Correlations of estrogen receptor (ER) related genomic transcription and ER gene expression with increasing AJCC stage of ER-positive breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1044-1044
Author(s):  
E. Andreopoulou ◽  
C. Hatzis ◽  
D. Booser ◽  
V. Valero ◽  
M. J. Wallace ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Stage Iv ◽  
Initial Presentation ◽  
Clinical Samples ◽  
Expression Levels ◽  
Pathologic Stage ◽  
Ajcc Stage ◽  
Er Positive ◽  
Positive Breast Cancer

1044 Background: Advanced stages of ER-positive breast cancer may have decreased tumor dependence on estrogen, possibly due to biological selection and/or progression. The sensitivity to endocrine therapy (SET) index measures transcriptional activity of the ER genomic pathway (165 ER-related genes). We investigated whether expression of genes for receptors ER (ESR1), progesterone receptor (PGR), or HER-2 (ERBB2), the SET index, or a housekeeper gene (GAPDH) vary by stage of ER-positive breast cancer. Methods: We evaluated gene expression profiles (Affymetrix U133 microarrays, Affymetrix, Santa Clara, CA) from 956 patients’ clinical samples of ER-positive breast cancer, including 290 new samples profiled at MDACC and 666 samples from published datasets. Microarray data were uniformly normalized, log-transformed, and expression levels for single genes and the SET index were compared to pathologic AJCC stage (315 patients were stage I, 362 stage IIA, 151 stage IIB, 29 stage III, 27 stage IV at initial presentation, and 72 stage IV previously treated and/or at relapse) using a median ordered regression analysis (p < 0.05 was significant). Results: SET index significantly decreased with advancing pathologic stage (p < 0.001), and PGR expression levels showed a similar, but lesser, effect (p = 0.014). However, expression levels of ESR1 and ERBB2 did not vary by stage. Overall, GAPDH gene expression increased with stage (p < 0.001), but that effect was only observed in stages III and IV. Expression of these genes was not significantly different between stage IV disease at initial presentation or at relapse. Conclusions: Expression levels of ESR1 and ERBB2 receptor genes did not vary, but ER-related genomic transcription (SET index and, to a lesser extent, PGR) declined significantly with increasing pathologic stage. This suggests that ER-positive breast cancer tends to have less transcriptional dependence on estrogen with increasing pathologic stage. The observed increase in expression of GAPDH in stages III and IV might reflect higher metabolic activity in advanced ER-positive breast cancer and deserves further study. [Table: see text]

scholarly journals Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

2010 ◽  
Vol 28 (7) ◽  
pp. 1161-1167 ◽  
Author(s):  
Anita K. Dunbier ◽  
Helen Anderson ◽  
Zara Ghazoui ◽  
Elizabeth J. Folkerd ◽  
Roger A'Hern ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Multivariable Analysis ◽  
Independent Set ◽  
Breast Cancers ◽  
Plasma Estradiol ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women. Materials and Methods Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively). Conclusion Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

scholarly journals Quantitative Gene Expression by Recurrence Score in ER-Positive Breast Cancer, by Age

2015 ◽  
Vol 32 (12) ◽  
pp. 1222-1236 ◽  
Author(s):  
Sandra M. Swain ◽  
Raquel Nunes ◽  
Carl Yoshizawa ◽  
Megan Rothney ◽  
Amy P. Sing
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Recurrence Score ◽  
Quantitative Gene Expression ◽  
Er Positive ◽  
Positive Breast Cancer

scholarly journals Low residual proliferation after short-term letrozole therapy is an early predictive marker of response in high proliferative ER-positive breast cancer

2011 ◽  
Vol 18 (6) ◽  
pp. 721-730 ◽  
Author(s):  
Philippe L Bedard ◽  
Sandeep K Singhal ◽  
Michail Ignatiadis ◽  
Ian Bradbury ◽  
Benjamin Haibe-Kains ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Response ◽  
Histological Grade ◽  
Low Grade ◽  
High Grade ◽  
Early Assessment ◽  
Short Term ◽  
Er Positive ◽  
Positive Breast Cancer

The gene expression grade index (GGI) is a 97-gene algorithm that measures proliferation and divides intermediate histological grade tumors into two distinct groups. We investigated the association between early changes in GGI and clinical response to neoadjuvant letrozole and compared this to Ki67 values. The paired gene expression data at the beginning and after 10–14 days of neoadjuvant letrozole treatment were available for 52 post-menopausal patients with estrogen receptor (ER)-positive breast cancer. Baseline values and changes in GGI, Ki67, and RNA expression modules representing oncogenic signaling pathways were compared to sonographic tumor volume changes after 3 months of treatment in the subsets of patients defined by high and low baseline GGI. The clinical response was observed in 80% genomic low-grade (24/30) and 59% genomic high-grade (13/22) tumors (P=0.10). Low residual proliferation after 10–14 days of neoadjuvant letrozole therapy, measured by either GGI or Ki67, was associated with sonographic response in genomic high-grade (GGI, P=0.003; Ki67, P=0.017) but not genomic low-grade (GGI, P=0.25; Ki67, P=1.0) tumors. The analysis of expression modules suggested that sonographic response to letrozole in genomic high-grade tumors was associated with an early reduction in IGF1 signaling (unadjusted P=0.018). The major conclusion of this study is that the early assessment of proliferation after short-term endocrine therapy may be useful to evaluate endocrine responsiveness, particularly in genomic high-grade ER-positive breast cancer.

