Evaluation of gene expression in normal upper airway cells of current and former smokers with suspected lung cancer may be helpful in improving the accuracy of bronchoscopy diagnosis, possibly reducing the need for invasive biopsies, According to a new study published in the New England Journal of Medicine (NEJM).
Doctors often use bronchoscopy to further evaluate possible cancerous lesions in the lung identified by CT scans. Although this procedure is relatively safe, it often cannot produce a definitive diagnosis because the instrument does not reach certain areas of the lung. In these cases, an invasive (surgical or needle) biopsy may be needed. But these procedures carry the risk of complications and some investigators have reported that more than a quarter of people undergoing lung biopsy result in benign lesions.
In an effort to help solve this problem, researchers looked at normal bronchial cells in the upper airways by taking advantage of the concept of “area of injury,” explained the study’s lead investigator, Dr. Avrum Spira, of the Faculty of Medicine of Boston University . When a person smokes, all cells in their airways are exposed to tobacco smoke, which causes damage to the DNA. An obvious pattern of DNA damage can be seen in the epithelial cells of smokers who develop lung cancer, according to Dr. Spira and his colleagues in a 2007 study.
Patterns of DNA damage in normal upper airway cells are like the “canary in the coal mine,” he explained in an interview.
Based on differences in the pattern of DNA damage, the researchers designed a distinctive gene expression-a genomic classifier-that could be used to screen normal bronchial airway cells obtained during a bronchoscopy to detect the presence of tumors within the Lungs. In the NEJM study, they applied the results of an earlier study and showed that “the classifier works in real-world clinical settings,” Dr. Spira said.
The study, which was funded in part by the Research Network for Early Detection NCI ( NCI’s Early Detection Research Network ), enrolled 639 current adult smokers and former smokers who were participating in two clinical studies: AEGIS 1 and AEGIS 2 . All patients underwent bronchoscopy due to suspected lung cancer, and a brush was used to collect epithelial cells from the main bronchus of the airway during bronchoscopy. The gene expression patterns of the epithelial cells were analyzed and the patients were followed up until a diagnosis was made or for 12 months after bronchoscopy. A total of 487 patients were found to have lung cancer.
The researchers found that a diagnosis could not be made in 272 patients with only the use of bronchoscopy. Of the patients who underwent a bronchoscopy that did not facilitate the diagnosis, 170 underwent invasive procedures to obtain a diagnosis (including surgery in 76 patients), 52 of whom were finally diagnosed with benign lung lesions.
The researchers also evaluated the sensitivity and specificity of bronchoscopy along with the classifier, because an accurate diagnostic test not only detects most of the cancers that are present (sensitivity) but also has a low chance of incorrectly indicating cancer in someone who does not have it (specificity).
Overall, the sensitivity of bronchoscopy along with the classifier was 97 percent compared to 75 for bronchoscopy alone. The sensitivity of the combined test was highly uniform in terms of nodule size, location and stage or type of cancer, the researchers report.
The genomic classifier incorrectly indicated cancer in 53 percent of people who did not have lung cancer. Although the test has a high index of false positive results, when both the bronchoscopy and the classifier were negative, the probability of the patient having cancer was reduced.
A negative test result can guide medical management and eliminate unnecessary invasive biopsies that may carry the risk of complications as well as costs to the health care system, Dr. Spira said. “A negative test gives peace of mind,” he explained.
One limitation of the study is to be assessed only in patients who had wide suspicion that had cancer, said Barry Kramer, MD, MPH, director of the Division of Cancer Prevention NCI ( NCI’s Division of Cancer Prevention ). “The report does not tell us how this would be in a real screening environment,” continued Dr. Kramer. “The prevalence of cancer in the two cohorts is 74 percent and 75 percent, much higher than in a general population of smokers or former cigarette smokers who have been tested, even with abnormalities detected on a chest computed tomography of low dose.
This is the first time that a genomic classifier for lung cancer in high-risk cohorts has been created and validated, said Sudhir Srivastava, Ph.D., MPH, head of the cancer biomarkers research group in the Division of Prevention Of NCI Cancer. The study, he continued, “provides greater support for the design of a similar approach for screening in an asymptomatic population.”
Initially, the test-known commercially as Percepta Bronchial Genomic Classifier-will be available in 30 to 40 medical centers as part of an early access program before it is more widely available, according to Veracyte, the company that produces the test.
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