Molecular characterization of breast cancer CTCs associated with brain metastasis

Debasish Boral,Antonio Scamardo,Tuan Z Tan,Haowen N Liu,Marc L Sprouse,Jean P Thiery,Dario Marchetti,David S Hong,Wei Yin,Monika Vishnoi,Jenny C Chang

doi:10.1038/s41467-017-00196-1

Abstract

The enumeration of EpCAM-positive circulating tumor cells (CTCs) has allowed estimation of overall metastatic burden in breast cancer patients. However, a thorough understanding of CTCs associated with breast cancer brain metastasis (BCBM) is necessary for early identification and evaluation of treatment response to BCBM. Here we report that BCBM CTCs is enriched in a distinct sub-population of cells identifiable by their biomarker expression and mutational content. Deriving from a comprehensive analysis of CTC transcriptomes, we discovered a unique “circulating tumor cell gene signature” that is distinct from primary breast cancer tissues. Further dissection of the circulating tumor cell gene signature identified signaling pathways associated with BCBM CTCs that may have roles in potentiating BCBM. This study proposes CTC biomarkers and signaling pathways implicated in BCBM that may be used either as a screening tool for brain micro-metastasis detection or for making rational treatment decisions and monitoring therapeutic response in patients with BCBM.

Highlights

The enumeration of epithelial cell adhesion molecule (EpCAM)-positive circulating tumor cells (CTCs) has allowed estimation of overall metastatic burden in breast cancer patients
We demonstrate that patients with breast cancer brain metastasis (BCBM) harbor CTCs with higher expression of proliferationrelated biomarkers, and unique signaling mechanisms that may be responsible for brain metastasis
Because the only FDA-cleared platform for clinical CTC testing—CellSearch®—identifies CTCs based on positivity for the epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and DAPI, plus absence of the lymphocytic marker CD4517, de-differentiated EpCAM—

Summary

Introduction

The enumeration of EpCAM-positive circulating tumor cells (CTCs) has allowed estimation of overall metastatic burden in breast cancer patients. Ultiple studies concur that circulating tumor cells (CTCs)—the “seeds” of fatal metastasis—intravasate into the bloodstream throughout the early stages of cancer promoting the generation of micro-metastatic reservoirs, some of which can progress to macro-metastatic disease[1, 2]. It may take years-to-decades for disseminated cancer cells to progress to radiologically detectable metastatic masses[3,4,5], by the time it is detected, the metastatic mass usually proliferates at an exponential rate precluding the use of curative treatment options[6,7,8]. This is true for breast cancer patients with brain metastasis (BCBM), 30% of whom are undiagnosed by current radiological methods and are diagnosed only at autopsy[9]

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