Clinical Utility of Chromosomal Aneusomy in Individuals at High Risk of Lung Cancer

Abstract

Introduction Low dose CT screening for lung cancer has a high false positive rate with frequent discovery of indeterminate pulmonary nodules. Noninvasive biomarkers are needed to reduce false positives and improve risk stratification. A retrospective longitudinal evaluation was performed to assess chromosomal aneusomy in sputum via fluorescence in situ hybridization (CA-FISH) in four nested case-control studies. Methods ROC analysis resulted in two grouped cohorts: High Risk (CO High Risk and CO Nodule; 68 Cases, 69 controls) and Screening (ACRIN/NLST and PLuSS; 97 Cases, 185 controls). The CA-FISH assay was a 4-target DNA panel encompassing EGFR and MYC genes, and the 5p15 and centromere 6 regions or the FGFR1 and PIK3CA genes. A 4-category scale: normal, probably normal, probably abnormal and abnormal was applied. Sensitivity, specificity, and positive and negative likelihood ratios (LR+, LR−) (with 95% CI) were estimated for each cohort. Results Sensitivity and specificity were, respectively, 0.67 (0.55, 0.78) and 0.94 (0.85, 0.98) for High Risk subjects and 0.20 (0.13, 0.30) and 0.84 (0.78, 0.89) for Screening subjects. LR+ and LR− were, respectively, 11.66 (4.44, 30.63) and 0.34 (0.24, 0.48) for High Risk; and 1.36 (0.81, 2.28) and 0.93 (0.83, 1.05) for Screening subjects. Conclusion The high positive likelihood ratio of sputum CA-FISH indicates it could be a useful adjunct to LDCT for lung cancer in high risk settings. For screening, however, its low positive likelihood ratio limits clinical utility. Prospective assessment of CA-FISH in the incidentally-identified indeterminate nodule setting is ongoing in the Colorado Pulmonary Nodule Biomarker Trial.

Colorectal cancer with indeterminate pulmonary nodules

“…The sensitivity and specificity in two cohorts were 82.09%, 88.41% and 80.52%, 86.08%, respectively [70]. Besides, other potential biomarkers, such as circulating tumor cells (FR+-CTCs), sputum CA-FISH, plasma biomarker panel, angiogenesis biomarkers (heparin-binding epidermal growth factor (HBEGF), epidermal growth factor (EGF), vascular (V) EGF-A, VEGF-C, and VEGF-D) and autoantibodies (p53, CAGE, NYESO-1, GBU4-5, SOX2, MAGE A4, and Hu-D) have also been reported in previous studies [71][72][73][74][75]. However, the selection of the perfect biomarker from various others makes clinicians confused.…”

Noninvasive biomarkers for lung cancer diagnosis, where do we stand?

“…Chromosomal aneusomy (CA) was demonstrated to be a potential biomarker in a study of high risk patients (68 cancers and 69 controls) and a screening cohort (97 cancers and 185 controls) (43). CA was assayed using a FISH analysis for a four-target DNA panel encompassing the EGFR and v-MYC avian myelocytomatosis viral oncogene homolog (MYC) genes, and the 5p15 and centromere 6 regions or the fibroblast growth factor 1 gene (FGFR1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA).…”

Quantifying the incremental value of deep learning: Application to lung nodule detection

“…Our first cohort, The Colorado Lung Nodule Cohort, consisted of individuals referred to pulmonologists, oncologists, or thoracic surgeons for evaluation of incidentally identified lung nodules on CT scans [21]. Individuals were required to have one or more lung nodules between 8 and 30 mm to be included and were excluded if nodules had solid calcification, or the patient had a low life expectancy (< 6 months) or known cancer.…”