A digital RNA signature of Circulating Tumor Cells predicting early therapeutic response in localized and metastatic breast cancer [Research Articles]

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 (p=0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC-Score correlates with overall survival (p= 0.02), as does persistent CTC signal after four weeks of treatment (p=0.01). In the subset with estrogen receptor (ER)-positive disease, failure to suppress ER-signaling within CTCs after three weeks of endocrine therapy predicts early progression (p=0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of ESR1 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.

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