scholarly journals Immunohistochemistry for Thymidine Kinase-1 (TK1): A Potential Tool for the Prognostic Stratification of Breast Cancer Patients

2021 ◽  
Vol 10 (22) ◽  
pp. 5416
Author(s):  
Giuseppe Nicolò Fanelli ◽  
Rosa Scarpitta ◽  
Paola Cinacchi ◽  
Beatrice Fuochi ◽  
Anna Szumera-Ciećkiewicz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Thymidine Kinase ◽  
Histological Grade ◽  
Her2 Status ◽  
Breast Cancer Patients ◽  
Thymidine Kinase 1 ◽  
Ki 67 ◽  
Pyrimidine Nucleotide ◽  
Prognostic Stratification ◽  
The Impact

Breast cancer (BC) is the most frequent non-cutaneous malignancy in women. Histological grade, expression of estrogen and progesterone receptors (ER and PgR), overexpression/amplification of the human epidermal growth factor receptor 2 (HER2) oncogene, and proliferative activity measured with ki-67 provide important information on the biological features of BC and guide treatment choices. However, a biomarker that allows a more accurate prognostic stratification is still lacking. Thymidine kinase-1 (TK1), a ubiquitous enzyme involved in the pyrimidine nucleotide recovery pathway, is a cell-proliferation marker with potential prognostic and predictive impacts in BC. Eighty (80) cases of invasive BC with a long-term follow-up were retrospectively selected, and clinicopathological data were collected for each patient. TK1 tissue expression was evaluated immunohistochemically. Data suggested that TK1 expression levels are positively correlated with ER and PgR expression, and negatively correlated with HER2 status and the impact on patients' distant recurrence-free survival (DRFS): in detail, among patients undergoing adjuvant chemotherapy, lower TK1 levels are correlated with better DRFS. Therefore, these results contribute to furthering the knowledge of TK1, suggesting a possible and important role of this enzyme as a biomarker in the stratification of BC patients.

scholarly journals SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Qiao Li ◽  
Manran Liu ◽  
Yan Sun ◽  
Ting Jin ◽  
Pengpeng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histological Grade ◽  
Metabolic Adaptation ◽  
Mitochondrial Activity ◽  
Cell Viability Assay ◽  
Ki 67 ◽  
The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

scholarly journals The Value of Ultrasound Diagnosed Axillary Lymph Node in Avoiding Axillary Surgery in Early Breast Cancer Patients

2020 ◽  
Author(s):  
Na Liu ◽  
Liu Yang ◽  
Xinle Wang ◽  
Meiqi Wang ◽  
Ruoyang Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Cancer Patients ◽  
Axillary Lymph Node ◽  
Histological Grade ◽  
False Negative ◽  
Axillary Lymph ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Axillary Surgery

Abstract Background: Axillary lymph node dissection can be avoided in early stage breast cancer patients with negative sentinel lymph node biopsy. However, the possibility of avoiding axillary surgery in patients without axillary lymph node metastasis (ALNM) by preoperative imaging is still under exploration. Thus, the objectives of this study were to investigate the high-risk factors of false negative of ALNM diagnosed by preoperative ultrasound (US) and to find out who could be avoided axillary surgery in the US negative ALNM patients.Methods: This study retrospectively analyzed 3,361 patients with primary early breast cancer diagnosed in the Breast Center of the Fourth Hospital of Hebei Medical University from January 2010 to December 2012. All patients had undergone routine preoperative US and then axillary lymph node dissected. This study investigated the clinicopathological features of axillary lymph node (ALN) negative patients diagnosed by preoperative US and its correlation with prognosis. The follow-up data for disease-free survival (DFS) and overall survival (OS) were obtained from 2,357 patients. Results: The sensitivity, specificity and accuracy of axillary US in this cohort were 66.24%, 76.62% and 73.87%. The proportion of patients in the false negative group was higher than that in true negative in the group of age < 50 years old (P = 0.002), tumor size > 2cm (P = 0.008), estrogen receptor (ER) positive (P = 0.005), progesterone receptor (PR) high expression (P = 0.007), nuclear-associated antigen Ki-67 (Ki-67) >20% (P = 0.030), visible vascular tumor thrombus (P < 0.001) and histological grade>2 (P < 0.001). Prognostic analysis of false negative and true negative ultrasonographic diagnosis of ALN metastasis: when ALNM was not found by preoperative ultrasound, there was no significant difference in patients with ALNM≤3 compared with patients without lymph node metastasis in patients of age ≥ 50 years old, tumor size ≤ 2cm, Ki-67 ≤ 20%, or histological grade ≤ 2. Conclusion: The surgery of ALN may be avoided for the preoperative US diagnosed ALNs negative in early breast cancer patients who had advanced age, small tumor size, low expression of Ki-67 and low histological grade.

