Circulating tumor cells (CTCs) dynamics after CDK4/6i for hormone-receptor positive (HR+) metastatic breast cancer (MBC): A biomarker analysis of the PACE randomized phase II study.
Authors: Gerratana Lorenzo , Ren Yue , Reduzzi Carolina , Regan Meredith M. , Mahtani Reshma L. , Ma Cynthia X. , DeMichele Angela , Meisel Jane Lowe , Miller Kathy , Jolly Trevor Augustus , Riley Elizabeth Carloss , Qamar Rubina , Sharma Priyanka , Reid Sonya A. , Ko Naomi Yu , Liu Yuan , Burstein Harold J. , Tolaney Sara M. , Cristofanilli Massimo , Mayer Erica L. 
Published: June 2023

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Background: PACE is a multicenter randomized phase II trial investigating palbociclib (P) in combination with fulvestrant (F) after progression on any CDK4/6 inhibitor (CDK4/6i), with or without the PD-L1 inhibitor avelumab (A), in HR+/HER2- MBC. CTCs are rare cells in the blood stream whose detection is associated with worse outcome and treatment resistance. Methods: Eligible patients (pts) had HR+/HER2- MBC with prior progression after ≥ 6 months (mo) of AI and CDK4/6i for MBC, or during/within 12 mo in the adjuvant setting, with ≤ 1 prior chemotherapy for MBC. Pts were randomized 1:2:1 to F, F+P, or F+P+A. CTC detection and enumeration were performed utilizing CellSearch (Menarini Silicon Biosystems) at baseline (BL), at time of first tumor assessment (TTA1), and at progression. Results were dichotomized using the standard CTC threshold (≥ 5 CTCs/7.5 ml) into a novel prognostic classification: StageIVindolent and StageIVaggressive (Cristofanilli et al 2019). Concurrent ctDNA Sequencing was performed using Guardant360 (Guardant Health). Results: Of the 220 randomized pts, 203 (92%) had sample available for BL CTC enumeration, 155 had detectable CTCs (70.5%), and 99 (48.8%) were StageIVaggressive. De novo disease at initial diagnosis was associated with StageIVaggressive (47.5% vs 30.8% StageIVindolent), and distribution of visceral versus non-visceral disease was similar across the two CTCs groups. StageIVaggressive represented 38.3%, 54.8%, and 46.2% of the F, F+P and F+P+A treatment groups, respectively. BL CTCs were prognostic in the overall cohort; median PFS was 5.7mo vs 3.5mo for StageIVindolent vs StageIVaggressive (HR: 1.69, 90%CI 1.27,2.24, P<0.001). Median PFS for the F, F+P and F+P+A arms was 1.9mo, 4.6mo and 5.4mo in StageIVaggressive compared to 8.2mo, 5.3mo and 8.3mo in StageIVindolent. Among patients in the StageIVaggressive subgroup, the F+P and F+P+A arms demonstrated improved outcomes compared to F alone. (F+P vs F HR 0.43, 90% CI 0.25-0.71, and F+P+A vs F HR 0.26, 90% CI 0.14-0.49). No benefit of F+P or F+P+A over F was observed in the StageIVindolent subgroup (F+P vs F HR 1.45, 90% CI 0.87 - 2.40 and F+P+A vs F HR 1.06, 90% CI 0.61 - 1.84, each p(interaction)<0.01). Changes in StageIV CTC characterization (indolent vs aggressive) between BL and TTA1 among the subset of 175/203 pts with both timepoints available are reported. Conclusions: Baseline CTC enumeration is prognostic in patients receiving F with or without CDK4/6i. The StageIVaggressive subgroup may derive preferential benefit with combinations of F+P or F+P+A over F alone. Findings should be confirmed in other studies. ctDNA analyses are ongoing. Clinical trial information: NCT03147287 . [Table: see text]