Circulating Tumor Cell Dynamics after CDK4/6 Inhibitor for Hormone Receptor–Positive Metastatic Breast Cancer: A Biomarker Analysis from the PACE Phase II Study

Abstract Purpose: Circulating tumor cells (CTC) are biomarkers associated with poor prognosis and treatment resistance in hormone receptor–positive (HR+)/HER2-negative metastatic breast cancer (MBC). This analysis evaluates the prognostic role of baseline CTC enumeration and its interaction with treatment regimens in patients progressing on CDK4/6 inhibitors. Experimental Design: The PACE trial is a phase II, multicenter, randomized study of patients with HR+/HER2− MBC experiencing progression on aromatase inhibitors and CDK4/6 inhibitors. Patients were randomized 1:2:1 to receive fulvestrant (F), F + palbociclib (F + P), or F + P + avelumab (F + P + A). Baseline CTCs were enumerated using CellSearch with a threshold of ≥5 CTCs/7.5 mL to classify patients as stage IVindolent or stage IVaggressive. Concurrent ctDNA analysis was performed using Guardant360. Progression-free survival (PFS) was the primary endpoint. Results: Among 220 randomly assigned patients, 203 were evaluable for baseline CTCs; 76% had detectable CTCs and 49% were stage IVaggressive. Patients with de novo MBC were more frequently stage IVaggressive (47.5% vs. 30.8%). Baseline CTCs were prognostic with median PFS of 5.7 months for stage IVindolent and 3.5 months for stage IVaggressive patients [HR = 1.69; 90% confidence interval (CI), 1.27–2.24; P < 0.001]. In stage IVaggressive patients, F + P and F + P + A improved PFS versus fulvestrant alone (HR = 0.43; 90% CI, 0.25–0.71 and HR = 0.26; 90% CI, 0.14–0.49, respectively). No benefit was observed in stage IVindolent patients (interaction P = 0.0148 and P = 0.0033, respectively). Conclusions: Baseline CTC enumeration provides significant prognostic information in HR+/HER2− MBC. Stage IVaggressive patients derive greater benefit from F + P or F + P + A over fulvestrant alone, independent of clinical or ctDNA features. This highlights the potential of CTCs to guide treatment decision-making.