Pulmotype was derived by taking advantage of insights from gene expression studies that established the extensive diversity in the molecular physiology of lung tumor histological types. Hundreds of antibodies were created and screened for their ability to distinguish different subtypes of cancer and further screened for their applicability in a tool for specifically discriminating lung adenocarcinomas from squamous cell carcinoma.
Development
Pulmotype was initially developed using a 550 patient cohort of lung cancer specimens from the Clearview Cancer Institute of Huntsville, AL. This protein expression dataset was used to identify markers with a significant ability to discriminate adenocarcinoma from squamous cell carcinoma histology. These markers and datasets were then used to derive a linear model that combines staining results for three selected squamous markers (SLC7A5, CK5/6, TRIM29) with two selected adenocarcinoma markers (MUC1, CEACAM5) into a weighted classifier for distinguishing adenocarcinoma from squamous cell carcinoma.
Validation
In order to validate the association between histologic diagnosis by Pulmotype and the putative “gold standard”, morphologic diagnosis on surgical resection specimen, 1,111 lung carcinoma specimens from three separate institutions (University of Alabama, Birmingham (UAB), Universitätsspital Zürich, and Invitromed) were assembled into tissue array cohorts. Staining with Pulmotype demonstrated that classification of tumors by the five antibody test was strongly associated with pathologist morphologic assessment. Pulmotype was also compared with a commonly used 2-marker panel comprised of TTF-1 and TP63. Pulmotype and TTF1/TP63 had nearly identical specificity, misclassifying very few patients relative to morphologic assessment by pathologists. However, the percentage of patients unclassified by TTF1/TP63 was twice that of Pulmotype. In clinical practice this might result in twice as many patients being denied Avastin therapy, if TTF1/p63 was used as opposed to Pulmotype.
The results of these studies, published in Modern Pathology, suggest that Pulmotype has an immediate role in the clinic for helping pathologists distinguish lung carcinoma histological types. The results also suggest that, if validated in prospectively defined clinical trials, this classifier might identify candidates for targeted therapy that are over-looked with current diagnostic approaches.