B.R.E.A.S.T. Breast canceR Enhanced AI-Supported Therapy: A New Interpretable Proteomics-Driven Machine Learning Framework for Therapy Response Prediction in Breast Cancer

Alessia Bono, Gabriele La Monica, Federica Alamia, Dennis Tocco, Antonino Lauria, Annamaria Martorana

Breast cancer is a heterogeneous disease characterized by substantial molecular diversity and variable treatment outcomes across patients. Despite advances in targeted and systemic therapies, anticipating individual benefit remains a major clinical challenge. In this context, Artificial Intelligence (AI) can support precision oncology by integrating high-dimensional molecular profiles with clinical and pharmacological information. Here, we present B.R.E.A.S.T. (Breast canceR Enhanced AI-Supported Therapy), an interpretable machine learning framework designed to predict therapy outcome from tumor proteomic profiles integrated with clinical and treatment annotations. Proteomic data from The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas (TCPA) were harmonized with outcome and therapy information, and thirteen supervised classifiers were systematically evaluated using stratified 5-fold cross-validation. Therapeutic outcome labels were operationally defined by integrating available treatment response annotations with complementary clinical outcome information. Across both cohorts, ensemble-based models consistently achieved the most stable and highest discriminative performance, supported by learning-curve analyses and consistent behavior across independent datasets. To enhance interpretability, we implemented a two-step feature selection strategy combining model-specific importance measures with a global consensus ranking, enabling the identification of a compact set of robust proteomic biomarkers associated with therapeutic outcome. Top-ranked features mapped to molecular programs relevant to breast cancer progression and treatment sensitivity, including regulators of cell survival, DNA damage response, PI3K/AKT/mTOR signaling, and invasion-related processes. Re-evaluation using only the top 30 globally ranked features preserved high predictive performance across both independent breast cancer cohorts, indicating that a parsimonious proteomic signature captures core molecular determinants of outcome. Overall, B.R.E.A.S.T. provides a robust and generalizable proteomics-driven framework for modeling outcome-associated therapeutic response patterns and supporting biologically informed biomarker discovery in breast cancer.