Unknown,Transcriptomics,Genomics,Proteomics

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Breast cancer and liver tissue biopsies used to develop and validate an index for liver contamination in metastatic breast cancer

ABSTRACT: PURPOSE: To develop an index capable of detecting and quantifying the extent of liver RNA contamination in liver biopsies of metastatic breast cancer METHODS: We developed a microarray-based gene expression liver index by comparing the expression levels of genes in liver tissue biopsies and in primary breast cancer biopsies. The predictive performance of the index was then evaluated in defined mixtures of liver and breast cancer RNA. A calibration curve was established to allow estimation of the liver RNA content in unknown metastatic breast cancer samples. A set of liver biopsies and primary breast cancer biopsies were used to identify genes that were expressed significantly higher in liver tissue. These genes were used in a liver index, which was validated in a new set of liver and primary breast cancer biopsies. A set of liver/breast cancer RNA mixtures was used to establish a calibration curve to allow quantification of liver contamination in metastatic breast cancer samples. The prediction error of the calibration curve was assessed in a new set of liver/breast cancer RNA mixtures and applied to estimate the liver content in a set of unknown metastatic breast cancer biopsies.

ORGANISM(S): Homo sapiens

SUBMITTER: Christos Hatzis

PROVIDER: E-GEOD-33116 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:There is 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 pre-analytical 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 SETER/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 progression-free (PFS) and overall survival (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% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical 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. 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 progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.485, 95% CI 0.265 to 0.889, p = 0.019; OS: HR 0.314, 95% CI 0.155 to 0.637, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good pre-analytical 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.

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Breast cancer and liver tissue biopsies used to develop and validate an index for liver contamination in metastatic breast cancer

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