Genetic variants of kinases suppressors of ras (KSR1) to predict survival in patients with ER-alpha positive metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11018-e11018
Author(s):  
Wu Zhang ◽  
Leonor Benhaim ◽  
Dongyun Yang ◽  
Armin Gerger ◽  
Pierre Oliver Bohanes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor Alpha ◽  
Mapk Pathway ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Lymph Node Status ◽  
Nucleotide Polymorphisms ◽  
Potential Marker

e11018 Background: In addition to its activating role of MAPK pathway, the protein kinase suppressor of ras 1 (KSR1) has been identified as a novel modulator of estrogen receptor alpha (ERα), as silencing of KSR1 in ERα+ breast cancer (BC) cells lines resulted in dowregulation of ERα transcriptional activity in the presence of oestradiol. Our previously data revealed the existence of single nucleotide polymorphisms (SNPs) in EGFR and ERα pathway genes that may predict clinical outcome in ERα positive metastatic BC (mBC) patients. With respect to those findings we aimed to evaluate the clinical implication of KSR1 SNPs on survival in patients with primary ERα+ mBC treated with tamoxifen. Methods: Tumoral DNA was obtained from 222 patients treated with tamoxifen withERα+ invasive BC who had undergone surgery between 1981 and 2003 (median age 56 [28-90]). Three relevant KSR1 SNPs were selected based on public literature resources and databases, including 2 SNPs localised in the regulating 3’untranslated region (rs224190, rs 1075952) and 1 non-synonymous SNP localised in the coding exon 7 region (rs2293180). All SNP were analysed using DNA sequencing with OS and DFS as primary endpoint. Results: The overall median follow-up was 6.4 years.In univariate analysis the rs2241906 SNP was significantly associated with DFS and OS and patients with the TT genotypedemonstrated shorter DFS (2.1 vs. 7.1 months, p=0.005) and OS ( 2.6 vs. 8.4 months p=0.002) than patients with the x/C genotypes. The associations remained significant in the multivariate analysis adjusting age, lymph node status and HER2 status (HR (95%CI): 4.81 (2.00-11.59) and 5.74 (2.29-14.43), for DFS and OS, respectively). The same significant correlation was retrieved with the SNP rs1075952 in linkage disequilibrium with rs2241906 that was used as a control. No relationship was shown between rs2293180 and survival. Conclusions: Our findings demonstrated that KSR1 polymorphisms could arise as a potential marker to predict survival in patients with mBC treated with tamoxifen. The putative role of KSR1 as a modulator of ERα activity could functionally explain our results yielding insight for further studies.

Is It The Time That We Can Depend on Bioscore as a New Staging System in Non-Metastatic Breast Cancer to Predict the Disease-Free Survival?

2021 ◽  
Author(s):  
Rehab Farouk Mohamed ◽  
Donia Hussein Abd El Hameed ◽  
Mohamed Alaa Eldeen Hassan
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Prognostic Value ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Free Survival ◽  
Disease Free

Abstract Purpose: Novel molecular characterization of breast cancer with cellular markers has allowed a new classification that offers prognostic value. This study investigates the prognostic value of the Bioscore among non-metastatic breast cancer patients with respect to disease free survival (DFS).Methods: This study included 317 patients with non-metastatic surgically treated breast cancer; they were identified in the period from January 2015 to December 2018 at Clinical Oncology Department of Assiut University Hospital. Many variables were used; pathologic stage (PS), T stage (T), nodal stage (N), grade (G), estrogen receptor (ER), progesterone receptors (PR), and human epidermal growth factor receptor (HER2) status. Univariate & two multivariate analyses were performed to identify which of these variables are associated with disease-free survival (DFS). Results: The only significant factors in the Univariate analysis were PS3, T2, T3, T4, N3, G2, G3, ER -ve, PR -ve, and HER2 –ve. The factors which were significant in the first multivariate analysis; PS3, G3, ER –ve, and in the second one were; T2, T4, N3, G3, and ER –ve. Two sets of models were built to determine the utility of combining variables. Models incorporating G and E status had the highest C-index (0.72) for T+N + G + ER in comparison with (0.69) for (PS+ G + ER) and the lowest AIC (953.01) for T + N + G + E and (966.9) for PS + G + E. Conclusions: This study confirms the prognostic significance of bioscore in non-metastatic breast cancer in concerning DFS.

scholarly journals Circulating Tumor Cells in Breast Cancer Patients: An Evolving Role in Patient Prognosis and Disease Progression

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Holly Graves ◽  
Brian J. Czerniecki
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Early Breast Cancer ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Breast Cancer Patients ◽  
Neoplastic Process

In this paper, we examine the role of circulating tumor cells (CTCs) in breast cancer. CTCs are tumor cells present in the peripheral blood. They are found in many different carcinomas but are not present in patients with benign disease. Recent advances in theories regarding metastasis support the role of early release of tumor cells in the neoplastic process. Furthermore, it has been found that phenotypic variation exists between the primary tumor and CTCs. Of particular interest is the incongruency found between primary tumor and CTC HER2 status in both metastatic and early breast cancer. Overall, CTCs have been shown to be a poor prognostic marker in metastatic breast cancer. CTCs in early breast cancer are not as well studied, however, several studies suggest that the presence of CTCs in early breast cancer may also suggest a poorer prognosis. Studies are currently underway looking at the use of CTC level monitoring in order to guide changes in therapy.

