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

Anna E. Barón, Severine Kako, William J. Feser, Heather Malinowski, Daniel Merrick, Kavita Garg, Stephen Malkoski, Shannon Pretzel, Jill M. Siegfried, Wilbur A. Franklin, York Miller, Holly J. Wolf, Marileila Varella-Garcia

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Abstract

Introduction Low-dose computed tomography 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 by fluorescence in situ hybridization (CA-FISH) in four nested case-control studies. Methods Receiver operating characteristic analysis resulted in two grouped cohorts: a high-risk cohort (Colorado High-Risk Cohort and Colorado Nodule Cohort [68 case patients and 69 controls]) and a screening cohort (American College of Radiology Imaging Network/National Lung Screening Trial and Pittsburgh Lung Screening Study [97 case patients and 185 controls]). The CA-FISH assay was 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). A four-category scale (normal, probably normal, probably abnormal, and abnormal) was applied. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) (with 95% confidence intervals [CIs]) were estimated for each cohort. Results Sensitivity and specificity were, respectively, 0.67 (95% CI: 0.55–0.78) and 0.94 (95% CI: 0.85–0.98) for high-risk participants and 0.20 (95% CI: 0.13–0.30) and 0.84 (95% CI: 0.78–0.89) for screening participants. The positive and negative LRs were, respectively, 11.66 (95% CI: 4.44–30.63) and 0.34 (95% CI: 0.24–0.48) for high-risk participants and 1.36 (95% CI: 0.81–2.28) and 0.93 (95% CI: 0.83–1.05) for screening participants. Conclusion The high positive LR of sputum CA-FISH indicates that it could be a useful adjunct to low-dose computed tomography for lung cancer in high-risk settings. For screening, however, its low positive LR limits clinical utility. Prospective assessment of CA-FISH in the incidentally identified indeterminate nodule setting is ongoing in the Colorado Pulmonary Nodule Biomarker Trial.

Original languageEnglish (US)
Pages (from-to)1512-1523
Number of pages12
JournalJournal of Thoracic Oncology
Volume12
Issue number10
DOIs
StatePublished - Oct 2017

Keywords

  • Early detection
  • Indeterminate nodules
  • Noninvasive biomarker
  • Positive likelihood ratio
  • Posttest probability

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    Barón, A. E., Kako, S., Feser, W. J., Malinowski, H., Merrick, D., Garg, K., Malkoski, S., Pretzel, S., Siegfried, J. M., Franklin, W. A., Miller, Y., Wolf, H. J., & Varella-Garcia, M. (2017). Clinical Utility of Chromosomal Aneusomy in Individuals at High Risk of Lung Cancer. Journal of Thoracic Oncology, 12(10), 1512-1523. https://doi.org/10.1016/j.jtho.2017.06.008