Baseline circulating tumor cells and association with early resistance in patients with metastatic breast cancer undergoing palbociclib therapy.

1111 Background: Palbociclib has significantly improved outcomes in metastatic breast cancer (MBC); however, a substantial proportion of patients experience early treatment resistance. Reliable biomarkers to identify high-risk patients prior to therapy initiation remain limited. Our previous work has demonstrated that circulating tumor cell (CTC) and ctDNA monitoring is associated with poor prognosis in MBC (ASCO 2025 #1042; AACR 2025 #3613). Here, we report new findings of the association between baseline CTC level and timing of resistance in patients receiving palbociclib. Methods: This study included 178 patients with ER+/HER2− MBC treated with palbociclib at the Robert H. Lurie Cancer Center between 2016 and 2025 (IRB: NU16B06), all of whom developed treatment resistance. Time to resistance was defined as the interval from treatment initiation to first documented resistance; the median follow-up period was 8.0 months. Patients were stratified a priori into early resistance (≤6 months; n = 71) and later resistance ( > 6 months; n = 107). Baseline CTCs were enumerated prior to treatment using FDA-approved CELLTRACKS system (Menarini). Associations between baseline CTC levels and time to resistance were assessed using Spearman rank correlation, treating CTC as a continuous variable and analyzing early and later resistance groups separately. Results: Among patients with early resistance, the median time to resistance was 3.25 months (range, 0.16–6.0), compared with 16.0 months (range, 6.5–57) among those with later resistance. Patients with early resistance exhibited higher baseline CTC levels on average than those with later resistance (mean CTC: 36.7 vs 25.8), although CTC distributions were highly right-skewed with substantial overlap between groups. Within the early resistance group, 29 of 71 patients had baseline CTC ≥5, with markedly higher mean CTC levels compared with patients with CTC < 5 (88.6 vs 0.8). In contrast, baseline CTC ≥5 was not associated with timing of resistance among patients with later resistance. Using Spearman rank correlation, higher baseline CTC levels were significantly associated with earlier resistance among patients with early resistance (ρ = −0.24, P = 0.043), whereas no association was observed in patients with resistance occurring beyond 6 months (ρ = 0.04, P = 0.71). Conclusions: Baseline CTC levels were associated with the timing of treatment resistance in patients with metastatic breast cancer receiving palbociclib, with a significant inverse correlation observed exclusively among patients experiencing early resistance within 6 months. These new findings suggest that elevated baseline CTC burden reflects aggressive disease biology underlying rapid treatment failure. Time-dependent assessment of CTC may provide clinically relevant insights into early resistance risk and inform clinical decision-making.