AbstractBackgroundCyclin-dependent kinase 4/6 inhibitors (CDKi) have changed the landscape for treatment of patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER−) metastatic breast cancer (MBC). However, next-line treatment strategies after CDKi progression are not yet optimized. We report here the impact of clinical and genomic factors on post-CDKi outcomes in a single institution cohort of HR+/HER2− patients with MBC.MethodsWe retrospectively reviewed the medical records of patients with HR+/HER2− MBC that received a CDKi between April 1, 2014 and December 1, 2019 at our institution. Data were summarized using descriptive statistics, the Kaplan-Meier method, and regression models.ResultsWe identified 140 patients with HR+/HER2− MBC that received a CDKi. Eighty percent of patients discontinued treatment due to disease progression, with a median progression-free survival (PFS) of 6.0 months (95% CI, 5.0-7.1), whereas those that discontinued CDKi for other reasons had a PFS of 11.3 months (95% CI, 4.6-19.4) (hazard ratio (HR) 2.53, 95% CI, 1.50-4.26 [P = .001]). The 6-month cumulative incidence of post-CDKi progression or death was 51% for the 112 patients who progressed on CDKi. Patients harboring PTEN mutations pre-CDKi treatment had poorer clinical outcomes compared to those with wild-type PTEN.ConclusionThis study highlights post-CDKi outcomes and the need for further molecular characterization and novel therapies to improve treatments for patients with HR+/HER2− MBC.