SET: a Robust 18-gene Predictor for Sensitivity to Endocrine Therapy for Metastatic Breast Cancer

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 index to measure gene expression microarray probe sets that were correlated with hormone receptors ( and ) and robust to preanalytical and analytical influences. We tested SET index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET assay to measure 18 informative, 10 reference transcripts, and sequence the ligand-binding domain (LBD) of using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET 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,  = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631,  = 0.001). Mutated LBD was detected in 8/53 (15%) of metastases, involving 1-98% of transcripts (all had high SET 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 was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated transcript.