AbstractIdentifying individual patient characteristics that contribute to long-term mental health deterioration following diagnosis of breast cancer (BC) is critical in clinical practice. The present study employed a supervised machine learning pipeline to address this issue in a subset of data from a prospective, multinational cohort of women diagnosed with stage I–III BC with a curative treatment intention. Patients were classified as displaying stable HADS scores (Stable Group; n = 328) or reporting a significant increase in symptomatology between BC diagnosis and 12 months later (Deteriorated Group; n = 50). Sociodemographic, life-style, psychosocial, and medical variables collected on the first visit to their oncologist and three months later served as potential predictors of patient risk stratification. The flexible and comprehensive machine learning (ML) pipeline used entailed feature selection, model training, validation and testing. Model-agnostic analyses aided interpretation of model results at the variable- and patient-level. The two groups were discriminated with a high degree of accuracy (Area Under the Curve = 0.864) and a fair balance of sensitivity (0.85) and specificity (0.87). Both psychological (negative affect, certain coping with cancer reactions, lack of sense of control/positive expectations, and difficulties in regulating negative emotions) and biological variables (baseline percentage of neutrophils, thrombocyte count) emerged as important predictors of mental health deterioration in the long run. Personalized break-down profiles revealed the relative impact of specific variables toward successful model predictions for each patient. Identifying key risk factors for mental health deterioration is an essential first step toward prevention. Supervised ML models may guide clinical recommendations toward successful illness adaptation.