scholarly journals Relationship between thymidine kinase 1 before radiotherapy and prognosis in breast cancer patients with diabetes

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Zhiwu Wang ◽  
Wei Zhang ◽  
Bingjie Huo ◽  
Liang Dong ◽  
Jing Zhang
Keyword(s):  
Breast Cancer ◽  
Thymidine Kinase ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Univariate Analysis ◽  
Clinical Parameters ◽  
Breast Cancer Patients ◽  
Thymidine Kinase 1 ◽  
Node Number ◽  
Significant Difference

Abstract In a retrospective study design, we explored the relationship between serum thymidine kinase 1 (TK1) concentration before radiotherapy and clinical parameters and evaluated the prognostic value of serum TK1 concentration before radiotherapy in breast cancer patients with type 2 diabetes mellitus. The present study finally consisted of 428 breast cancer patients with a mean age of 53.0 years. Compared with low TK1 group, the high TK1 group tended to have larger tumor size (P=0.011) and had more lymph node number (P=0.021). Significant differences were also observed in clinical stages I, II and III (P=0.000). There was no significant difference between TK1 and other clinical parameters. For disease-free survival (DFS), the univariate analysis indicated that the high TK1 increased the risk of poor prognosis (HR = 2.38, 95% CI: 1.64–4.23, P=0.000). The Kaplan–Meier curve indicated the high TK1 group was poorer than that in the low TK1 group (P=0.002). For the overall survival (OS), similar results were found that the high TK1 was related to poor OS (HR = 1.89, 95% CI: 1.34–3.67, P=0.000). The multivariate Cox regression indicated that the TK1 was still associated with DFS (HR = 1.83, 95% CI: 1.22–3.17, P=0.001) and OS (HR = 1.63, 95% CI: 1.19–2.08, P=0.006). The high pretreatment serum TK1 levels in breast cancer patients were associated with poor OS and DFS. TK1 could be a potential predictive factor in differential diagnosis of poor prognosis from all patients.

scholarly journals Rate of reclassification of HER2-equivocal breast cancer cases to HER2-negative per the 2018 ASCO/CAP guidelines and response of HER2-equivocal cases to anti-HER2 therapy

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241775
Author(s):  
James Crespo ◽  
Hongxia Sun ◽  
Jimin Wu ◽  
Qing-Qing Ding ◽  
Guilin Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Disease ◽  
Cancer Center ◽  
Her2 Status ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Testing ◽  
Primary Disease ◽  
The Impact

Purpose The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline on HER2 testing in breast cancer permits reclassification of cases with HER2-equivocal results by FISH. The impact of such reclassification is unclear. We sought to determine the proportion of HER2-equivocal cases that are reclassified as HER2-negative and the impact of anti-HER2 therapy on survival in HER2-equivocal cases. Methods We reviewed medical records of breast cancer patients who had HER2 testing by fluorescence in stitu hybridization (FISH) and immunohistochemistry (IHC) performed or verified at The University of Texas MD Anderson Cancer Center during April 2014 through March 2018 and had equivocal results according to the 2013 ASCO/CAP guideline. The population was divided into 2 cohorts according to whether the biopsy specimen analyzed came from primary or from recurrent or metastatic disease. HER2 status was reclassified according to the 2018 ASCO/CAP guideline. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method, and the relationship between anti-HER2 therapy and clinical outcomes was assessed. Results We identified 139 cases with HER2-equivocal results according to the 2013 ASCO/CAP guideline: 90 cases of primary disease and 49 cases of recurrent/metastatic disease. Per the 2018 ASCO/CAP guideline, these cases were classified as follows: overall, HER2-negative 112 cases (80%), HER2-positive 1 (1%), and unknown 26 (19%); primary cohort, HER2-negative 85 (94%), HER2-positive 1 (1%), unknown 4 (4%); and recurrent/metastatic, HER2-negative 27 (55%) and unknown 22 (45%). Five patients in the primary-disease cohort and 1 patient in the recurrent/metastatic-disease cohort received anti-HER2 therapy. There was no significant association between anti-HER2 therapy and OS or EFS in either cohort (primary disease: OS, p = 0.67; EFS, p = 0.49; recurrent/metastatic-disease, OS, p = 0.61; EFS, p = 0.78. Conclusions The majority of HER2-equivocal breast cancer cases were reclassified as HER2-negative per the 2018 ASCO/CAP guideline. No association between anti-HER2 therapy and OS or EFS was observed. HER2-equivocal cases seem to have clinical behavior similar to that of HER2-negative breast cancers.

Breast cancer in "young" women: Age cutoff and clinicopathologic features.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12019-e12019
Author(s):  
Gang Nie ◽  
Haibo Wang ◽  
Yuhua Song ◽  
Yan Mao ◽  
Weihong Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Family History ◽  
Cancer Patients ◽  
Older Patients ◽  
Age Groups ◽  
Her2 Status ◽  
Lymph Node Status ◽  
Breast Cancer Patients ◽  
Ki 67

e12019 Background: Age of patients play a key role in outcome of breast cancer, and therefore influences choice of treatment. In most studies, "young" is defined as being below 40 or 35 years. However, there are conflicts concerning definition of younger and older patients. In this study, we aim to establish a more appropriate age cut-off between “younger” and “older” breast cancer patients. Methods: A total of 5984 female breast cancer patients recruited in the Breast Cancer Registry of the Affiliated Hospital of Qingdao University during 2008 to 2014 were enrolled. Patients were divided into 11 groups by every 5 years’ age difference. The clinical characteristics and overall survival (OS) were compared among these age groups. Results: Among the five groups under age 45 (n = 1771, 30.0%), larger proportion of patients underwent breast conservation surgery in the “30-34” group (p = .027), and more patients were found with family history in the “25-29” group than in other groups (p = .029). No significant difference was found in OS (p = .059), clinicopathological stage, lymph node status, ER/PR status, HER2 status, or Ki-67 status among those five groups. For patients above 45 (n = 4813, 70.0%), differences were found in OS (p = .001) and significant differences with clinicopathological features (lymph node status, ER/PR status, HER2 status and Ki-67 status) were shown between younger and the older age groups (p = .001) among the six groups, except for family history (p = .066). Conclusions: Clinicopathological characteristics and survival status are similar among breast cancer patients under 45 years and vitiate among older patients. Age 45 is an appropriate cut-off for clinical grouping of breast cancer patients by age .

Limited impact of tamoxifen following dose-intensive L-FAC multimodality therapy of breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10741-10741
Author(s):  
K. W. Jabboury ◽  
A. Wong ◽  
K. Sexton ◽  
L. Rogers ◽  
K. King ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histological Grade ◽  
Dose Intensity ◽  
Breast Cancer Patients ◽  
Relapse Free Survival ◽  
Who Grade ◽  
Free Survival ◽  
Hand Foot Syndrome ◽  
The Impact ◽  
Grade Iii

10741 Background: Front-line dose-intensive L-FAC has demonstrated a favorable 5-year relapse free survival pattern (ASCO 2004 #739). Tamoxifen was given for 5 years to ER+ patients after L-FAC completion. We evaluated the impact of adding tamoxifen to L-FAC. By design, this pilot study excluded low-risk patients not candidates for chemotherapy. Methods: 109 breast cancer patients were enrolled (4 excluded due to treatment violations) from 6/1989 to 1/2003: 20 Stage I (S), 52 S-II, 22 S-III, for a total of 94 patients. 11 S-IV patients were excluded from survival analysis. Adverse tumor presentations included: ER- 49, PgR- 60, P53+ 24, non-diploid 39, histological grade III 37, CerbB2+ 33. L-FAC included 72 hour (h) iv infusion 400mg/m2/day (d) 5-fluorouracil (F) modulated by iv bolus 200mg/m2/d X3 leucovorin (L), concomitantly with 24h iv d1 600–1000mg/m2 cyclophosphamide (C), 48h iv d2 + d3 60mg/m2 doxorubicin (A). S-I and S-II were given 6 courses and 8 for S-III. Increasing A + C dose level and/or shortening treatment intervals < 3 weeks with growth factors provided intensification. 40 patients received tamoxifen. Results: At a median follow-up of 74 months (range 9–214), 73 (78%) are alive (1 with relapse). Relapse free survival was: S-I 95%, S-II 81%, S-III 78%. At average course intervals of 18 days, dose intensity A/C mg/m2/wk was 24.2 / 335.4 with evidence of WHO grade III/IV stomatitis in 43%, neutropenia 59%, cumulative thrombocytopenia 50%, hand-foot syndrome 32% of patients. Aside from delayed relapse associated with tamoxifen, relapse-free survival >82 months was similar with and without tamoxifen. No relapse was observed after >53 months in ER- tumors despite showing higher frequency of adverse tumor risk factors. Conclusion: The impact of adding tamoxifen appears quite limited in a patient population with adverse tumor presentation treated with dose-intensive L-FAC. No significant financial relationships to disclose.

Prognostic value of the genomic grade index (GGi) as compared to centrally measured Ki-67 IHC and mitotic index in early breast cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11094-11094
Author(s):  
F. Bertucci ◽  
J. M. Le Doussal ◽  
D. Birnbaum ◽  
R. Tagett ◽  
A. Martinec ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Mitotic Index ◽  
Prognostic Value ◽  
Cox Regression ◽  
Histological Grade ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Genomic Grade Index ◽  
Grade Index

11094 Background: Genomic grading has been proposed to improve tumor grading. The genomic grade index (GGi) is a 97-gene continuous measure which resolves 80% of histological grade 2 (HG 2) tumors into HG 1 and HG 3 risk categories. GGi has higher prognostic value than HG in patients treated with and without systemic adjuvant endocrine and chemotherapy. A key issue is whether the GGi adds prognostic information to centrally-determined mitotic index and Ki-67 IHC. Methods: The control arm of the PACS 01 trial included 996 women with node-positive (N+) early breast cancer treated with six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) and tamoxifen as required. 128 genomic profiles could be obtained from available frozen tumor samples using Affymetrix U133 Plus 2.0 gene chips through the “Carte d'Identite des Tumeurs” program of the French Ligue Nationale contre le Cancer. The Genomic Grade index (GGi) was computed using Ipsogen MapQuant Dx(R). Central Elston-Ellis grade, mitotic index (mitosis / mm2), and Ki-67 IHC (% positive cells) were available for 125 patients. The GGi and histological parameters were correlated to the 5-year metastasis status (MFS-5) by ROC analysis and to the metastasis hazard (follow-up of 6.2 ± years) by Cox regression. Results: In ER+ patients (n=93), the GGi was the only significant correlate to metastasis hazard in multivariate Cox regression with histological parameters (HR = 3.5 [1.7–7.5], p<0.001). It was the best predictor of MFS-5 (ROC AUC = 0.83, p=1E-6) when compared to histological parameters (ROC AUC = 0.71, 0.72 and 0.66 resp. p=0.003 to 0.03). In HG 2 subgroup (n=43), the GGi was the only significant predictor of MFS-5 (ROC AUC = 0.81, p=0.016). Conclusions: In our sample of N+ ER+ breast cancer patients, the GGi improved prognostication compared to centrally-measured mitotic index and Ki-67 IHC used alone and in combination. Moreover, the GGi was the only prognostic factor in histological grade 2 patients. [Table: see text]

scholarly journals Immunohistochemical Evaluation of FGD3 Expression: A New Strong Prognostic Factor in Invasive Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3824
Author(s):  
Tommaso Susini ◽  
Giulia Saccardin ◽  
Irene Renda ◽  
Milo Giani ◽  
Enrico Tartarotti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Factor ◽  
Invasive Breast Cancer ◽  
Molecular Subtype ◽  
Histological Grade ◽  
Disease Free Survival ◽  
Individual Risk ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Cox Analysis

Among new prognostic factors for breast cancer, the most promising one seems to be FGD3 (Facio-Genital Dysplasia 3) gene, whose expression improves outcome by inhibiting cell migration. The aim of the study was to evaluate the prognostic role of FGD3 in invasive breast cancer in a series of 401 women, treated at our unit, by evaluating the expression of this gene by immunohistochemistry. Patients with high FGD3 expression showed a significantly better disease-free survival (DFS) (p < 0.001) and overall survival (OS) (p < 0.001). The prognostic value of FGD3 expression was stronger than that of classical pathologic parameters such as histological grade of differentiation, Ki-67 index and molecular subtype. By multivariate Cox analysis, FGD3 expression was confirmed as significant and independent prognostic factor, ranking second after age at diagnosis (≤40 years) for DFS (p = 0.003) and the second strongest predictor of OS, after AJCC Stage (p < 0.001). Our data suggest that inclusion of FGD3 evaluation in the routine workup of breast cancer patients may result in a more accurate stratification of the individual risk. The possibility to assess FGD3 expression by a simple and cheap technique such as immunohistochemistry may enhance the spread of its use in the clinical practice.

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