Genomic markers of resistance to first-line (1L) therapy with a CDK4/6 inhibitor (CDKi) and endocrine therapy (ET) in patients (pts) with hormone receptor–positive (HR+) metastatic breast cancer (MBC).

1083 Background: Pts with HR+ MBC exhibit variable responses to 1L ET + CDKi therapy. We analyzed clinicopathologic features and genomic landscapes of biopsies obtained at the time of the diagnosis of MBC to identify determinants of sensitivity/resistance to 1L CDKi, with a focus on distinguishing endocrine-sensitive from endocrine-resistant (ETR) disease. Methods: A single center cohort included pts with biopsies obtained within 3 months of diagnosis of HR+, HER2-negative MBC (distant recurrent and de-novo DNIV), diagnosed between 2013 - 2020. Tumors underwent targeted DNA sequencing (OncoPanel). Clinical data were obtained from the EMBRACE database. Results: The entire cohort included 666 pts, of them 321 (48%) treated with 1L ET + CDKi. Among pts who received adjuvant ET (n = 347), 54 (15.6%) had primary ETR, 140 (40.3%) secondary ETR, and 153 (44.1%) were endocrine-sensitive. Of these pts, 56% (n = 191) received 1L CDKi therapy. The median time to next treatment (TTNT) in pts treated with 1L CDKi differed significantly by disease presentation, with a median of 1.3 years (95% CI, 0.9–1.5) for recurrent MBC and 2.3 years (95% CI, 1.7–3.6) for DNIV (log-rank p = 0.0005). TTNT also varied significantly according to endocrine sensitivity, with median TTNT of 0.6, 0.9, and 1.8 years for primary ETR, secondary ETR, and endocrine-sensitive disease, respectively (p = 0.0005). In the entire cohort, SNVs/indels were most frequent in PIK3CA , TP53 , and CDH1. CCND1 , FGFR1 , and MYC amplifications were most frequent amplifications. TP53 and ESR1 mutations were enriched in ETR tumors, compared with ET sensitive cancers (q 36 months, mutations in TP53 and N F1 were significantly enriched in the poor responders (q < 0.2). We also evaluated the association between specific genomic alterations and TTNT on 1L CDKi; mutations in TP53 , NF1 , and ERBB2 , as well as amplifications of RAD21 , FGFR1 and deletions of RB1 , CDKN2A were associated with shorter TTNT on 1L ET plus CDKi (q < 0.2). Conclusions: In our cohort, distinct genomic alterations were associated with ETR and shorter TTNT on 1L CDKi. These findings underscore the biology of ETR and support the clinical relevance of early genomic profiling to refine risk stratification and guide therapeutic decision-making. Notably, the high prevalence of ESR1 alterations in ETR tumors carries important implications for adjuvant and 1L treatment strategies, particularly the potential role of oral selective estrogen receptor degraders in this setting.