Abstract 5248: CDK4/6 inhibition (CDK4/6i) is effective in the real-world setting for hormone receptor-positive metastatic breast cancer (HR+ MBC) with ESR1 mutations and fusions

Background For HR+ MBC, ESR1 point mutations (ESR1-MUT) are a common mechanism of acquired resistance to aromatase inhibition (AI); ESR1 fusions (ESR1-FUS) are rare and promote intrinsic resistance to ER-targeting drugs. Retrospective analyses of CDK4/6i trials suggest ESR1-MUT does not cause CDK4/6i resistance, but whether CDK4/6i is effective for ESR1-MUT, or for ESR1-FUS, in the real-world setting is unknown. Methods Real-world evidence was sourced from the GuardantInform database of commercial payer claims and ctDNA tests from 170,000+ individuals. Patients with MBC who started CDK4/6i within 30 days of ctDNA testing were categorized as ESR1-MUT vs. ESR1-WT and analyzed for time-to-next-treatment (TTNT). Separately, cases with ESR1-FUS detected by tissue RNA-Seq were extracted from a clinicopathologic database at an academic cancer center. Results There was no significant difference in TTNT on CDK4/6i for ESR1-MUT vs. ESR1-WT. As expected, ESR1-MUT had shorter overall survival (OS), even after adjustment for age, CDK4/6i drug, and prior treatment (HR 0.58 (0.42-0.82), p=0.002, multivariable Cox). Endocrine partner analysis was limited by lack of clinical annotation to 27% of cases: AI was given to 55% of ESR1-WT and 25% of ESR1-MUT; fulvestrant was given to 39% of ESR1-WT and 68% of ESR1-MUT. Additional stratified analyses will be presented. In the clinicopathologic database, we identified 4 ESR1-FUS cases, and all received CDK4/6i. Progression-free survival durations on CDK4/6i were 4, 10, 11, and 33+ months. Conclusions Using real-world evidence, we demonstrate that CDK4/6i is effective in both ESR1-MUT and ESR1-WT HR+ MBC, supporting the use of CDK4/6i in this setting. CDK4/6i may be additionally beneficial for patients with ESR1-FUS. Future directions include expanding the ESR1-FUS cohort and deciphering the heterogeneity of CDK4/6i responses in this patient population. ESR1-WT ESR1-MUT p-value n=612 n=145 TTNT, median days (95% CI) 99 (85-121) 102 (85-152) 0.84 (log-rank) OS, median years (95% CI) 5.1 (4.5-NA) 2.2 (2.0-NA) Citation Format: Jamie O. Brett, Caroline M. Weipert, Lauren L. Ritterhouse, Nicole Zhang, Junhua Yu, Lianne Y. Ryan, Laura M. Spring, Miguel N. Rivera, Jochen K. Lennerz, Dora Dias-Santagata, Leif W. Ellisen, Aditya Bardia, Seth A. Wander. CDK4/6 inhibition (CDK4/6i) is effective in the real-world setting for hormone receptor-positive metastatic breast cancer (HR+ MBC) with ESR1 mutations and fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5248.