Background: ETR to prior adjuvant ET poses challenges to first-line treatment (1L tx) of HR+, HER2– mBC. Understanding patient (pt)/disease heterogeneity is crucial for developing new txs that target specific ETR mechanisms to improve pt outcomes. We investigate ETR, including prevalence, genomic profiles, and survival outcomes in pts with HR+, HER2– mBC treated in the 1L setting. Methods: This retrospective two-cohort study of pts initiating 1L systemic tx for mBC (diagnosed after Jan 1, 2015) used data from the Flatiron Health (FH) electronic health record-derived de-identified database (FH cohort), and FH-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB cohort; solid biopsy FMI test required). The de-identified data originated from ~280 US cancer clinics (~800 sites of care). Pts with ETR to prior adjuvant ET were defined per ESMO guidelines (table footnote); primary ETR (1ETR) was divided into pts relapsing within 1 year (yr) or 1–2 yrs of adjuvant ET. Genomic profiles were assessed in the CGDB cohort. In both cohorts, real-world (rw) progression-free survival (PFS) and overall survival (OS) were estimated in pts who received 1L tx with fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i). Results: In the FH cohort (N = 4052), 16.1% of pts had 1ETR (ET <1 yr: 7.9%) and 33.9% had secondary ETR (2ETR). In the CGDB cohort (N = 696), ESR1 mutations (ESR1m) were present in 10.8% of 158 pts with 1ETR (ET <1 yr: 4.2%; 1–2 yrs: 16.1%) and 19.9% of 317 pts with 2ETR. In pts who received 1L F + CDK4/6i, shorter median (m) rwPFS (statistically significant) and OS (not significant) were seen in pts with 1ETR vs. 2ETR, but outcomes were not affected by the presence of ESR1m in pts with 2ETR. Conclusions: Overall, half of pts with 1L HR+, HER2– mBC have ETR to prior adjuvant ET. Pts with ETR have tumors with heterogeneous genomic profiles and varied survival outcomes. ESR1m are infrequent in pts with 1ETR and <1 yr of adjuvant ET but are more common in 2ETR. In pts treated with 1L F + CDK4/6i, PFS and OS were worse with 1ETR than 2ETR. This study highlights the importance of further understanding the heterogeneity in molecular profiles and outcomes within ETR.

* Relapsing during <2 yrs of adjuvant ET.

^† Relapsing during ≥ 2 yrs of adjuvant ET or ≤ 1 yr from last ET.

^‡ Risk set adjustment applied in survival analyses to account for delayed entry of pts in the cohort post-index date.