<i>CBFB</i> mutations as a predictive biomarker of endocrine therapy benefit in hormone receptor–positive (HR+) breast cancer: Discovery and validation in 3,799 patients.

1089 Background: Endocrine therapy (ET) is the mainstay approach for treating HR+ breast cancer, yet resistance frequently limits efficacy. Identifying reliable genomic biomarkers to predict superior treatment response remains an unmet clinical need. Methods: We performed unbiased genomic analysis of HR+ patients from the MSK-CHORD cohort (n=2,058), stratified by disease stage (metastatic vs. non-metastatic). Outcomes included progression-free survival (PFS), recurrence-free survival (RFS), and overall survival (OS). FDR-corrected Cox models were used for gene-level discovery. A chemotherapy-treated subset of the MSK-CHORD cohort served as a control to assess treatment specificity. Findings were externally validated in the independent METABRIC cohort (n=1,741). Results: Beyond known resistance biomarkers (ESR1, TP53, RB1), loss-of-function mutations in CBFB emerged as a significant predictor of ET benefit. CBFB mutations were present in 6.7% of metastatic breast cancer (MBC; n=80) and 6.3% of non-MBC (n=54). In MBC patients, CBFB mutations were associated with significantly longer PFS (HR=0.44; p=0.0002); in the adjuvant setting, RFS was similarly improved (HR=0.48; p=0.009). OS was prolonged in both settings (HR=0.49 and 0.50; p&lt;0.05 for both). CBFB mutations were enriched in lobular histology (OR=2.3; p&lt;0.0001); however, multivariable Cox regression confirmed CBFB as an independent predictor after adjusting for histology (HR=0.46; p=0.0003). To provide biological validation, we analyzed RUNX1, the obligate functional partner of CBFB in the CBF transcription complex. Combined CBFB/RUNX1 mutations (n=122, 10.2% in MBC; n=82, 9.5% in non-MBC) demonstrated consistent predictive benefit (HR=0.48 and 0.56; p&lt;0.0001 and p=0.007, respectively). Notably, the survival benefit associated with CBFB or CBF-complex mutations was absent in chemotherapy-treated controls, confirming treatment-specific predictive value rather than general prognostic effect. In the METABRIC validation cohort, CBFB mutations (5.9%; 103/1,741) independently predicted longer relapse-free survival (HR=0.59; p=0.005) and OS (HR=0.52; p&lt;0.0001). Gene expression analysis revealed that CBFB mutations were associated with significantly lower APOBEC gene family expression (p&lt;0.001), suggesting a mechanistic link between CBF-complex loss and reduced APOBEC-mediated mutagenesis, an established driver of endocrine resistance. Conclusions: We identify CBF-complex (CBFB/RUNX1) mutations as a novel genomic biomarker of ET benefit in HR+ breast cancer, independent of disease stage and histology, and validated across two large cohorts. These findings highlight a subset of patients with exceptional outcomes and provide a potential mechanistic link between CBF alterations and APOBEC-mediated resistance.