Machine Learning and Mechanistic Modeling for Prediction of Metastatic Relapse in Early-Stage Breast Cancer

For patients with early-stage breast cancer, predicting the risk of metastatic relapse is of crucial importance. Existing predictive models rely on agnostic survival analysis statistical tools (eg, Cox regression). Here we define and evaluate the predictive ability of a mechanistic model for time to distant metastatic relapse.

The data we used for our model consisted of 642 patients with 21 clinicopathologic 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 five covariates with the best predictive power. These were further considered to individually predict the model parameters by using a backward selection approach. Predictive performances were compared with classic Cox regression and machine learning algorithms.

The mechanistic model was able to accurately fit the data. Covariate analysis revealed statistically significant association of Ki67 expression with α (P = .001) and EGFR expression with μ (P = .009). The model achieved a c-index of 0.65 (95% CI, 0.60 to 0.71) in cross-validation and had predictive performance similar to that of random survival forest (95% CI, 0.66 to 0.69) and Cox regression (95% CI, 0.62 to 0.67) as well as machine learning classification algorithms.

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 for routine management of patients with breast cancer.