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Targeted exome DNA sequencing analysis of POETIC Good/Poor Responders to aromatase inhibitors based on change in Ki67

ABSTRACT: Using RNAseq, we compare the 15% of poorest responders (PRs, n=177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant aromatase inhibitors to good responders (GRs, n=190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In the POETIC trial, 4,480 postmenopausal women with primary ER+ BC were randomised 2:1 to receive either treatment with a non-steroidal AI (letrozole or anastrozole) for 2 weeks before and 2 weeks after surgery or to no perisurgical treatment. Only AI-treated patients with HER2- tumors, paired baseline and surgery Ki67 available, and baseline Ki67 immunohistochemistry (IHC) >10% (to minimise imprecision in proportional Ki67 falls) were included for selection. Data is targeted exome DNA sequencing analysis of POETIC Good/Poor Responders to aromatase inhibitors based on change in Ki67.

PROVIDER: EGAS00001007303 | EGA |

REPOSITORIES: EGA

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Baseline RNAseq analysis of POETIC Good/Poor Responders to aromatase inhibitors based on change in Ki67

Project description:Using RNAseq, we compare the 15% of poorest responders (PRs, n=177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant aromatase inhibitors to good responders (GRs, n=190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In the POETIC trial, 4,480 postmenopausal women with primary ER+ BC were randomised 2:1 to receive either treatment with a non-steroidal AI (letrozole or anastrozole) for 2 weeks before and 2 weeks after surgery or to no perisurgical treatment. Only AI-treated patients with HER2- tumors, paired baseline and surgery Ki67 available, and baseline Ki67 immunohistochemistry (IHC) >10% (to minimise imprecision in proportional Ki67 falls) were included for selection. Data is baseline RNAseq analysis of POETIC Good/Poor Responders to aromatase inhibitors based on change in Ki67.

| EGAS00001007302 | EGA

cc09fe92-a6fb-4ff9-92b3-f093d762d874 - samples

Project description:Using RNAseq, we compare the 15% of poorest responders (PRs, n=177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant aromatase inhibitors to good responders (GRs, n=190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In the POETIC trial, 4,480 postmenopausal women with primary ER+ BC were randomised 2:1 to receive either treatment with a non-steroidal AI (letrozole or anastrozole) for 2 weeks before and 2 weeks after surgery or to no perisurgical treatment. Only AI-treated patients with HER2- tumors, paired baseline and surgery Ki67 available, and baseline Ki67 immunohistochemistry (IHC) >10% (to minimise imprecision in proportional Ki67 falls) were included for selection. Data is baseline RNAseq and targeted exome DNA sequencing analysis of POETIC Good/Poor Responders to aromatase inhibitors based on change in Ki67.

| EGAD00001010919 | EGA

Molecular profiling of aromatase inhibitor-treated post-menopausal breast tumors identifies immunerelated correlates of resistance

Project description:To identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of aromatase inhibitor (AI) treatment. Analysis of gene-expression measured in core-cut biopsies at baseline and surgery from patients received 2-week’s presurgical AI revealed: i) the molecular response to AI treatment varies greatly between patients, consistent with the variable clinical benefit from AI treatment; ii) higher baseline expression of an inflammatory signature is associated with poor antiproliferative response, and should be assessed further as a novel biomarker and potential target for AI-treated patients.

2020-06-29 | GSE153470 | GEO

Impact of aromatase inhibitor treatment on global gene expression and its association with antiproliferative response in ER+ breast cancer in postmenopausal patients

Project description:Endocrine therapy reduces breast cancer mortality by 40%; but resistance remains a major clinical problem. Identification of gene signatures associated with resistance during endocrine treatment should enable rational therapeutic choices to be made to combat this in individual patients. Here we present an in-depth analysis of global gene-expression that was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week’s presurgical AI (n=198) or no presurgical treatment (Control n=56) in the POETIC trial, using changes-in and residual-of the proliferation marker, Ki67 as end-points, to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI-therapy resistance. Our study revealed a high degree of heterogeneity in adaptive mechanisms after as little as 2-weeks’ AI-therapy, however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors.

