Background: Patients (pts) with HR+/HER2- aBC may eventually become resistant to endocrine therapies and CDK4/6 inhibitors (CDK4/6i). ML algorithms on EHR linked with NGS data may enable more accurate predictions of therapeutic resistance and identify clinicogenomic (CG) risk factors. Methods: HR+/HER2- aBC pts treated between Jan 2015 – Dec 2022 with at least one NGS test report before line end were identified in ConcertAI’s Genome360 oncology database, consisting of molecular alterations abstracted from NGS reports linked with deeply curated US-based EHR. XGBoost (XGB) and Cox proportional hazards (CoxPH) models were trained to predict real-world progression-free survival (rwPFS) derived from curated tumor progression (TP), as assessed by the providers based on clinical observations, pathology results, and radiologic evidence. Data was split into 60:20:20 for training/validation/test. Pts in the 1st and 4th quartiles of predicted risk from XGB model were defined as low- and high-risk. Predictors were identified from Shapley Additive exPlanations (SHAP)-derived marginal hazard ratios (HR), derived in the 180 days prior to index date, and included demographics, labs, vitals, comorbidities, concomitant medications, procedures, tumor properties, and molecular alterations as features. Results: Among 624 pts (CDK4/6i treated = 519) with median age = 62.5 years and 10.5% black, 46.8% developed TP. The test cumulative dynamic ROC-AUC in the best-performing XGB model was 0.68. The precision at 180 days (%TP = 27) was 40%. The 180-day cumulative incidence of TP in low- and high-risk groups was 11.6% vs 37.7%. Higher line number, lower hemoglobin (HGB), higher alkaline phosphatase (ALP), presence of liver metastasis, and history of thoracic radiation were clinical risk factors. Genomic risk factors were FGF aberrations, alterations in TP53 and in genes within the MAPK, cell cycle, and ESR pathways, and co-alterations in the PIK3CA+TP53, and MAPK+ESR pathways. ALP-by-TP53 interaction was found. ALP level was a risk factor in TP53-wildtype (wt) but not in TP53-mutant (mut) pts. Conclusions: ML on EHR linked with NGS data enables identification of high-risk pts and multimodal predictors of CDK4/6i resistance among women with HR+/HER2- aBC, identifying both known and undescribed interactions between clinical and genomic risk factors as well as co-alteration risk factors.