Transcription profiling of human breast cancer samples that were treated with tamoxifen identifier a 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Zhang Y
PROVIDER: S-ECPF-GEOD-12093 | biostudies-other | 2009 Jul
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Classification of tamixifen-treated breast cancer patients into high and low risk groups using the 76-gene signature
2008-10-07 | GSE12093 | GEO
Project description:Classification of tamixifen-treated breast cancer patients into high and low risk groups using the 76-gene signature Experiment Overall Design: 136 breast cancer samples that were treated with tamoxifen were classified using the 76-gene signature
2008-10-26 | E-GEOD-12093 | biostudies-arrayexpress
Project description:Background: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings. Results: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29-3.13; p=0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response. Conclusions: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen. Experiment Overall Design: dataset of microarray experiments from primary breast tumors of patients treated by Tamoxifen in adjuvant setting. No replicate, no reference sample.
| S-ECPF-GEOD-9195 | biostudies-other
Project description:Background: Recently a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N-) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. Materials and Methods: Gene expression profiling of frozen samples from 198 N- systemically untreated patients was performed at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were performed with the genomic risk and adjusted for the clinical risk, defined by Adjuvant!Online. Results: The actual 5- and 10-year time to distant metastasis (TDM) were 98% (88%-100%) and 94% (83%-98%) respectively for the good profile group and 76% (68%- 82%) and 73% (65%-79%) for the poor profile group. The actual 5- and 10-year overall survival (OS) were 98% (88%-100%) and 87% (73%-94%) respectively for the good profile group and 84% (77%-89%) and 72% (63%-78%) for the poor profile group. We observed a strong time-dependency of this signature, leading to an adjusted HR of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years, and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for TDM and OS respectively. Conclusion: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases. Experiment Overall Design: dataset of microarray experiments from primary breast tumors used to validate the 76-gene signature (VERIDEX). No replicate, no reference sample.
| S-ECPF-GEOD-7390 | biostudies-other
Project description:Biopsies and surgical specimens were obtained from breast tumours treated and non-treated with celecoxib 400mg twice daily for 2 weeks
| S-ECPF-MTAB-566 | biostudies-other
Project description:To identify molecular markers indicative of response to tamoxifen and easily implemented in the routine setting, we recently reported three gene signatures that could stratify post-menopausal tamoxifen-treated, estrogen receptor-positive (ER+) patients according to outcome in the adjuvant setting. Here, we evaluated the predictive potential of the total of 14 genes included in the 3 gene signatures using 2 hormone-naïve Dutch ER+ cohorts of a total of 285 recurrent breast cancer patients treated with first-line tamoxifen. mRNA levels were measured by reverse transcriptase quantitative PCR (RT-qPCR) and the length of progression-free survival (PFS) was used as the primary endpoint. A Mann-Whitney U test was used to select for differentially expressed genes between tumors of patients who showed or did not show progressive disease within 6 months after start of tamoxifen treatment. Cox univariate and multivariate regression analysis for PFS were used to further assess their (independent) predictive potential. Five (BCAR3, BCL2, ESR1, IGF1R, and NCOA1) of the 14 genes analyzed showed significantly higher mRNA levels in tumors of patients who showed no disease progression within 6 months. Only BCAR3, BCL2 and NAT1 were significantly associated with a favorable PFS in multivariate analysis that included the traditional predictive factors: age, dominant relapse site, disease-free interval, ER and progesterone receptor (PGR), and adjuvant chemotherapy. This study shows that BCAR3, BCL2 and NAT1 in particular exhibit predictive promise regarding the efficacy of tamoxifen treatment in recurrent disease, in addition to the previously shown favorable outcome in the adjuvant setting.
| S-EPMC5528606 | biostudies-literature
Project description:Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I-III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1-3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19 2 and CYP2C19 17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19 17. Patients with at least one CYP2C19 2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19 2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19 2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19 2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment.
| S-EPMC3695326 | biostudies-literature
Project description:Breast cancer molecular prognostic tools that predict recurrence risk have mainly been established on endocrine-treated patients and thus are not optimal for the evaluation of benefit from endocrine therapy. The Stockholm tamoxifen (STO-3) trial which randomized postmenopausal node-negative patients to 2-year tamoxifen (followed by an optional randomization for an additional 3-year tamoxifen vs nil), versus no adjuvant treatment, provides a unique opportunity to evaluate long-term 20-year benefit of endocrine therapy within prognostic risk classes of the 70-gene prognosis signature that was developed on adjuvantly untreated patients.We assessed by Kaplan-Meier analysis 20-year breast cancer-specific survival (BCSS) and 10-year distant metastasis-free survival (DMFS) for 538 estrogen receptor (ER)-positive, STO-3 trial patients with retrospectively ascertained 70-gene prognosis classification. Multivariable analysis of long-term (20 years) BCSS by STO-3 trial arm in the 70-gene high-risk and low-risk subgroups was performed using Cox proportional hazard modeling adjusting for classical patient and tumor characteristics.Tamoxifen-treated, 70-gene low- and high-risk patients had 20-year BCSS of 90 and 83%, as compared to 80 and 65% for untreated patients, respectively (log-rank p < 0.0001). Notably, there is equivalent tamoxifen benefit in both high (HR 0.42 (0.21-0.86), p = 0.018) and low (HR 0.46 (0.25-0.85), p = 0.013) 70-gene risk categories even after adjusting for clinico-pathological factors for BCSS. Limited tamoxifen exposure as given in the STO-3 trial provides persistent benefit for 10-15 years after diagnosis in a time-varying analysis. 10-year DMFS was 93 and 85% for low- and high-risk tamoxifen-treated, versus 83 and 70% for low- and high-risk untreated patients, respectively (log-rank p < 0.0001).Patients with ER-positive breast cancer, regardless of high or low 70-gene risk classification, receive significant survival benefit lasting over 10 years from adjuvant tamoxifen therapy, even when given for a relatively short duration.
| S-EPMC5668340 | biostudies-other
Project description:The biological tumor samples (ie, breast tumor specimens) consisted of freshly frozen breast tumors from a population-based cohort of 315 women representing 65% of all breast cancers resected in Uppsala County, Sweden, from January 1, 1987 to December 31, 1989. Estrogen receptor status was determined by biochemical assay as part of the routine clinical procedure. An experienced pathologist determined the Elston-Ellis grades of the tumors, classifying the tumors into low, medium and high-grade tumors. The clinico-pathological characteristics accompanying each tumor include p53 status, ER status, tumor grade, lymph node status and patient age. Experiment Overall Design: All tumor specimens were assessed on U133 A and B arrays.
| S-ECPF-GEOD-3494 | biostudies-other
Project description:Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, even though distal regulatory elements play a central role in controlling transcription patterns. We used the histone mark H3K4me1 to analyze gain and loss of enhancer activity genome-wide in primary colon cancer lines relative to normal colon crypts. We identified thousands of variant enhancer loci (VELs) that comprise a signature that is robustly predictive of the in vivo colon cancer transcriptome. Furthermore, VELs are enriched in haplotype blocks containing colon cancer genetic risk variants, implicating these genomic regions in colon cancer pathogenesis. We propose that reproducible changes in the epigenome at enhancer elements drive a specific transcriptional program to promote colon carcinogenesis.
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