{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:37:51Z","timestamp":1787315871026,"version":"build-2736575974"},"posted":{"date-parts":[[2026,5,21]]},"group-title":"Oncology","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Beyond estrogen receptor (ER) positivity, no genomic biomarker reliably identifies ER+ breast cancer patients who derive differential benefit from endocrine therapy (ET). We performed an unbiased genomic screen to discover genes predicting ET response and characterized the top candidate across clinical settings, treatment modalities, and an independent validation cohort.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Experimental Design<\/jats:title>\n                  <jats:p>We screened 240 genes in 1,197 metastatic ET-treated patients from the MSK-CHORD clinical genomics database using Cox proportional hazards regression with false discovery rate (FDR) correction. The top candidate, core-binding factor subunit beta (CBFB), was characterized across four cohorts defined by disease setting (metastatic\/adjuvant) and treatment (ET\/chemotherapy), with multivariable adjustment, gene-by-treatment interaction testing, left-truncation sensitivity analysis for guarantee-time bias, and external validation in METABRIC (N = 1,499 ER+).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    CBFB mutations (prevalence, \u223c5%) were the only gene associated with improved time to progression (TTP). In metastatic ET patients, CBFB-mutated tumors (n = 80) demonstrated significantly longer TTP (hazard ratio [HR], 0.44; 95% CI, 0.29\u20130.67; P = .0002, FDR q = .010) with no chemotherapy benefit (HR, 1.16; P = .65). The gene-by-treatment interaction was significant (HR, 0.37; P = .009). Effects were robust to multivariable adjustment (HR, 0.46\u20130.50), independent of histology, and preserved under left-truncated Cox regression (HR, 0.38). In the adjuvant setting, CBFB mutations predicted improved recurrence-free survival (HR, 0.52; 95% CI, 0.31\u20130.85; P = .010), with no effect under chemotherapy. In METABRIC, CBFB mutations predicted improved ER+ overall survival (HR, 0.52; P = 9.3 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>CBFB mutations identify \u223c5% of ER+ breast cancers with exceptional ET benefit. As CBFB is included on all major cancer gene panels, this biomarker requires no additional testing infrastructure for clinical implementation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CBFB Translational Relevance<\/jats:title>\n                  <jats:p>\n                    Endocrine therapy is the standard of care for estrogen receptor (ER)\u2013positive breast cancer. Yet beyond ER positivity, clinicians lack genomic biomarkers that identify patients with exceptional response to endocrine treatment. We report that core-binding factor subunit beta (CBFB) mutations predict an extended duration of response to endocrine therapy (hazard ratio, 0.44; P = .0002) with no chemotherapy benefit (hazard ratio, 1.16; P = .65). The gene-by-treatment interaction (P = .009) formally establishes CBFB as a predictive rather than a prognostic biomarker, and the survival association was independently validated in the METABRIC cohort (hazard ratio, 0.52; P = 9.3 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ). Because CBFB is already sequenced on major cancer gene panels in clinical use, no additional testing infrastructure is required: CBFB mutation status is a low-cost candidate for prospective validation in endocrine-therapy studies, and, if confirmed, could be reported alongside existing panel results to inform treatment decisions.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.18.26353467","type":"posted-content","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T22:55:19Z","timestamp":1779404119000},"source":"Crossref","is-referenced-by-count":1,"title":["CBFB mutations predict endocrine therapy benefit in estrogen receptor\u2013positive breast cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6106-2307","authenticated-orcid":false,"given":"Adar","family":"Yaacov","sequence":"first","affiliation":[{"name":"Helmsley Cancer Center, Shaare Zedek Medical Center, Jerusalem, Israel"},{"name":"Faculty of Medicine, 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