Interpretable Machine Learning Models to Predict the Resistance of Breast Cancer Patients to Doxorubicin from Their microRNA Profiles

Abstract Doxorubicin is a common treatment for breast cancer. However, not all patients respond to this drug, which sometimes causes life‐threatening side effects. Accurately anticipating doxorubicin‐resistant patients would therefore permit to spare them this risk while considering alternative treatments without delay. Stratifying patients based on molecular markers in their pretreatment tumors is a promising approach to advance toward this ambitious goal, but single‐gene gene markers such as HER2 expression have not shown to be sufficiently predictive. The recent availability of matched doxorubicin‐response and diverse molecular profiles across breast cancer patients permits now analysis at a much larger scale. 16 machine learning algorithms and 8 molecular profiles are systematically evaluated on the same cohort of patients. Only 2 of the 128 resulting models are substantially predictive, showing that they can be easily missed by a standard‐scale analysis. The best model is classification and regression tree (CART) nonlinearly combining 4 selected miRNA isoforms to predict doxorubicin response (median Matthew correlation coefficient (MCC) and area under the curve (AUC) of 0.56 and 0.80, respectively). By contrast, HER2 expression is significantly less predictive (median MCC and AUC of 0.14 and 0.57, respectively). As the predictive accuracy of this CART model increases with larger training sets, its update with future data should result in even better accuracy.