Association between bisphosphonate use in metastatic breast cancer (MBC) and overall survival.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 102-102 ◽  
Author(s):  
A. Mathew ◽  
M. Q. Rosenzweig ◽  
A. Brufsky
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cohort Study ◽  
Bone Metastasis ◽  
Adjuvant Therapy ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Cox Proportional Hazards Model ◽  
Her2 Status ◽  
Metastatic Setting

102 Background: Preclinical studies on bisphosphonates in breast cancer have suggested an anti-tumor effect in addition to its bone protective role. However, randomized controlled trials of bisphosphonates versus placebo have found little evidence of increased overall survival (OS) in MBC. We conducted a retrospective single-institution cohort study of MBC patients to evaluate the association between bisphosphonate use and overall survival. Methods: Baseline demographic and tumor specific data were collected on newly diagnosed MBC patients between January 1998 and December 2009. Other variables included the number and sites of each metastasis, use of baseline neoadjuvant and adjuvant chemotherapy, and use of hormone therapy. Bisphosphonate use was defined as present if it was administered for a period of at least 3 months in the metastatic setting. Overall survival was determined from the date of diagnosis of first metastatic disease. Survival analysis was performed using the Kaplan-Meier method and Cox proportional-hazards model. Results: Data were available on 737 patients with MBC, of whom 434 died during a median follow-up of 2 years; median age was 50.3 years. 92% of patients were Caucasian; 32% were both ER and PR-negative; and 31% were HER2-positive. Over 67% of MBC patients had bone metastasis and nearly 80% received bisphosphonates. Multivariate analysis found an overall survival benefit for bisphosphonate use, with a hazard ratio of 0.63 (95% confidence interval: 0.48-0.84; p<0.002), when adjusted for variables with significant effect on survival on univariate analysis and other known prognostic variables. These variables include age, stage at diagnosis, race, hormone receptor status, HER2 status, and number of metastatic sites, presence of bone metastasis and the use of adjuvant therapy. The administration of adjuvant therapy did not yield a significant survival advantage in the analyses. Conclusions: This retrospective cohort study provides evidence for an OS benefit with the use of bisphosphonates in MBC even after controlling for other significant prognostic factors.

scholarly journals Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 543
Author(s):  
Rosaria Benedetti ◽  
Chiara Papulino ◽  
Giulia Sgueglia ◽  
Ugo Chianese ◽  
Tommaso De Marchi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Mirna Expression ◽  
Estrogen Receptor Alpha ◽  
Estrogen Signaling ◽  
Integrated Analysis ◽  
Tumor Resistance ◽  
Estrogen Receptor Signaling

The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.

scholarly journals The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eui Jung Moon ◽  
Stephano S. Mello ◽  
Caiyun G. Li ◽  
Jen-Tsan Chi ◽  
Kaushik Thakkar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Invasion ◽  
Critical Role ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Invasion And Metastasis ◽  
Stat3 Signaling ◽  
Inducible Genes ◽  
Transcriptional Target

AbstractHypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

scholarly journals Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment

2021 ◽  
Vol 22 (14) ◽  
pp. 7430
Author(s):  
Hiromi Sato ◽  
Ayaka Shimizu ◽  
Toya Okawa ◽  
Miaki Uzu ◽  
Momoko Goto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metastatic Breast ◽  
Principal Component ◽  
Pentose Phosphate ◽  
Metastatic Brain Tumors ◽  
Pentose Phosphate Pathways ◽  
Culture Supernatants

The role of astrocytes in the periphery of metastatic brain tumors is unclear. Since astrocytes regulate central nervous metabolism, we hypothesized that changes in astrocytes induced by contact with cancer cells would appear in the metabolome of both cells and contribute to malignant transformation. Coculture of astrocytes with breast cancer cell supernatants altered glutamate (Glu)-centered arginine–proline metabolism. Similarly, the metabolome of cancer cells was also altered by astrocyte culture supernatants, and the changes were further amplified in astrocytes exposed to Glu. Inhibition of Glu uptake in astrocytes reduces the variability in cancer cells. Principal component analysis of the cancer cells revealed that all these changes were in the first principal component (PC1) axis, where the responsible metabolites were involved in the metabolism of the arginine–proline, pyrimidine, and pentose phosphate pathways. The contribution of these changes to the tumor microenvironment needs to be further pursued.

scholarly journals Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Thomas Grinda ◽  
Natacha Joyon ◽  
Amélie Lusque ◽  
Sarah Lefèvre ◽  
Laurent Arnould ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Large Scale ◽  
Tumour Progression ◽  
Primary Tumour ◽  
Multivariable Analysis ◽  
Real Life ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Risk Of Death

AbstractExpression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.

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