2020-02-24 | GSE126870 | GEO

ena-DATASET-ICR-18-08-2016-18:34:21:662-52 - samples

Project description:Presurgical studies allow study of the relationship between mutations and response of estrogen receptor positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in Phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 Controls). In poor responders (based on Ki67 change) we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in approximately 30% of tumours. In Phase II we combine targeted sequencing on another 28 treated patients with Phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

| EGAD00001002651 | EGA

Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

| EGAS00001001940 | EGA

Major impact of sampling methodology on gene expression in estrogen receptor positive breast cancer

Project description:To investigate the impact of sampling methodology on gene expression data from primary estrogen receptor positive (ER+) breast cancer biopsies. Analysis of global gene-expression measured in core-cut biopsies at baseline and surgery from patients randomised to receive either 2-week’s presurgical aromatase inhibitor (AI, n=157) or no presurgical treatment (n=56) revealed genes most markedly altered in the AI group (e.g. FOS, DUSP1, RGS1, FOSB) were equally altered in the no-treatment group; some widely investigated genes that were apparently unaffected in the AI group (e.g. MYC) were counter-altered in the Control group masking actual AI-dependent changes. In the absence of a Control group these artefactual changes would likely lead to the most affected genes being the erroneous focus of research. The findings are likely relevant to all archival collections of ER+ breast cancer.

2018-10-22 | GSE105777 | GEO

Estrogen Receptor Positive Breast Cancer: Aromatase Inhibitor Response Study

Project description:<p>Highly variable outcomes are observed in patients with estrogen receptor positive (ER+) breast cancer who undergo preoperative estrogen deprivation therapy with aromatase inhibitors (AI). In this study, 46 baseline tumor and normal genomes and 31 baseline tumor/normal exomes of participants selected from two clinical trials of neoadjuvant AI therapy on ER+ breast cancer were sequenced to identify somatic alterations that correlate with response to AI, to screen for therapeutic targets and to elucidate the genetic landscape of ER+ breast cancer. From the same set of patients we later performed deep genomic characterization of a subset of matched primary tumors after four months of AI therapy, generating comprehensive information about the range of changes that occur when ER+ breast cancers are subjected to estrogen deprivation. This data includes whole genome sequence and transcriptome data. To better understand tumor heterogeneity and the evolution of resistance to estrogen-deprivation therapy, a subset of these tumours, along with 38 additional cases were sequenced to greater depth using targeted capture with a gene panel.</p>

| phs000472 | dbGaP

Molecular changes in premenopausal estrogen receptor-positive primary breast cancer after oophorectomy

Project description:For premenopausal women with primary ER+ breast cancer, oophorectomy (OvX) is an evidence-based cost-effective option and is standard treatment in many countries. However, there is virtually no data describing the effects of OvX on breast tumour biology. We therefore characterized the endocrine and genome-wide transcriptional impact of OvX in 56 premenopausal women with ER+ breast cancer for two weeks prior to mastectomy. Plasma estradiol concentrations decreased from 421±305 to 24.1±24.5 pmol/l (mean±sd) 24 hours after OvX and to 8.8±7.3pmol/l two weeks later at mastectomy. Ki67 decreased in 33/36 (91.7%) tumours. The expression of 655 genes changed significantly (FDR<1%) with an absolute mean fold-change (FC) ≥1.25 (257 up, 398 down). Archetypal oestrogen-regulated genes, proliferation-associated genes and putative progesterone-regulated genes were strongly down-regulated. The gene expression changes did not differ according to HER2 status and correlated strongly with those after aromatase inhibitor (AI) treatment in 81 postmenopausal women. However, after OvX the mean FC was significantly higher compared to AI. In conclusion, changes in tumoural gene expression after OvX were largely similar but of a greater magnitude to those observed after AI in postmenopausal patients but OvX appeared to have a greater effect on progesterone-regulated genes than AI.

2018-02-14 | GSE97221 | GEO

Expression data from MCF-7aro aromatase inhibitor-resistant, tamoxifen-resistant and LTEDaro lines.

Project description:MCF-7aro cells were used to generate a cell culture model system that is resistant to 3 aromatase inhibitors (AIs), letrozole, anastrozole and exemestane. For comparison, the MCF-7aro cells were also used to generate the tamoxifen-resistant cells as well as long-term estrogen deprived, LTEDaro. Affymetrix microarray analysis was performed to determine changes in gene expression that are unique to AI-resistance. Keywords: cell lines, aromatase inhibitor resistance, tamoxifen resistance

2008-03-22 | GSE10911 | GEO

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