Distinct molecular profiles of interval and screen-detected tumors in a real-world breast cancer registry.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15587-e15587
Author(s):  
Sharon Wilks ◽  
Kristi McIntyre ◽  
Linda K. Han ◽  
Michelina Marie Cairo ◽  
Julie Barone ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Real World ◽  
Ductal Carcinoma ◽  
Expression Profiles ◽  
Distant Metastases ◽  
Breast Cancers ◽  
Real World Data ◽  
Biological Difference ◽  
Significant Difference

e15587 Background: Interval breast cancers (BC) are detected between routine screening mammograms and are associated with worse prognosis, requiring more aggressive treatment compared to screen-detected BC identified during scheduled mammograms. Identifying molecular differences between interval BC and screen detected BC may lay the foundation for developing novel therapies. In this study, we compared gene expression profiles of interval BC to screen-detected BC. Methods: This analysis included a subset of 2260 patients enrolled in the FLEX Registry (NCT03053193), an ongoing, prospective study evaluating primary tumor samples from stage I-III BC patients who receive 70-gene risk of recurrence testing (70GS), 80-gene molecular subtyping (80GS), and consent to collection of clinically annotated full genome data. Interval BC were diagnosed < 12 months following a normal screening mammogram. Breast tumors were classified by 70GS as having a Low Risk (LR) or High Risk (HR) of distant metastases. Tumors were classified as Luminal, HER2, or Basal type by 80GS. Differential gene expression analysis was performed with limma and subsequent pathway analysis with DAVID and GSEA. Differences in the proportion of 70GS or 80GS results, 70GS index, and Ki67 were assessed by Chi-squared test or t-test. Results: In this study, 81% (1834/2260) of patients had screen-detected BC and 19% (426) had interval BC. A higher proportion of interval BC (51%) were HR compared to screen-detected BC (44%; p = 0.01). Most LR tumors were invasive ductal carcinoma (78% interval and 73% screen-detected) and over 99% were Luminal type. Between the two LR groups, 70GS indices were similar and there was no significant difference in transcriptional profiles. Basal and HER2 subtypes were more frequent among HR interval BC compared to screen-detected BC (p = 0.03). HR interval BC had 70GS indices of higher risk compared to HR screen-detected BC (p = 0.02). Differentially expressed genes in HR interval BC compared to HR screen-detected BC were associated with MYC signaling and mitosis, which was concordant with higher Ki67 by IHC (p = 0.007). Conclusions: This real-world data analysis shows interval BC are not all biologically High Risk and can be further stratified by the 70GS, aiding in treatment decisions. Preliminary results suggest that following 70GS LR classification, there is no biological difference between interval BC and screen-detected BC. In contrast, there are distinct biological processes associated with HR interval BC, which may have implications in the management of these cancers. Clinical trial information: NCT03053193.

scholarly journals In Silico Discovery of Mitosis Regulation Networks Associated with Early Distant Metastases in Estrogen Receptor Positive Breast Cancers

2013 ◽  
Vol 12 ◽  
pp. CIN.S10329 ◽  
Author(s):  
Yuriy Gusev ◽  
Rebecca B. Riggins ◽  
Krithika Bhuvaneshwar ◽  
Robinder Gauba ◽  
Laura Sheahan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
In Silico ◽  
Expression Profiles ◽  
Metastatic Breast ◽  
Distant Metastases ◽  
Mitotic Checkpoint ◽  
Breast Cancers ◽  
Estrogen Receptor Positive

The aim of this study was to perform comparative analysis of multiple public datasets of gene expression in order to identify common genes as potential prognostic biomarkers. Additionally, the study sought to identify biological processes and pathways that are most significantly associated with early distant metastases (<5 years) in women with estrogen receptor-positive (ER+) breast tumors. Datasets from three published studies were selected for in silico analysis of gene expression profiles of ER+ breast cancer, using time to distant metastasis as the clinical endpoint. A subset of 44 differently expressed genes (DEGs) was found common to all three studies and characterized by mitotic checkpoint genes and pathways that regulate mitotic spindle and chromosome dynamics. DEG promoter regions were enriched with NFY binding sites. Analysis of miRNA target sites identified significant enrichment of miR-192, miR-193B, and miR-16–1 targets. Aberrant mitotic regulation could drive increased genomic instability leading to a progression towards an early onset metastatic phenotype. The relative importance of mitotic instability may reflect the clinical utility of mitotic poisons in metastatic breast cancer, including poisons such as the taxanes, epothilones, and vinca alkaloids.

scholarly journals Comparative gene expression profiling of mouse ovaries upon stimulation with natural equine chorionic gonadotropin (N-eCG) and tethered recombinant-eCG (R-eCG)

2020 ◽  
Author(s):  
Kwan-Sik Min ◽  
Jong-Ju Park ◽  
So-Yun Lee ◽  
Munkhzaya Byambaragchaa ◽  
Myung-Hwa Kang
Keyword(s):  
Gene Expression ◽  
Chorionic Gonadotropin ◽  
Expression Profiles ◽  
Expression System ◽  
Laboratory Animals ◽  
Metabolic Clearance ◽  
Qrt Pcr ◽  
Significant Difference ◽  
Equine Chorionic Gonadotropin

