Recommended Citation
Lu M, Wu KH, Trudeau S, Jiang M, Zhao J, and Fan E. A genomic signature for accurate classification and prediction of clinical outcomes in cancer patients treated with immune checkpoint blockade immunotherapy. Sci Rep 2020; 10(1):20575.
Document Type
Article
Publication Date
11-25-2020
Publication Title
Sci Rep
Abstract
Tumor mutational burden (TMB) is associated with clinical response to immunotherapy, but application has been limited to a subset of cancer patients. We hypothesized that advanced machine-learning and proper modeling could identify mutations that classify patients most likely to derive clinical benefits. Training data: Two sets of public whole-exome sequencing (WES) data for metastatic melanoma. Validation data: One set of public non-small cell lung cancer (NSCLC) data. Least Absolute Shrinkage and Selection Operator (LASSO) machine-learning and proper modeling were used to identify a set of mutations (biomarker) with maximum predictive accuracy (measured by AUROC). Kaplan-Meier and log-rank methods were used to test prediction of overall survival. The initial model considered 2139 mutations. After pruning, 161 mutations (11%) were retained. An optimal threshold of 0.41 divided patients into high-weight (HW) or low-weight (LW) TMB groups. Classification for HW-TMB was 100% (AUROC = 1.0) on melanoma learning/testing data; HW-TMB was a prognostic marker for longer overall survival. In validation data, HW-TMB was associated with survival (p = 0.0057) and predicted 6-month clinical benefit (AUROC = 0.83) in NSCLC. In conclusion, we developed and validated a 161-mutation genomic signature with "outstanding" 100% accuracy to classify melanoma patients by likelihood of response to immunotherapy. This biomarker can be adapted for clinical practice to improve cancer treatment and care.
Medical Subject Headings
Antineoplastic Agents; Immunological/therapeutic use; B7-H1 Antigen/genetics; Biomarkers; Pharmacological; Biomarkers; Tumor/genetics; Carcinoma; Non-Small-Cell Lung/genetics/pathology; Forecasting/methods; Genomics; Humans; Immune Checkpoint Inhibitors/classification/therapeutic use; Immunotherapy/methods; Kaplan-Meier Estimate; Machine Learning; Melanoma/genetics/pathology; Mutation; Neoplasms/genetics/pathology; Treatment Outcome; Exome Sequencing
PubMed ID
33239757
Volume
10
Issue
1
First Page
20575
Last Page
20575
