigarette smoke and whether such profiling might detect smokers in whom the mutagenic effects of cigarette smoke have resulted in lung cancer — given that only 10% to15% of smokers develop lung cancer," they write. A diagnostic using this approach might eliminate the need for additional tests that are costly, incur risk, and prolong the evaluation of suspected lung cancer patients.

Combined Cytopathology and Gene-Expression Biomarker May Reduce Need for Further Invasive Testing

In the present analysis, patients underwent routine diagnostic bronchoscopy. The research team obtained bronchial airway epithelial cells from the uninvolved right main-stem bronchus with an endoscopic cytobrush. If they observed a suspicious lesion in the right main-stem bronchus, the researchers collected brushings from the uninvolved left main-stem bronchus.

Patients were classified as having lung cancer if their bronchoscopy or subsequent lung biopsy showed lung tumor cells. Participants were considered to be cancer free if their bronchoscopy or subsequent lung biopsy yielded a non–lung-cancer pathology or if their radiographic abnormality resolved on follow-up chest imaging.

Dr. Spira and his team found that combining cytopathology with the gene-expression biomarker improves the diagnostic sensitivity of the overall bronchoscopy procedure from 53% to95%. "In the setting of our study, where disease prevalence was 50%, a negative bronchoscopy and negative biomarker for lung cancer resulted in a 95% negative predictive value, potentially allowing these individuals to be followed nonaggressively with serial imaging studies," the group reports.

For individuals with a negative bronchoscopy and positive gene-expression signature, the positive predictive value was about 70%, and these individuals would probably require further invasive testing to confirm the presumptive lung cancer diagnosis, they explain. "However, compared with bronchoscopy alone, the strong negative predictive value of the combined cytopathology and gene-expression biomarker test should substantially reduce the number of individuals requiring further invasive diagnostic testing."

"What is exciting about this is that we are not sampling the tumor itself," Dr. Spira told Medscape. "This is a canary-in-the-coal-mine approach, and it's a powerful concept that is being adopted in a variety of cancers."

Nat Med. Published online before print March 4, 2007.

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