Abstract Background: Equine chorionic gonadotropin (eCG) induces super-ovulation in laboratory animals. Notwithstanding its extensive usage, limited information is available regarding the differences between the in vivo effects of natural eCG (N-eCG) and recombinant eCG (R-eCG). This study aimed to investigate the gene expression profiles of mouse ovaries upon stimulation with N-eCG and R-eCG produced from CHO-suspension (CHO-S) cells. R-eCG gene was constructed and transfected into CHO-S cells and quantified. Subsequently, we determined the metabolic clearance rate (MCR) of N-eCG and R-eCG up to 24 h after intravenous administration through the mice tail vein and identified differentially expressed genes in both ovarian tissues, via quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC).Results: R-eCG was markedly expressed initially after transfection and maintained until recovery on day 9. Glycan chains were substantially modified in R-eCG protein produced from CHO-S cells and eliminated through PNGase F treatment. The MCR was higher for R-eCG than for N-eCG, and no significant difference was observed after 60 min. Notwithstanding their low concentrations, R-eCG and N-eCG were detected in the blood at 24h post-injection. Microarray analysis of ovarian tissue revealed that 20 of 12,816 genes assessed therein were significantly up-regulated and 43 genes were down-regulated by >2-fold in the group that received R-eCG (63 [0.49%] differentially regulated genes in total). The microarray results were concurrent with and hence validated by those of RT-PCR, qRT-PCR, and IHC analyses.Conclusions: The present results indicate that R-eCG can be adequately produced through a cell-based expression system through post-translational modification of eCG and can induce ovulation in vivo. These results provide novel insights into the molecular mechanisms underlying the up- or down-regulation of specific ovarian genes and the production of R-eCG with enhanced biological activity in vivo.

scholarly journals Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5550
Author(s):  
Morten Fink ◽  
Anders Schwartz Vittrup ◽  
Lars Bastholt ◽  
Inge Marie Svane ◽  
Marco Donia ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Real World ◽  
Negative Impact ◽  
Cox Proportional Hazards Model ◽  
Induction Phase ◽  
Discontinue Treatment ◽  
Real World Data ◽  
World Data ◽  
Significant Difference

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30–40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination therapy with ipilimumab and nivolumab is the first line of treatment for many patients with metastatic melanoma. In this follow-up study, with real-world data from the nationwide DAMMED database, we investigated whether there was a difference in progression-free survival (PFS) and overall survival (OS) for patients who discontinued or did not discontinue treatment within the first four doses of treatment due to irAEs. In total, 448 patients were treated with ipilimumab and nivolumab. Of these, 133 patients discontinued due to irAEs in the induction phase. Using the Cox proportional hazards model, there was no significant difference in PFS when comparing the group that discontinued with the group that did not discontinue. The group that discontinued had a significantly longer OS than the group that received the full length of treatment. Therefore, we conclude that there is no significant negative impact on efficacy for patients who discontinue due to irAEs in the induction phase of combination immunotherapy for metastatic melanoma.

scholarly journals Identification and Validation of a Predictive Immune-related Genes Signature for the Prognosis of Cholangiocarcinoma

2020 ◽  
Author(s):  
Rui Zhang ◽  
Chen Chen ◽  
Qi Li ◽  
Jialu Fu ◽  
Dong Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
High Risk ◽  
Risk Score ◽  
Risk Model ◽  
Predictive Accuracy ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Immune Related Genes

Abstract Background: Immune-related genes (IRGs) play a crucial role in the initiation and progression of cholangiocarcinoma (CCA). However, immune signatures have rarely been used to predict prognosis of CCA. The aim of this study was to construct a novel model for CCA to predict survival based on IRGs expression data.Methods: The gene expression profiles and clinical data of CCA patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were integrated to establish and validate prognostic IRG signatures. Differentially expressed immune-related genes were screened. Univariate and multivariate Cox analysis were performed to identify prognostic IRGs, and the risk model that predicts outcomes was constructed. Furthermore, receiver operating characteristic (ROC) and Kaplan-Meier curve were plotted to examine predictive accuracy of the model, and a nomogram was constructed based on IRGs signature, combining with other clinical characteristics. Finally, CIBERSORT was used to analyze the association of immune cells infiltration with risk score.Results: We identified that 223 IRGs were significantly dysregulated in patients with CCA, among which five IRGs (AVPR1B, CST4, TDGF1, RAET1E and IL9R) were identified as robust indicators for overall survival (OS), and a prognostic model was built based on the IRGs signature. Meanwhile, patients with high risk had worse OS in training and validation cohort, and the area under the ROC was 0.898 and 0.846, respectively. Nomogram demonstrated that immune risk score contributed much more points than other clinicopathological variables, with a C-index of 0.819 (95% CI, 0.727-0.911). Finally, we found that IRGs signature was positively correlated with the proportion of CD8+ T cells, neurophils and T gamma delta, while negatively with that of CD4+ memory resting T cells.Conclusions: We established and validated an effective five IRGs-based prediction model for CCA, which could accurately classify patients into groups with low and high risk of poor prognosis.

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