Biomarkers to improve clinical assessment of indeterminate lung nodules

2011

Early Detection Award

York Miller, MD

University of Colorado Denver, AMC and DC

Aurora

Wilbur Franklin, MD

University of Colorado Denver, AMC and DC

Aurora

Kavita Garg, MD

University of Colorado Denver, AMC and DC

Aurora

Computed tomography (CT) has a high false-positive rate. Less than 5% of people with nodules found through CT actually have lung cancer. Cells from benign nodules differ from malignant ones in two ways: they have a normal number of chromosomes and they make the same proteins as normal lung cells. Dr. York Miller is taking advantage of these differences. His team is developing a sputum-based test to determine whether a nodule is malignant or benign. The test will help decide whether the nodule requires follow-up.

Research Summary

Lung cancer is the leading cause of cancer death in the world and has a dismal 16% 5 year survival rate. One reason for this discouraging statistic is that until recently, no early detection test had been validated. The National Lung Screening Trial (NLST) has recently demonstrated that CT screening results in a 20.3% decrease in lung cancer mortality compared to chest radiograph screening. It is now clear that CT scans will be increasingly used for lung cancer screening.

CT scans detect lung nodules in 20-50% of patients, while only 1-2% have lung cancer. Thus, CT scanning has low specificity (many false positive tests) for lung cancer. Patients and physicians are often put in the situation of having to decide between serial CT scans to look for nodule enlargement (which takes months) or an immediate biopsy strategy. Each approach has potential drawbacks: serial observation can result in delay in diagnosis and an immediate biopsy strategy can lead to unnecessary morbidity and expense. Biomarker based testing to determine risk for lung cancer is not currently available, but would be invaluable in aiding clinical decision making in this setting.

We propose to further refine and validate two promising risk biomarkers, abnormal chromosome numbers in sputum cells and a blood test assessing multiple bioactive proteins as guides to clinical decision making for patients and physicians confronted with indeterminate lung nodules and compare their performance to prediction models based on nodule and patient characteristics.

Technical Abstract

The overarching concept guiding our work is that combinations of biomarkers and imaging characteristics will be most robust in predicting which patients with lung nodules should receive an aggressive diagnostic and/or therapeutic approach and which patients should be monitored for nodule stability over time. Our objectives are to improve two biomarker tests that already have shown significant promise-- sputum chromosomal aneusomy by fluorescence in situ hybridization (CA-FISH) and the analysis of multiple serum analytes by a highly multiplexed aptamer-based assay developed by SomaLogic, Inc.-- and then to compare test performance with predictive models based on nodule and patient characteristics. These objectives are based on two separate hypotheses: 1. The current CA-FISH assay panel can be further improved by the development of two sub-panels, one for detection of squamous cell carcinoma of the lung (SCC) and the second for the detection of adenocarcinoma of the lung (AC). 2. The current aptamer-based analysis can be further improved by developing separate assays specifically designed for the detection of AC, SCC, K-ras, and EGFR-mutated lung tumors. The assays will then be applied to sputum and blood specimens from the Pittsburgh SPORE Pittsburgh Lung Screening Study (PLuSS) and Colorado SPORE Lung Nodule cohorts, in concert with analysis of the CT characteristics of the corresponding lung nodules, including size, volume, density, location, or airway involvement, to compare test performances and to assess whether combining tests would be valuable.

Key words

Adenocarcinoma

Biomarker or biomarker testing

Early detection

Epidermal growth factor receptor (EGFR)

KRAS

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Squamous cell lung cancer

Stage I

Stage II