Pre-treatment circulating tumor cells are a significant predictor of progression in patients with metastatic breast cancer undergoing abemaciclib therapy

Background: Abemaciclib, a CDK4/6 inhibitor widely used in the treatment of metastatic breast cancer (MBC), has significantly improved progression-free survival. However, despite these therapeutic benefits, a substantial proportion of patients still experience recurrence. This ongoing clinical challenge highlights the urgent need for reliable biomarkers that can identify high-risk individuals before treatment initiation which remains insufficiently explored. Our previous work showed that monitoring circulating tumor cells (CTCs) and ctDNA mutations can serve as a predictive tool for poor prognosis in MBC (ASCO 2025 #1042; AACR 2025 #3613; CCR 2024). Here, we report new findings demonstrating that baseline CTC levels provide important predictive value for identifying recurrence risk in patients receiving abemaciclib. Methods: A total of 66 ER + /HER2 − MBC patients were enrolled, and due to treatment discontinuation and re-initiation among some individuals, 76 courses of abemaciclib therapy were administered at Northwestern Memorial Hospital (2016-2024, IRB: NU16B06). The median follow-up period was 36.3 months. Blood samples (7.5 mL) were collected from patients prior to initiating abemaciclib therapy. CTC enumeration (classified as CK+/DAPI+/CD45−) was performed in FDA-approved CELLTRACKS System. Statistical analyses were conducted using causal inference with ensemble learning approaches. Results: Of the 76 treatment courses, 28 patients had CTC counts ≥5, while 48 patients had CTC counts <5. All patients were categorized into two cohorts based on progression after abemaciclib treatment. First analysis (cut-off: 6 months): Cohort 1 (early progression <6 months): 29 patients (range: 0.5-5.5 months; median: 2.75 months); Cohort 2 (late progression ≥6 months): 36 patients (range: 6.5-45 months; median: 17.5 months), plus 11 patients with no progression at the end of the study (follow-up: >12 to >70 months). The mean CTC count in Cohort 1 was 9.2, significantly higher than 6.1 in Cohort 2 (P < 0.01). Second analysis (cut-off: 12 months): Cohort 1 (early progression <12 months): 41 patients (range: 0.5-11 months; median: 3.75 months). Cohort 2 (late progression ≥12 months): 24 patients, plus the same 11 patients with no progress. The mean CTC count in Cohort 1 was 11.2, significantly higher than 2.8 in Cohort 2 (P < 0.01). There was no significant difference in CTC levels between the late-progression group (mean 2.3) and the no-progression group (mean 3.1). Conclusions: These findings demonstrate, for the first time, that pre-treatment CTC levels serve as a strong predictor of progress following abemaciclib therapy. Early identification of elevated CTCs in patients with MBC may therefore be critical for optimizing CDK4/6 inhibitor treatment strategies and identifying patients who may benefit from alternative therapeutic approaches.