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

Author:

Cohen Evan N.12ORCID,Jayachandran Gitanjali12,Gao Hui12,Peabody Phillip12,McBride Heather B.12,Alvarez Franklin D.12,Kai Megumi13,Song Juhee4ORCID,Shen Yu4ORCID,Willey Jie S.13,Lim Bora135ORCID,Valero Vicente13,Ueno Naoto T.136ORCID,Reuben James M.12

Affiliation:

1. Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2. Department of Hematopathology Research, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

3. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

5. Breast Cancer Research Program, Baylor College of Medicine, Houston, TX 77030, USA

6. Cancer Biology and Therapeutic Program, University of Hawai’i Cancer Center, Honolulu, HI 96822, USA

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.

Funder

University of Texas MD Anderson’s Cancer Center

NCI’s Research Specialist

Showa Denko Materials Co., Ltd.

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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