Pearson, Alexander T.

8549 Background: First-line treatment of early stage non-small cell lung cancer (NSCLC) is surgical resection, but with a 5-year survival of only 54%, rates of future relapse are high. Identifying patients at high risk of relapse can help guide adjuvant treatment decisions. Deep convolutional neural network (DCNN) AI models trained on tumor histology have shown incredible flexibility as potential biomarkers, both in lung cancer and more generally across many malignancies. While DCNN models can obtain extremely accurate results when used for routine purposes such as diagnosis, subtyping, and grading of malignancies, most models trained for prognostication or treatment response prediction do not reach performance sufficient for clinical application. Uncertainty quantification (UQ) – a family of techniques that give DCNN models the ability to report confidence alongside predictions – is an underexplored avenue in cancer AI that may help further improve performance and clinical application of models designed to provide clinicians with estimations of risk. Methods: To explore the potential use of UQ in clinically-oriented DCNN models, we trained models on a single-institution, retrospective digital tumor histology slide cohort from patients with Stage I-III NSCLC who underwent surgical resection to predict risk of future relapse. Estimation of uncertainty was performed using dropout as a Bayesian approximation, and uncertainty thresholds were calculated from training sets using a novel method to identify and remove low-confidence predictions. For comparison, a separate multivariate logistic regression was trained in cross-validation using known clinical risk factors. Results: We trained DCNN models on slides from 198 patients (40 relapsed, 158 without relapse). In this cohort, 130 patients had stage I disease (65.6%), 42 had stage II (21.2%), and 26 had stage III (13.2%). The average age was 69 years, 85% were current or previous smokers, and 38 received guideline-concordant adjuvant chemotherapy. Without UQ, a DCNN model predicted risk of future relapse with an average area under receiver operator curve (AUROC) of 0.74 across three-fold cross-validation. Using UQ estimation, 63% of slides were reported with high confidence. Relapse prediction was significantly improved in the high-confidence cohort, with an average AUROC of 0.83 in cross-validation. With a specificity of 70%, this corresponds to an average sensitivity of 86.8% across the three cross-folds (79.1%, 85.5%, and 95.7%). In comparison, a clinical-only multivariate regression model predicted relapse with a cross-validated AUROC of 0.67. Conclusions: This method of uncertainty quantification appears to be a powerful tool to predict lung cancer recurrence risk from digital histopathology while simultaneously providing clinicians with a measurement of algorithm trustworthiness.

Abstract The molecular and functional diversity of regulatory T-cells (Tregs) in health and in disease remains unclear. We previously described in colorectal cancer (CRC) patients a subpopulation of RORγt+ Tregs with elevated expression of β-catenin and pro-inflammatory properties. Here we observed progressive expansion of RORγt+ Tregs in inflammatory bowel disease (IBD) patients during inflammation and early dysplasia. Activating Wnt/β-catenin signaling in human and murine Tregs was sufficient to recapitulate the disease-associated increase in frequencies of RORγt+ Tregs expressing IL-17, IFN-γ, and TNFa. We found that binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt/β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Tregs. Activation of ꞵ-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.