Change in topoisomerase 1 (Top1) positive circulating tumor cells impacts overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol

Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTCs) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP). Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656/852 (77%) of patients was processed with ApoStream® to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers (Top1, Top2, Ki67, RAD51, ABCG2, H2AX, TUNEL) in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses. Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median 47-63 CTCs/ml; range 0-2020 CTCs/ml). Top1, Top2, and TUNEL expression was detected in 52%-90% of samples; no significant associations with OS were observed in pre-treatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared to those with higher positivity (14.1 months vs. 11.0 months, respectively, HR 0.7, P=0.02); this difference was not seen in TPC-treated patients (HR 1.12, P=0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR 0.57, P=0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.

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