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There is a clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2−) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR  index to measure gene expression microarray probe sets that were correlated with hormone receptors ( ESR1  and  PGR ) and robust to preanalytical and analytical influences. We tested SET ER/PR  index in biopsies of metastastic HR+/HER2− breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR  assay to measure 18 informative, 10 reference transcripts, and sequence the ligand-binding domain (LBD) of  ESR1  using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR  index in metastatic samples predicted longer PFS and OS when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955,  p  = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631,  p  = 0.001). Mutated  ESR1  LBD was detected in 8/53 (15%) of metastases, involving 1−98% of  ESR1  transcripts (all had high SET ER/PR  index). A signature based on probe sets with good preanalytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR  was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2− breast cancer, especially in the absence of mutated  ESR1  transcript.

SETER/PR: a robust 18-gene predictor for sensitivity to endocrine therapy for metastatic breast cancer