Breast cancer is the second leading cause of cancer-related deaths in women. Triple negative breast cancer (TNBC) is an aggressive subtype that affects 10–25% mostly African American women. TNBC has the poorest prognosis of all subtypes with rapid progression leading to mortality in younger patients. So far, there is no targeted treatment for TNBC. To that end, here we show that c-Abl is one of several tyrosine kinases that phosphorylate and activate geminin’s ability to promote TNBC. Analysis of >800 breast tumor samples showed that geminin is overexpressed in ∼50% of all tumors. Although c-Abl is overexpressed in ∼90% of all tumors, it is only nuclear in geminin overexpressing tumors. In geminin-negative tumors, c-Abl is only cytoplasmic. Inhibiting c-Abl expression or activity (using imatinib or nilotinib) prevented geminin Y150 phosphorylation, inactivated the protein, and most importantly converted overexpressed geminin from an oncogene to an apoptosis inducer. In pre-clinical orthotopic breast tumor models, geminin-overexpressing cells developed aneuploid and invasive tumors, which were suppressed when c-Abl expression was blocked. Moreover, established geminin overexpressing orthotopic tumors regressed when treated with imatinib or nilotinib. Our studies support imatinib/nilotonib as a novel treatment option for patients with aggressive breast cancer (including a subset of TNBCs)-overexpressing geminin and nuclear c-Abl.

No abstract

e19172 Background: For AML patients who are ineligible for intensive induction, novel therapies have greatly improved treatment options, though practice challenges individualizing care have hindered effective integration. In a quality improvement (QI) program conducted in 3 community oncology systems, we assessed practice patterns and barriers involving the use of novel therapies for AML. Methods: We surveyed 15 hematology team members to assess barriers to quality AML care and audited electronic medical records (EMR) of 100 patients across 3 community oncology centers. EMR demographics, disease characteristics, and treatment selection were reviewed. To address suboptimal guideline-aligned care, teams participated in audit-feedback sessions to develop action plans for resolving identified gaps. Results: The EMR audit demonstrated a lack of documentation for clinically important metrics necessary for individualized treatment selection and monitoring, including performance status and testing for targetable biomarkers (Table). Additionally, there was low documented use of novel therapies, such as venetoclax and gemtuzumab ozogamicin (GO), and no documented use of FLT3 or IDH inhibitors. Further, the audit revealed low adherence to guideline recommendations for frontline regimens – notably, 33.3% patients with FLT3 or IDH mutations (n = 15) were receiving low dose cytarabine alone, and 50% patients with a documented performance status of 3+ (n = 2) received intensive induction therapy. Survey findings indicated very low or low confidence in aligning practice with guidelines (20%), identifying patients who are not candidates for intensive induction (27%), and ordering/interpreting molecular tests (33%). Appropriate treatment selection (47%) and integration of molecular testing (27%) were reported as top challenges for individualized AML care. During audit-feedback sessions, teams identified improved collaboration with hematopathologists, assessment of patient mutational status, and patient engagement in treatment planning as actions they plan to integrate. Conclusions: These findings reveal important performance gaps in individualized AML care in community settings, which may inform future QI initiatives. [Table: see text]