Abstract PS2-08-06: Biomarker analysis of patients treated with abemaciclib rechallenge after progression on abemaciclib plus endocrine therapy from the Phase II AGAIN Study (WJOG14220B)

Abstract Background: We previously conducted a phase II study evaluating abemaciclib (ABE) rechallenge after progression on ABE plus endocrine therapy in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. This study demonstrated a progression-free survival (PFS) benefit for patients treated with ABE plus fulvestrant (FUL) following progression on ABE plus aromatase inhibitor (AI)/tamoxifen (TAM). However, there are currently no robust biomarkers to identify patients likely to benefit from ABE rechallenge. This study presents the results of a biomarker analysis of liquid biopsies, including those collected at the time of disease progression after ABE rechallenge. Methods: We obtained liquid biopsies before ABE rechallenge, at 2 months (m) after rechallenge, and at disease progression to identify biomarkers associated with response or resistance to ABE. We analyzed circulating tumor DNA (ctDNA) using a targeted next-generation sequencing panel. Results: By the end of the study period, 54 of 64 patients had discontinued treatment due to disease progression, and liquid biopsies were obtained at progression. The most frequently acquired gene alterations at progression were TP53 mutations (n = 7, 13.0%) and CCND1 amplification (n = 5, 9.3%). Median overall survival (OS) in patients with TP53 mutations at progression was 18.8 m (95% confidence interval [CI], 10.8–not applicable [NA]) compared to 28.6 m (95% CI, 25.3–NA) in those with wild-type TP53. Moreover, TP53 mutations at progression were associated with shorter OS (hazard ratio [HR], 0.24; 95% CI, 0.07–0.8; p = 0.02). Among patients who switched from ABE plus AI/TAM to ABE plus FUL (n = 27), the most frequently acquired alternation was CCND1 amplification (n = 4, 14.8%), which was associated with shorter median PFS (HR, 0.19; 95% CI, 0.05–0.7; p = 0.01) and OS (HR, 0.16; 95% CI, 0.03–0.8; p = 0.02). In patients who switched from ABE plus FUL to ABE plus AI (n = 37), TP53 mutation was the most common newly acquired alteration at progression (n = 6, 16.2%). Conclusions: In this study of ABE rechallenge, TP53 mutation at disease progression may be associated with poorer survival outcomes. CCND1 amplification may be associated with resistance to ABE in patients who switched from ABE plus AI/TAM to ABE plus FUL. Citation Format: M. Nishimura, T. Kogawa, K. Sugiyama, Y. Ozaki, Y. Tanabe, C. Funasaka, S. Kurozumi, A. Yoshimura, T. Iwasa, H. Sakai, M. Morita, S. Watanabe, T. Fujii, M. Yamamoto, Y. Tsuji, M. Terada, T. Ota, S. Tokunaga, M. Shimokawa, T. Takano. Biomarker analysis of patients treated with abemaciclib rechallenge after progression on abemaciclib plus endocrine therapy from the Phase II AGAIN Study (WJOG14220B) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-08-06.