Bronchial/Nasal Gene-Expression Tests for Early Detection of Lung Cancer
Boston, MA—Diagnosing lung cancer by swabbing a patient’s nose may be possible in the not-too-distant future. Changes in nasal gene expression in patients with lung cancer have been found to correlate with changes in gene expression in the bronchus, opening the door to the possibility of nasal gene expression as an early diagnostic biomarker of lung cancer, said Avrum Spira, MD, MSc, Director, Translational Bioinformatics Program, Boston University Clinical and Translational Science Institute.
“What’s in the nose may be a very good surrogate for what’s going on deeper within your lung,” Dr Spira said at the Second Global Biomarkers Consortium annual conference.
Evolving Biomarkers for Lung Cancer Diagnosis
Because the discovery of molecular biomarkers has not yet resulted in cures with the use of targeted therapies, efforts should be directed toward early detection and screening. Currently, fewer than 1 of 5 patients with lung cancer is diagnosed at stage I, a potentially curable stage, and a similarly small proportion is alive 5 years after their diagnosis, Dr Spira said.
The vast majority of lung cancers occur in persons with a history of tobacco smoke exposure, but only 10% to 15% of smokers will develop lung cancer during their lifetime. The challenge, said Dr Spira, is how to identify the high-risk subset.
The National Lung Screening Trial (NLST) was a landmark study that found that annual computed tomography (CT) scans of the lung in asymptomatic smokers reduced lung cancer mortality by 20%. By the inclusion criteria used in the NLST (ie, age >50 years, >30 pack-years of smoking), approximately 9 million individuals in the United States would be eligible for screening; however, only 50% of lung cancers occur in this population, Dr Spira said, creating a need for molecular biomarkers to personalize lung cancer screening decisions.
“I would argue that the second and more urgent need right now is developing biomarkers that can distinguish a benign lesion from a malignancy that’s found on routine CT screening,” said Dr Spira. “CT screening is incredibly sensitive, but has a very high false-positive rate…leading to a lot of unnecessary invasive procedures.”
Numerous molecular biomarkers are in development. “In the next 3 to 5 years, a number of them are going to be emerging in the clinic to guide both screening and diagnostic decisions in this setting,” Dr Spira said.
A bronchial airway gene-expression biomarker will be available as a Clinical Laboratory Improvement Amendments (CLIA) test in early 2014. “We’re in the process of extending that same type of biomarker into nasal epithelium so that we have less invasive sampling and the ability to go into the screening setting,” Dr Spira said.
“Field of Injury” Paradigm
The bronchial biomarkers are based on the “field of injury” paradigm that smoking alters epithelial gene expression through the respiratory tract, and that variability in airway epithelial-cell genomic response to and damage from smoking are linked to lung cancer.
The sensitivity of bronchoscopy for diagnosing lung cancer is only 50% to 60%, and is even lower in the early stages of lung cancer. Many bronchoscopies are therefore nondiagnostic, in which case gene-expression information can be used to select patients for biopsy and patients who can be noninvasively monitored with repeat imaging studies.
In Dr Spira’s work as founder of Allegro Diagnostics, an 80-gene biomarker profile was identified that could distinguish between smokers who do and do not have lung cancer.
The 80 gene-expression biomarker has been validated in 2 independent cohorts, with an 80% sensitivity and specificity for lung cancer. “More important, if we combine our gene-expression biomarker with the routine cytology collected at bronchoscopy, you get 95% sensitivity and 95% negative predictive value,” Dr Spira said. “So we can almost, not quite but almost, rule out lung cancer.”
Based on successful validation, the BronchoGen gene-expression test will be launched as a CLIA assay in 2014. A clinical validation study of smokers undergoing bronchoscopy for suspected lung cancer is ongoing. Data from the first 350 patients show an area under the curve (AUC) of 0.77 in distinguishing cancer from noncancerous nodules, and a negative predictive value of approximately 90%. The sensitivity of BronchoGen for nodules that are <3 cm and for stage I disease was 88% compared with 66% for bronchoscopy, and the sensitivity for stage I and II diseases was 86% compared with only 40% for bronchoscopy. When the biomarker test was combined with bronchoscopy, the sensitivities increased to 96% and 93%, respectively.
Early data suggest that airway gene-expression alterations precede the development of lung cancer in high-risk smokers with dysplasia, making intervention in the preventive setting a possibility. In a phase 1 chemoprevention trial, P13K gene-expression alterations were reversible with the administration of myo-inositol.
Further research has extended the field of injury to the upper airway. RNA obtained from nasal mucosal brushings has been used to demonstrate that the gene-expression changes in the nasal epithelium reflect the changes observed in the bronchial epithelium in smokers. In a diagnostic trial funded by Allegro, cells are being collected from the bronchus and nasal epithelium; microarray analysis is being performed to identify biomarkers in the nose in an attempt to diagnose lung cancer. From the first 100 patients, 60 genes were found to be altered in patients with lung cancer compared with patients without lung cancer.
“Those genes that change in your nose when you have lung cancer change in almost the identical matter in your bronchus,” said Dr Spira.
A nasal gene-expression biomarker has since been developed. From a training set of 100 patients, a 5-gene nasal biomarker yielded the maximum AUC (ie, 0.74). The biomarker was tested on 84 independent samples, achieving a 0.71 AUC. “It’s not quite as good as what we’ve seen in the bronchial airways, but there’s still a relatively good signal-to-noise ratio for lung cancer diagnosis,” Dr Spira said.
In the clinical workflow, he envisions the nasal test being used in patients who have a very small lung lesion on CT that would not undergo bronchoscopy. “A more important place for the nasal testing is as a screening tool, upstream of CT,” Dr Spira said. “It might be used to decide who should get annual CTs of their chest. The most exciting potential unmet need is to stratify high-risk smokers, not simply to a CT screening protocol, but also into chemoprevention trials.”