Seattle-based Indi (Integrated Diagnostics) has announced publication in the Journal of Thoracic Oncology (JTO) reporting positive results from a landmark clinical trial that confirms the firm’s Xpresys Lung laboratory-based molecular blood test service for non-invasive, objective assessment of pulmonary nodules, helps identify benign nodules with high probability — can allow potential avoidance of unnecessary invasive lung cancer testing and reduced anxiety for patients. Consequently, when combined with the current standard of care, Xpresys Lung may be able to help reduce unnecessary invasive procedures, improve patient outcomes, reduce complications, and lessen the healthcare system cost burden. Currently, patients whose nodules are initially deemed likely benign are generally followed up by CT scans performed over a two-year interval. If the clinician’s initial assessment of the patient’s lung nodule is later found incorrect, the cancers are usually discovered early enough in the follow-up period for therapeutic intervention. Conversely, when a physicians initially assesses a patient’s nodule as indicating a higher lung cancer probability, he or she will order biopsies or surgeries to identify cancer — invasive procedures that often end up identifying the nodules as benign or turn out to be non-diagnostic.
The 2013 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines cite data showing a false negative rate for biopsies of 10 to 70 percent — and that even surgeries have a somewhat horrendous false positive rate of 18 to 34 percent — metrics suggesting the tens of thousands of patients are undergoing unnecessary invasive, dangerous, and costly procedures on benign nodules each year.
“Each year in the U.S. alone, approximately 3,000,000 people present with lung nodules; over a half a million fall into the indeterminate range,” says Indi CEO Albert A. Luderer, Ph.D.. “Current estimates suggest the majority of these nodules turn out to be benign. Xpresys Lung is designed to reduce the risks and costs these patients face by allowing more pulmonologists to diagnose their patients as likely benign. Today’s research makes a strong case for expanded access to Xpresys Lung as a tool to help reduce over-treatment, lower costs and risks, and aid in reducing patient anxiety.”
The research findings, published online before print by the JTO, show that when the Xpresys Lung test indicates likelihood of a nodule being benign, that assessment will be correct in 84 percent to 98 percent of test incidences — and each nodule will receive its own individual score based on its molecular signature.
This result reprises the Xpresys Lung test’s performance demonstrated in earlier research published in Science Translational Medicine. In October, 2014 Indi announced that the company has secured contractual agreements with MultiPlan and five other PPOs (preferred provider organizations) for Xpresys Lung, the other PPOs being: FedMed, Fortified Provider Network, InterWest Health, Stratose, and Three Rivers Provider Network. Together, these managed care organizations cover more than 130 million insured lives; which, combined with Indi’s existing commercial insurance contracts, means that well over 200 million insured individuals are under managed care contracts providing access to Xpresys Lung.
“These contracts demonstrate the game-changing clinical and economic value that Xpresys Lung offers,” says Dr. Luderer. “Indi’s test is designed to help physicians more confidently identify lung nodules as likely benign, reducing the need for unnecessary invasive procedures and their attendant risks, saving money, and lowering patient anxiety. We are confident the cost savings associated with Xpresys Lung will assist with the efforts of providers and carriers to secure ‘pay-for-performance’ incentives under the Affordable Care Act.”
The paper published in the Journal of Thoracic Oncology entitled “Validation of a Multi-Protein Plasma Classifier to Identify Benign Lung Nodules” (JTO: January 14, 2015 doi: 10.1097/JTO.0000000000000447) is coauthored by Anil Vachani, Harvey I. Pass, William N. Rom, David E. Midthun,Eric S. Edell, Michel Laviolette, Xiao-Jun Li, Pui-Yee Fong, Stephen W. Hunsucker, Clive Hayward, Peter J. Mazzone, David K. Madtes, York E. Miller, Michael G. Walker, Jing Shi, Paul Kearney, Kenneth C. Fang, and Pierre P. Massion, who note that indeterminate pulmonary nodules (IPNs) lack clinical or radiographic features of benign etiologies and consequently often precipitate the employment of unnecessarily invasive procedures, suggesting potential roles for diagnostic alternatives using molecular biomarkers. The primary objective of their study was to validate whether a multivariate classifier that identifies likely benign lung nodules by assaying plasma protein expression levels, would yield a probability estimate range based on high negative predictive values (NPVs) for patients with 8 to 30 mm IPNs.
They report that this study was performed using a highly sensitive analytic technique called multiple reaction monitoring mass spectroscopy (MRM-mass spec), a classifier comprising five diagnostic and six normalization proteins in a blinded analysis of an independent validation set of plasma samples. The trial was structured as a retrospective, multi-center, case-control analysis of 141 blood samples from patients 40 years or older with lung-nodules ranging from eight to 30 mm in diameter. Researchers used the classifier, Xpresys Lung, which comprises five diagnostic proteins from multiple pathways associated with lung cancer and six normalization proteins, in a blind analysis of these independent plasma samples. The test measures the relative abundance of these proteins using a highly sensitive analytic technique called multiple reaction monitoring mass spectroscopy (MRM-mass spec).
All study samples were from patients with either benign nodules or early-stage non-small cell lung cancer (NSCLC), that were matched for nodule size, age, gender and clinical location. A sample-matching strategy yielded classifier scores for the overall subject cohort, results of which are statistically independent of the patient’s age, tobacco use history, chronic obstructive pulmonary disease (COPD) diagnosis, or nodule size. Consequently, data from the resulting classifier offers potential to complement the various risk factors that are currently used in clinically assessing lung nodules. The Xpresys Lung classifier also demonstrated incremental diagnostic performance in combination with a four-parameter clinical model.
“Strengths of the study include the use of independent samples from geographically dispersed centers with diverse patient populations, including two not participating in the classifier’s discovery studies,” says Pierre P. Massion, M.D. , the Ingram Professor of Cancer Research at Vanderbilt University Medical Center in Nashville, Tennessee, another of the study’s principal investigators and a senior coauthor of the JTO paper. The current research focus of Dr. Massion’s lab is on early lung cancer detection with emphasis is on lung tumorigenesis, on using genomic and proteomic approaches to identify molecular markers of lung neoplasia, and to test those in multidisciplinary early detection strategies. The lab team uses new genetic discovery strategies including microarray (genomic, cDNA and tissue) and cytogenetics to identify new molecular markers of lung cancer.
The paper’s coauthors conclude that: “this proteomic classifier provides a range of probability estimates for the likelihood of a benign etiology that may serve as a non-invasive, diagnostic adjunct for clinical assessments of patients with IPNs.”
“It is widely understood that a large percentage of patients with indeterminate lung nodules undergo unnecessary invasive testing due to the difficulty of diagnosing these nodules with current protocols,” says Anil Vachani, M.D., Director of Clinical Research, Interventional Pulmonary Services, and an Assistant Professor of Medicine at the Hospital of the University of Pennsylvania and the Veteran’s Administration Medical Center, and lead author of the JTO study. “This is the first clinical validation study of a non-invasive tool that physicians can use to aid diagnosis of these patients — who are often taken on a diagnostic odyssey that may include procedures such as lung biopsies and even surgery. The study results suggest this classifier may be an important new tool for pulmonologists seeking to identify which indeterminate nodules are benign.”
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Journal of Thoracic Oncology