A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer

Abstract

The multiplicity of new therapies for breast cancer presents a challenge for treatment selection. We describe a 17-gene digital signature of breast circulating tumor cell (CTC)-derived transcripts enriched from blood, enabling high-sensitivity early monitoring of response. In a prospective cohort of localized breast cancer, an elevated CTC score after three cycles of neoadjuvant therapy is associated with residual disease at surgery ( = 0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC score correlates with overall survival ( = 0.02), as does persistent CTC signal after 4 weeks of treatment ( = 0.01). In the subset with estrogen receptor (ER)-positive disease, failure to suppress ER signaling within CTCs after 3 weeks of endocrine therapy predicts early progression ( = 0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of mutations, pointing to diverse mechanisms of acquired endocrine drug resistance. Thus, CTC-derived digital RNA signatures enable noninvasive pharmacodynamic measurements to inform therapy in breast cancer. Digital analysis of RNA from CTCs interrogates treatment responses of both localized and metastatic breast cancer. Quantifying CTC-derived ER signaling during treatment identifies patients failing to respond to ER suppression despite having functional ESR1. Thus, noninvasive scoring of CTC-RNA signatures may help guide therapeutic choices in localized and advanced breast cancer. .

Tracking cancer progression: from circulating tumor cells to metastasis

“…In general, most of these studies have been performed in low numbers of patients and the prognostic value of these gene signatures will have to be tested in larger clinical trials. In localized and metastatic breast cancer, a recent analysis identified a 17-gene digital signature in CTCs that was associated with residual disease at surgery and with treatment response [121]. Another study developed an assay based on eight CTC-derived transcripts in prostate cancer that was predictive of abiraterone response in the metastatic setting and of early dissemination in localized disease [122].…”

A single cell atlas of the healthy breast tissues reveal clinically relevant clusters of breast epithelial cells

“…Similarly, signatures derived through scRNA-seq of a chemoresistant subpopulation of TNBCs did not show overlap with any of our normal cell clusters (Kim et al, 2018). Genes in the breast cancer-specific RNA signature that detect circulating tumor cells did not show overlap with any specific cluster, but genes like PIP, CXCL14, and SFRP2, which are markers of circulating tumor cells are enriched in clusters 4, 6 and 12, respectively (Kwan et al, 2018). Thus, genomic aberrations and transcription programming rather than cell-of-origin may have given rise to drug resistant and metastatic subpopulations of tumor cells.…”

Prognostic significance of a combined gene expression analysis in EpCAM(+) CTCs in metastatic breast cancer based on a long follow-up

“…In MBC patients with ER-positive primary tumors, it has been proposed that lack of ER expression in CTCs could be a possible mechanism of resistance to endocrine therapy (50), and that is also associated to increased migration and invasion (51). In MBC patients with ER-positive disease, the presence of ESR1 mutations in CTCs is one of the diverse mechanisms of acquired endocrine drug resistance and could explain failure to suppress ER signaling within CTCs after 3 weeks of endocrine therapy (52). Another study has shown that in MBC ESR1 mutations were absent in primary tumor tissue samples and were detected only in metastases obtained after CTC characterization (53).…”