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

Abstract

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.

The E2F Pathway Score as a Predictive Biomarker of Response to Neoadjuvant Therapy in ER+/HER2− Breast Cancer

“…Recently, several clinical trials have demonstrated that the addition of CDK4/6 selective inhibitors to endocrine therapy has improved progression-free survival as well as overall survival in patients with advanced breast cancer [ 83 , 84 , 85 ]. Since CDK is considered a key molecule for several cell cycle transitions, targeting this pathway has been studied in multiple cancer types in the last decade [ 86 , 87 , 88 , 89 , 90 , 91 ]. However, it also remains challenging to accurately identify patients who respond to the targeted therapies.…”

ColoType: a forty gene signature for consensus molecular subtyping of colorectal cancer tumors using whole-genome assay or targeted RNA-sequencing

“…Targeted RNA-seq is increasingly being used for clinical diagnostics 25 , 35 , 36 . For solutions requiring, say 25 to a few hundred genes, the cost of a sample’s library preparation is at least comparable to the cost of materials for other technologies.…”

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

“…(accession number GSE20194; n = 278) [51], Symmans et al (GSE25066; n = 508) [24], Vera-Ramirez et al (GSE28844; n = 33) [22], Noguchi et al (GSE32646; n = 115) [52], and Massarweh et al (GSE33658; n = 11) [23]. We used metastasis cohorts (Wang et al GSE2034 [18]; n = 286, Bos et al GSE12276 [17]; n = 204, Siegel et al GSE110590 [20]; n = 16, Sinn et al GSE124647 [53]; n = 140), which have the data of metastatic tumors, to investigate the G2M pathway scores in metastatic tumors. The GSE110590 cohort contained 16 samples of the primary tumors as well as 62 samples of the metastatic tumors from patients with matching primary tumors.…”