ABSTRACT
Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients' response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.
Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic/drug effects , Molecular Targeted Therapy , Neoplasms/drug therapy , Precision Medicine , Synthetic Lethal Mutations , Transcriptome/drug effects , Aged , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/immunology , Clinical Trials as Topic , Female , Follow-Up Studies , Humans , Immunotherapy , Male , Neoplasms/genetics , Neoplasms/pathology , Prognosis , Prospective Studies , Retrospective Studies , Survival RateABSTRACT
Predicting oncologic outcome is challenging due to the diversity of cancer histologies and the complex network of underlying biological factors. In this study, we determine whether machine learning (ML) can extract meaningful associations between oncologic outcome and clinical trial, drug-related biomarker and molecular profile information. We analyzed therapeutic clinical trials corresponding to 1102 oncologic outcomes from 104 758 cancer patients with advanced colorectal adenocarcinoma, pancreatic adenocarcinoma, melanoma and nonsmall-cell lung cancer. For each intervention arm, a dataset with the following attributes was curated: line of treatment, the number of cytotoxic chemotherapies, small-molecule inhibitors, or monoclonal antibody agents, drug class, molecular alteration status of the clinical arm's population, cancer type, probability of drug sensitivity (PDS) (integrating the status of genomic, transcriptomic and proteomic biomarkers in the population of interest) and outcome. A total of 467 progression-free survival (PFS) and 369 overall survival (OS) data points were used as training sets to build our ML (random forest) model. Cross-validation sets were used for PFS and OS, obtaining correlation coefficients (r) of 0.82 and 0.70, respectively (outcome vs model's parameters). A total of 156 PFS and 110 OS data points were used as test sets. The Spearman correlation (rs ) between predicted and actual outcomes was statistically significant (PFS: rs = 0.879, OS: rs = 0.878, P < .0001). The better outcome arm was predicted in 81% (PFS: N = 59/73, z = 5.24, P < .0001) and 71% (OS: N = 37/52, z = 2.91, P = .004) of randomized trials. The success of our algorithm to predict clinical outcome may be exploitable as a model to optimize clinical trial design with pharmaceutical agents.
