Phenotypic Plasticity in Circulating Tumor Cells Is Associated with Poor Response to Therapy in Metastatic Breast Cancer Patients

Authors

Evan N Cohen
Gitanjali Jayachandran
Hui Gao
Phillip Peabody
Heather B McBride
Franklin D Alvarez
Megumi Kai
Juhee Song
Yu Shen
Jie S Willey
Bora Lim
Vicente Valero
Naoto T Ueno
James M Reuben

Publication Date

3-6-2023

Journal

Cancers

Abstract

Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC counts decreased with therapy, and progressors had higher CTC counts than non-progressors. CTC count was prognostic primarily at the start of therapy in univariate and multivariate analyses but had less prognostic utility at 6 months to 1 year later. In contrast, gene expression, including both epithelial and mesenchymal markers, identified high-risk patients after 6-9 months of treatment, and progressors had a shift towards mesenchymal CTC gene expression on therapy. Cross-sectional analysis showed higher CTC-related gene expression in progressors 6-15 months after baseline. Furthermore, patients with higher CTC counts and CTC gene expression experienced more progression events. Longitudinal time-dependent multivariate analysis indicated that CTC count, triple-negative status, and CTC expression of FGFR1 significantly correlated with inferior progression-free survival while CTC count and triple-negative status correlated with inferior overall survival. This highlights the utility of protein-agnostic CTC enrichment and multimodality analysis to capture the heterogeneity of CTCs.

Keywords

EMT, biomarkers, biopsy, blood, breast cancer, breast neoplasms/pathology, circulating, circulating tumor cells (CTCs), circulating/pathology, liquid biopsy, metastatic process, neoplasms/diagnosis, neoplastic cells, tumor

DOI

10.3390/cancers15051616

PMID

36900406

PMCID

PMC10000974

PubMedCentral® Posted Date

3-6-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes