scholarly journals The Clinical Impact of Neoadjuvant Endocrine Treatment On Luminal-Like Breast Cancers and Its Prognostic Significance: Results From a Single-institution Prospective Cohort Study

2022 ◽  
Author(s):  
Covadonga Martí ◽  
Laura Yébenes ◽  
José María Oliver ◽  
Elisa Moreno ◽  
Laura Frías ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Maximum Size ◽  
Fold Change ◽  
Endocrine Treatment ◽  
Breast Cancers ◽  
Single Institution ◽  
Luminal A ◽  
Prognostic Information ◽  
Surgical Sample

Abstract Purpose: Neoadjuvant endocrine treatment (NET) has become a useful tool for the downstaging of luminal-like breast cancers in postmenopausal patients. It enables us to increase breast conserving surgery (BCS) rates, and provides an opportunity for assessing in vivo NET effectiveness and studying any biological changes that may act as valid biomarkers. The purpose of this study was to evaluate the safety and effectiveness of NET, and to assess the role of Ki67 proliferation rate changes as an indicator of endocrine responsiveness.Methods: From 2016 to 2020, a single-institution cohort of patients treated with NET and further surgery was evaluated. In patients with Ki67≥10%, a second core biopsy was performed after four weeks. Information regarding histopathological and clinical changes was gathered.Results: A total of 115 estrogen receptor positive (ER+)/HER2 negative patients were included. The median treatment duration was 5.0 months (IQR: 2.0-6.0). Median maximum size in the surgical sample was 40% smaller than pretreatment size measured by ultrasound (p<.0001). Median pretreatment Ki67 expression was 20.0% (IQR: 12.0-30.0), and was reduced to 5.0% (IQR: 1.8-10.0) after four weeks, and to 2.0% (IQR: 1.0-8.0) in the surgical sample (p<.0001). BCS was performed on 98 patients (85.2%). No pathological complete responses were recorded. A larger Ki67 fold-change after four weeks was significantly related to a PEPI score of 0 (p<.002). No differences were observed between luminal A- and B-like tumors with regard to fold-change and PEPI score.Conclusions: In our cohort, NET has proven effective for tumor size and Ki67 downstaging. This results in a higher rate of conservative surgery, aids in therapeutic decision-making, provides prognostic information, and constitutes a safe and well-tolerated approach

scholarly journals New generation breast cancer cell lines developed from patient-derived xenografts

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Jessica Finlay-Schultz ◽  
Britta M. Jacobsen ◽  
Duncan Riley ◽  
Kiran V. Paul ◽  
Scott Turner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Luminal A ◽  
New Generation

Abstract Background Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics. Methods Established breast cancer PDX were processed into cell suspensions and placed into standard 2D cell culture; six emerged into long-term passageable cell lines. Cell lines were assessed for protein expression of common luminal, basal, and mesenchymal markers, growth assessed in response to estrogens and endocrine therapies, and RNA-seq and oncogenomics testing performed to compare relative transcript levels and identify putative oncogenic drivers. Results Three cell lines express ER and two are also progesterone receptor (PR) positive; PAM50 subtyping identified one line as luminal A. One of the ER+PR+ lines harbors a D538G mutation in the gene for ER (ESR1), providing a natural model that contains this endocrine-resistant genotype. The third ER+PR−/low cell line has mucinous features, a rare histologic type of breast cancer. The three other lines are ER− and represent two basal-like and a mixed ductal/lobular breast cancer. The cell lines show varied responses to tamoxifen and fulvestrant, and three were demonstrated to regrow tumors in vivo. RNA sequencing confirms all cell lines are human and epithelial. Targeted oncogenomics testing confirmed the noted ESR1 mutation in addition to other mutations (i.e., PIK3CA, BRCA2, CCND1, NF1, TP53, MYC) and amplifications (i.e., FGFR1, FGFR3) frequently found in breast cancers. Conclusions These new generation breast cancer cell lines add to the existing repository of breast cancer models, increase the number of ER+ lines, and provide a resource that can be genetically modified for studying several important clinical breast cancer features.

scholarly journals Prognostic Significance of Progesterone Receptor–Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer

2013 ◽  
Vol 31 (2) ◽  
pp. 203-209 ◽  
Author(s):  
Aleix Prat ◽  
Maggie Chon U. Cheang ◽  
Miguel Martín ◽  
Joel S. Parker ◽  
Eva Carrasco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progesterone Receptor ◽  
Tumor Cells ◽  
Prognostic Value ◽  
Prognostic Significance ◽  
Cáncer De Mama ◽  
Breast Cancers ◽  
Luminal A ◽  
Data Set ◽  
Gene And Protein Expression

Purpose Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. Patients and Methods Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) –positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance. Results Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) –positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. Conclusion Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.

scholarly journals Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4606
Author(s):  
Ashraf N. Abdalla ◽  
Amal Qattan ◽  
Waleed H. Malki ◽  
Imran Shahid ◽  
Mohammad Akbar Hossain ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
New Drugs ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Mcf7 Cells ◽  
Hsp90 Inhibition ◽  
Luminal A

The hormonal luminal-A is the most pre-dominant sub type of breast cancer (BC), and it is associated with a high level of cyclin D1 in Saudi patients. Tamoxifen is the golden therapy for hormonal BC, but resistance of cancer cells to tamoxifen contributes to the recurrence of BC due to many reasons, including high levels of AIB1 and cyclin D1. Overcoming drug resistance could be achieved by exploring alternative targetable therapeutic pathways and new drugs or combinations. The objective of this study was to determine the differentially enriched pathways in 12 samples of Saudi women diagnosed with luminal-A using the PamChip peptide microarray-based kinase activity profiling, and to compare the activity of HAA2020 and dinaciclib with tamoxifen in singles and combinations in the MCF7 luminal-A cell line. Our results of network and pathway analysis of the 12 samples highlighted the importance of VEGFR and CDKs in promoting luminal-A breast cancer. The activation of VEGF signaling via VEGFR-2 leads to activation of PI3K/AKT kinases and an increase of cell survival, and leads to activation of Hsp90, which induces the phosphorylation of FAK1, resulting in cytoskeleton remodeling. PLC-gamma 1 is also activated, leading to FAK-2 and PKC activation. Notably, the G1/S cell cycle phases and phosphorylation processes contribute to the top seven tumorigenesis processes in the 12 samples. Further, the MTT combination of HAA2020 and dinaciclib showed the best combination index (CI), was more clonogenic against MCF7 cells compared to the other combinations, and it also showed the best selectivity index (SI) in normal MRC5 cells. Interestingly, HAA2020 and dinaciclib showed a synergistic apoptotic and G1 cell cycle effect in MCF7 cells, which was supported by their synergistic CDK2, cyclin D1, and PCNA inhibition activities. Additionally, the combination showed VEGFR-2 and Hsp90 inhibition activities in MCF7 cells. The results show the significance of targeting VEGFR-2 and cyclin D1 in Saudi luminal-A breast cancer patients, and the effect of combining HAA2020 and dinaciclib on those targets in the MCF7 model. It also warrants further preclinical and in vivo investigations for the combination of HAA2020 and dinaciclib as a possible future second-line treatment for luminal-A breast cancers.

scholarly journals Prognostic Significance of Low Claudin3 Expression in Luminal Breast Cancers

2017 ◽  
Vol 11 ◽  
pp. 117822341774585
Author(s):  
Lakmini Mudduwa ◽  
Harshini Peiris ◽  
Shania Gunasekara ◽  
Deepthika Abeysiriwardhana ◽  
Thusharie Liyanage
Keyword(s):  
Breast Cancer ◽  
Prognostic Significance ◽  
Molecular Classification ◽  
Rank Test ◽  
Recurrence Free Survival ◽  
Breast Cancers ◽  
Luminal A ◽  
Cancer Specific Survival ◽  
Free Survival ◽  
Luminal B

Aim: To study the prognostic value of immunohistochemically detected low Claudin3 expression in breast cancers. Methods: This retrospective study included patients with breast cancer who were investigated at our unit from 2006 to 2015. Tissue microarrays were constructed, and immunohistochemical staining was done to assess the Claudin3 expression and to classify breast cancers according to the immunohistochemical surrogates for molecular classification. Kaplan-Meier model and log-rank test were used for recurrence-free survival and breast cancer–specific survival analysis. Results: Of the 853 patients, overall low expression of Claudin3 was seen in 18.4%. Recurrence-free survival of patients with overall low Claudin3 breast cancers was poor in luminal A ( P = .006) and luminal B (Her2−) ( P = .009) subtypes compared with those who had Claudin3 expression in each group. Conclusions: Assessment of Claudin3 expression by immunohistochemistry is suggested for luminal A and luminal B (Her2−) subtypes to identify patients with poor prognosis.

Continuous Quantitative Monitoring of Mural, Platelet-Dependent, Thrombus Kinetics in the Crushed Rat Femoral Vein

1991 ◽  
Vol 65 (04) ◽  
pp. 425-431 ◽  
Author(s):  
F Stockmans ◽  
H Deckmyn ◽  
J Gruwez ◽  
J Vermylen ◽  
R Acland
Keyword(s):  
Thrombus Formation ◽  
Femoral Vein ◽  
Maximum Size ◽  
Digital Analysis ◽  
Video Recordings ◽  
Quantitative Monitoring ◽  
Set Up ◽  
Kinetics Of ◽  
Quantitative Nature

SummaryA new in vivo method to study the size and dynamics of a growing mural thrombus was set up in the rat femoral vein. The method uses a standardized crush injury to induce a thrombus, and a newly developed transilluminator combined with digital analysis of video recordings. Thrombi in this model formed rapidly, reaching a maximum size 391 ± 35 sec following injury, after which they degraded with a half-life of 197 ± 31 sec. Histological examination indicated that the thrombi consisted mainly of platelets. The quantitative nature of the transillumination technique was demonstrated by simultaneous measurement of the incorporation of 111In labeled platelets into the thrombus. Thrombus formation, studied at 30 min interval in both femoral veins, showed satisfactory reproducibility overall and within a given animalWith this method we were able to induce a thrombus using a clinically relevant injury and to monitor continuously and reproducibly the kinetics of thrombus formation in a vessel of clinically and surgically relevant size

Breast carcinoma in young females below the age of 35 years - histopathological and prognostic significance

1970 ◽  
Vol 2 (3) ◽  
pp. 198-202
Author(s):  
D Ghartimagar ◽  
A Ghosh ◽  
OP Talwar ◽  
R Narasimhan
Keyword(s):  
Breast Carcinoma ◽  
Young Women ◽  
Early Stage ◽  
Prognostic Significance ◽  
Age Group ◽  
Breast Cancers ◽  
Young Females ◽  
Younger Age ◽  
Grade 3 ◽  
Group Grade

Background: Breast cancers rarely occur in young women but are known to have more aggressive behaviors and poorer outcome. We here compare the significance of breast carcinoma in female below the age of 35 to the age over 35 whose specimens were submitted to Manipal teaching hospital, Pokhara. Materials and Methods: All cases of mastectomy with carcinoma from January 2000 to September 2011 were included in the study. Clinical and histopathological datas of all cases were reviewed and collated. Results: A total of 148 mastectomy specimens were received, among which, 23 cases (16%) were below 35 years; whereas 125 cases (84%) were above 35 years of age. In both groups, Stage II was the commonest stage but stage III was much more common in older group (33% versus 9%) and stage I was more common in younger age group (39% versus 27%). Bloom Richardson grading showed that in the older age group, grade 1 is the commonest grade (50%) while in the younger group; grade 3 is the commonest (39%). Patients were followed for a varying period of 6 months to 5 years. Two cases (2% of followed up cases) in older group and 3 cases (15% of followed up cases) in the younger group showed recurrence. Conclusion: Breast carcinoma in the patients younger than 35 years though presented at an early stage has higher grade tumor and poorer outcome. DOI: http://dx.doi.org/10.3126/jpn.v2i3.6021 JPN 2012; 2(3): 198-202

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals The roles and prognostic significance of ABI1-TSV-11 expression in patients with left-sided colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Zhang ◽  
Zhaohui Zhong ◽  
Mei Li ◽  
Jingyi Chen ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
The Cancer Genome Atlas ◽  
Actin Dynamics ◽  
Elevated Expression ◽  
Sw480 Cells ◽  
And Migration

AbstractAbnormally expressed and/or phosphorylated Abelson interactor 1 (ABI1) participates in the metastasis and progression of colorectal cancer (CRC). ABI1 presents as at least 12 transcript variants (TSVs) by mRNA alternative splicing, but it is unknown which of them is involved in CRC metastasis and prognosis. Here, we firstly identified ABI1-TSV-11 as a key TSV affecting the metastasis and prognosis of left-sided colorectal cancer (LsCC) and its elevated expression is related to lymph node metastasis and shorter overall survival (OS) in LsCC by analyzing data from The Cancer Genome Atlas and TSVdb. Secondly, ABI1-TSV-11 overexpression promoted LoVo and SW480 cells adhesion and migration in vitro, and accelerated LoVo and SW480 cells lung metastasis in vivo. Finally, mechanism investigations revealed that ABI1-isoform-11 interacted with epidermal growth factor receptor pathway substrate 8 (ESP8) and regulated actin dynamics to affect LoVo and SW480 cells biological behaviors. Taken together, our data demonstrated that ABI1-TSV-11 plays an oncogenic role in LsCC, it is an independent risk factor of prognosis and may be a potential molecular marker and therapeutic target in LsCC.

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