Machine learning and mechanistic modeling for prediction of metastatic relapse in early-stage breast cancer

Purpose For patients with early-stage breast cancer, prediction of the risk of metastatic relapse is of crucial importance. Existing predictive models rely on agnostic survival analysis statistical tools (e.g. Cox regression). Here we define and evaluate the predictive ability of a mechanistic model for the time to metastatic relapse. Methods The data consisted of 642 patients with 21 clinicopathological variables. A mechanistic model was developed on the basis of two intrinsic mechanisms of metastatic progression: growth (parameter α ) and dissemination (parameter μ ). Population statistical distributions of the parameters were inferred using mixed-effects modeling. A random survival forest analysis was used to select a minimal set of 5 covariates with best predictive power. These were further considered to individually predict the model parameters, by using a backward selection approach. Predictive performances were compared to classical Cox regression and machine learning algorithms. Results The mechanistic model was able to accurately fit the data. Covariate analysis revealed statistically significant association of Ki67 expression with α (p=0.001) and EGFR with μ (p=0.009). Achieving a c-index of 0.65 (0.60-0.71), the model had similar predictive performance as the random survival forest (c-index 0.66-0.69) and Cox regression (c-index 0.62 - 0.67), as well as machine learning classification algorithms. Conclusion By providing informative estimates of the invisible metastatic burden at the time of diagnosis and forward simulations of metastatic growth, the proposed model could be used as a personalized prediction tool of help for routine management of breast cancer patients.