Abstract Purpose: Circulating tumor cells (CTCs) 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 HR+/HER2- MBC patients experiencing progression on aromatase inhibitors (AI) 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 StageIV indolent or StageIV aggressive. Concurrent ctDNA analysis was performed using Guardant360®. Progression-free survival (PFS) was the primary endpoint. Results: Among 220 randomized patients, 203 were evaluable for baseline CTCs; 76% had detectable CTCs, and 49% were StageIV aggressive. Patients with de novo MBC were more frequently StageIV aggressive (47.5% vs. 30.8%). Baseline CTCs were prognostic, with median PFS of 5.7 months for StageIV indolent and 3.5 months for StageIV aggressive patients (HR 1.69, 90% CI 1.27-2.24, P0.001). In StageIV aggressive patients, F+P and F+P+A improved PFS versus F 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 StageIV indolent patients (interaction p=0.0148 and p=0.0033, respectively). Conclusions: Baseline CTC enumeration provides significant prognostic information in HR+/HER2- MBC. StageIV aggressive patients derive greater benefit from F+P or F+P+A over F alone, independent of clinical or ctDNA features. This highlights the potential of to guide treatment decision-making.
Gerratana et al. (Mon,) studied this question.