SEATTLE (FRONTLINE MEDICAL NEWS) – A new biomarker for bronchial epithelium that helps identify smokers with suspicious lesions who have lung cancer is now ready for clinical use. And one for nasal epithelium that could be used for screening may not be far behind.

“There is clearly a critical unmet need to develop molecular biomarkers to address some of the challenges that we now face since we have instituted CT screening for lung cancer,” Dr. Avi Spira said at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Although the National Lung Screening Trial established that annual chest CT among high-risk current and former smokers reduces their risk of death from lung cancer (N Engl J Med. 2011;365:395-409), the vast majority of those who screen positive do not have lung cancer. Also, screening only patients who meet criteria set by the trial will pick up less than half of all lung cancers in the United States.

“That leads to two critical unmet needs for molecular biomarkers in the so-called post–National Lung Screening Trial era,” said Dr. Spira, professor of medicine, pathology and laboratory medicine, and bioinformatics; chief of the division of computational biomedicine; and director of the translational bioinformatics program, Clinical and Translational Science Institute, all at Boston University.

“The first is … we desperately need molecular biomarkers that can distinguish a benign nodule found on CT versus a malignant one,” he said. “The second and arguably longer-term biomarker that we need is to distinguish which smokers would benefit from CT screening annually.”

Much of his team’s research in this area builds on the concept of field of injury. “The idea here is if you smoke, even though lung cancer tends to develop deep within the parenchyma of your lung, all of the epithelial cells that line your respiratory tract have genomic alterations that reflect the presence of that cancer,” Dr. Spira explained. Thus, profiling epithelial cells anywhere in the airway could be used for early detection and risk assessment.

He and his colleagues developed a 23-gene signature for use on bronchial epithelial cells. The biomarker was validated in the Airway Epithelium Gene Expression In the Diagnosis of Lung Cancer (AEGIS) 1 and 2 trials among 639 current and former smokers undergoing bronchoscopy for suspicious nodules seen on CT.

With 1 year of follow-up, biomarker sensitivity was 88%-89%, while specificity was 47% (N Engl J Med. 2015;373:243-251). “However the negative predictive value, which is really what drives the clinical utility of this test, is above 90%. And that’s what we believe will drive physicians to use the test – [determining] who can they avoid sending for an unnecessary [biopsy] procedure,” Dr. Spira said. Bronchoscopy alone had sensitivity of about 75%, but bronchoscopy combined with the gene signature had sensitivity of 97%.

Subgroup analyses showed the biomarker had superior sensitivity for detecting lung cancer when lesions measured no more than 3 cm or were located in the lung periphery, and when patients had early-stage disease. In addition, it performed similarly well across different types of tumors.

Of special note, among patients whose pretest probability of cancer fell in the intermediate range (10%-60%), bronchoscopy had an 83% nondiagnostic rate, but the biomarker had 88% sensitivity and a 91% negative predictive value. “That means if you have a nondiagnostic bronchoscopy in a patient who is at intermediate pretest risk for disease, a negative gene expression test would mean there is a less than 10% chance this is cancer. That’s where a physician might feel, okay, I don’t have to go on and do a biopsy, I can watch that patient serially with CT scans of the chest,” Dr. Spira said.

The biomarker test is now clinically available (Percepta, manufactured by Veracyte). “I think it’s exciting because it’s the first of what I believe are many molecular biomarkers that are going to be emerging in the clinical space for the early detection of lung cancer,” he said.

“The multimillion dollar question is why are we seeing gene expression changes in normal-appearing cells so far away from where the tumor arises? We don’t have the full answer to that yet, but based on the genes that are changing, we have developed some hypotheses,” Dr. Spira said.

Some of the down-regulated genes are involved in antioxidant and DNA repair pathways, suggesting that the smokers who ultimately get cancer have less of a protective response to smoking. And some of the up-regulated genes include ones in the PI3 kinase signaling pathway.

“I would argue that what we are seeing in the proximal airway isn’t necessarily reflecting the presence of the cancer but the susceptibility, and that’s a really important distinguishing factor because then perhaps the test could be used as a screening tool,” Dr. Spira maintained.

As not all smokers at elevated risk for lung cancer will undergo bronchoscopy, one of the investigators’ future goals is to move biomarker testing to a less invasive site. They are currently focusing on the nose, using nasal epithelium collected by brushings from the inferior turbinate.

An analysis of nasal epithelium collected at the time of bronchoscopy in the AEGIS trials has shown that a 200-gene signature performs well for distinguishing between patients with and without lung cancer, Dr. Spira reported. Furthermore, the changes in gene expression profile in the nose were similar to those seen in the bronchus.

Such a biomarker might have best clinical utility in two other settings, he proposed. The first would be in patients having nodules that are clearly not accessible by bronchoscopy, in which case the biomarker would be applied for diagnosis. The second would be in smokers being seen for routine annual exams, in which case it would be used to identify those who should have CT surveillance.

“We are hopeful that the nasal epithelium can serve as a less invasive surrogate for the bronchus and ultimately allow us to move airway profiling into the screening setting for lung cancer in the longer term,” he concluded.

Dr. Spira disclosed that he receives intellectual property rights and consulting fees from, and has an ownership interest in, Veracyte Inc.