scholarly journals Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

2011 ◽  
Vol 29 (31) ◽  
pp. 4160-4167 ◽  
Author(s):  
Chungyeul Kim ◽  
Gong Tang ◽  
Katherine L. Pogue-Geile ◽  
Joseph P. Costantino ◽  
Frederick L. Baehner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Tamoxifen Resistance ◽  
Linear Predictor ◽  
Treatment And Prevention ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

scholarly journals Concordance among gene-expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 502-502 ◽  
Author(s):  
A. Prat ◽  
J. S. Parker ◽  
C. Fan ◽  
M. C. U. Cheang ◽  
L. D. Miller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Adjuvant Tamoxifen ◽  
Er Positive ◽  
Positive Breast Cancer

scholarly journals Clinical and Molecular Characteristics of ER-Positive Breast Cancer Tumors Identified as Ultralow Risk by the 70-Gene Signature in a Randomized Clinical Trial

2020 ◽  
Author(s):  
Annelie Johansson ◽  
Nancy Yiu-Lin Yu ◽  
Adina Iftimi ◽  
Nicholas P. Tobin ◽  
Laura van't Veer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
High Risk ◽  
Gene Signature ◽  
Tumor Characteristics ◽  
Breast Cancer Patients ◽  
Fatal Disease ◽  
Er Positive ◽  
Gene Modules ◽  
Positive Breast Cancer

Abstract BackgroundBreast cancer tumors are heterogenous, including their metastatic potential and time to distant metastasis. Patients with estrogen receptor (ER)-positive tumors have a continuous long-term risk of fatal disease decades after diagnosis. Recently, ER-positive breast cancer patients classified as having ultralow risk tumors by the 70-gene expression signature (MammaPrint) were associated with a minimal risk of fatal disease. However, the underlying tumor characteristics of ultralow risk tumors are unknown.MethodsSecondary analysis of the Stockholm tamoxifen randomized trial (STO-3, 1976-1990) enrolling postmenopausal lymph node-negative breast cancer patients. Immunohistochemistry of the clinically used breast cancer markers (n=727 patients) and gene expression profiling by Agilent microarrays (n=652 patients) were performed in 2014. Ultralow risk tumors, identified by the 70-gene signature, were compared to other ER-positive tumors (of low/high risk) and Luminal A and B PAM50 subtype tumors (ER-positive, low/high risk) by the clinical markers and multi-gene modules, representative of specific biological processes and pathways, using Fisher’s exact test. Furthermore, differential gene expression analysis was performed contrasting ultralow risk tumors to other ER-positive tumors (of low/high risk) using t-statistics and false discovery rate (FDR).ResultsUltralow risk tumors were significantly (P<0.05) more likely to be of smaller tumor size, lower tumor grade, progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative and Ki-67-low. Moreover, several multi-gene modules were significantly differentially expressed in ultralow risk tumors, including AKT/mTOR, proliferation-marker AURKA, HER2/ERBB2, IGF1, PTEN-loss, PI3KCA-mutations, and immune response-modules IMMUNE1 and STAT1. Furthermore, ultralow risk tumors showed significantly (FDR<0.001) lower expression of genes involved in the immune response, histone modulation, PI3K/Akt/mTOR pathway, and higher expression of homeobox genes and genes involved in epithelial-to-mesenchymal transition, among others.ConclusionsUltralow risk tumors have significantly different tumor characteristics compared to other ER-positive tumors. Identifying clinical and biological characteristics of low-risk tumors is important to improve our understanding of non-fatal versus fatal breast cancer.Trial registrationThe trial center for the STO-3 trial was the Regional Cancer Center Stockholm-Gotland in Sweden. However, the start of the trial in 1976 was well before trial registration started in Sweden, therefore information on trial number is not available.

scholarly journals Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen

2012 ◽  
Vol 23 (11) ◽  
pp. 2866-2873 ◽  
Author(s):  
A. Prat ◽  
J.S. Parker ◽  
C. Fan ◽  
M.C.U. Cheang ◽  
L.D. Miller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Adjuvant Tamoxifen ◽  
Er Positive ◽  
Positive Breast Cancer
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