Background: Post failure of 3 lines of systemic treatments in breast cancers, Standard of Care guidelines recommend palliative care or clinical trials for such patients. We retrospectively evaluated the efficacy of ultra-personalized treatment in a cohort of patients (n = 27) with advanced refractory breast cancers. These patients had availed of Encyclopedic Tumor Analysis (ETA), based on which each patient received individualised organ- and label-agnostic treatment regimens. Methods: ETA was performed on freshly biopsied tumor tissue and peripheral blood. ETA interrogated gene alterations, gene expression, immunohistochemistry (IHC) in tumor tissue and in vitro chemoresistance profiling (CRP) of viable tumor cells. Findings of ETA were integrated to generate patient-specific therapy recommendations. All patients underwent whole body PET-CT and brain MRI scans prior to start of treatment. Treatment response was determined from follow-up PET-CT scans and used to calculate Objective Response Rate (ORR), Disease Control Rate (DCR) and Progression Free Survival (PFS).Results: Among the 27 patients who received personalized treatment guided by ETA, partial response (PR) was observed in 16 patients (ORR = 59.1%). At the most recent follow-up 26 patients continued to exhibit PR or Stable Disease (SD) (DCR = 96.3%). Median PFS was 115 days. There were no grade IV adverse events or any treatment related deaths. Most patients reported qualitative improvements in symptomatic and functional status. Conclusion: ETA guided treatments can offer viable treatment options in advanced refractory breast cancers yielding meaningful ORR and disease control in majority of patients.